Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)
Phase: PHASE3
Conditions: Recurrent B Acute Lymphoblastic Leukemia
Sponsor: National Cancer Institute (NCI)

 
 
 
 
 
i 

 
 
AALL1331 
 
Version Date: 12/19/2019 
1 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
AALL1331 
 
 
Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC# 765986) in First Relapse of 
Childhood B-Lymphoblastic Leukemia (B-ALL) 
 
IND Sponsor for Blinatumomab: DCTD, NCI 
 
A Groupwide Phase III Study 
Participating Countries: Australia, Canada, New Zealand and United States 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
Patrick Brown, MD 
1650 Orleans Street, CRB1 RM 2M49 
Baltimore, MD. 21231 
Phone: (410) 614-4915 
Fax: 
(410) 955-8897 
E-mail: pbrown2@jhmi.edu 
 
 
 
Activated: 
12/08/14 
Version Date:  
12/19/2019 
Closed: 
09/30/19 
Amendment 
#10A 

 
 
AALL1331 
 
Version Date: 12/19/2019 
2 
 
ABBREVIATIONS 
 
Abbreviation 
Term 
 
aGVHD 
Acute graft versus host disease 
B-ALL 
B-Lymphoblastic Leukemia 
CR 
Complete remission 
DFS 
Disease free survival 
GVHD 
Graft vs. host disease 
HR 
High risk 
HSCT  
Hematopoietic stem cell 
transplant 
IEM 
Isolated extramedullary 
IR 
Intermediate risk 
IS 
Immune suppression 
LR 
Low risk 
MRD 
Minimal residual disease 
PFS 
Progression free survival 
Ph+ 
Philadelphia chromosome 
positive 
TF 
Treatment failure 
TKI 
Tyrosine kinase inhibitor 
URD 
Unrelated Donor 
 
 
 

 
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TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
12 
ABSTRACT 
15 
EXPERIMENTAL DESIGN SCHEMA 
16 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
17 
1.1 
Primary Aims 
17 
1.1.1 
To compare disease free survival (DFS) of HR and IR relapse B-ALL patients 
who are randomized following Induction Block 1 chemotherapy to receive either 
two intensive chemotherapy blocks or two 5-week blocks of blinatumomab 
(HR/IR Randomization). (Closed effective September 18, 2019) 
17 
1.1.2 
To compare DFS of LR relapse B-ALL patients who are randomized following 
Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy 
plus blinatumomab (LR Randomization). 
17 
1.2 
Secondary Aims 
17 
1.2.1 
To compare overall survival (OS) of HR and IR relapse B-ALL patients who are 
randomized following Induction Block 1 chemotherapy to receive either two 
intensive chemotherapy blocks or two 5 week blocks of blinatumomab (HR/IR 
Randomization). (Closed effective September 18, 2019) 
17 
1.2.2 
To compare OS of LR relapse B-ALL patients who are randomized following 
Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy 
plus blinatumomab (LR Randomization). 
17 
1.3 
Exploratory Aims 
17 
1.3.1 
To compare the rates of MRD ≥ 0.01% at the end of Block 2 and Block 3 for HR 
and IR relapse B-ALL patients in HR/IR randomization. (Closed effective 
September 18, 2019) 
17 
1.3.2 
To estimate, for treatment failure (TF) patients not previously receiving 
blinatumomab, the hematologic complete remission rate (CR), rate of MRD 
< 0.01%, and proportion able to proceed to hematopoietic stem cell transplant 
(HSCT) in CR after treatment with blinatumomab. 
17 
1.3.3 
To assess the feasibility and safety of rapid taper of immune suppression for the 
subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-HSCT with no 
acute graft versus host disease (aGVHD). 
17 
1.3.4 
To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-
response relationships for measures of safety and effectiveness. 
17 
2.0 
BACKGROUND 
18 
2.1 
Overview 
18 
2.2 
Rationale for Selected Approach and Trial Design 
18 
2.2.1 
Rationale for Consolidated First Relapse B-ALL Trial 
18 
2.2.2 
Rationale for Studying Blinatumomab in First Relapse of B-ALL 
19 
2.2.3 
Rationale for Risk Stratification 
21 
2.2.4 
Rationale for Backbone Chemotherapy Treatment (Blocks 1, 2 and 3) 
22 
2.2.5 
Rationale for Backbone Chemotherapy Treatment (post-Block 3) 
24 
2.2.6 
Therapy for CNS3 Patients 
24 
2.2.7 
Treatment of Testicular Relapse 
25 

 
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2.2.8 
Treatment Failure (TF) 
26 
2.2.9 
Additional non-randomized Pilot Intervention for Very High Risk Subset of 
HSCT Recipients based on MRD and aGVHD 
26 
2.2.10 Rationale for closure of the HR/IR Randomization (Amendment #10) 
27 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
28 
3.1 
Study Enrollment 
28 
3.1.1 
Patient Registration 
28 
3.1.2 
IRB Approval 
28 
3.1.3 
Study Enrollment 
29 
3.1.4 
Timing 
30 
3.1.5 
Staged Consent 
30 
3.1.6 
Risk Assignment, Randomization, and Treatment Assignment 
31 
3.1.7 
Callbacks 
32 
3.1.8 
Drug Preparation and Administration 
33 
3.1.9 
Inclusion of Women and Minorities 
33 
3.2 
Patient Eligibility Criteria 
33 
3.2.1 
Age 
33 
3.2.2 
Diagnosis 
33 
3.2.3 
Prior Therapy 
34 
3.2.4 
Performance Status 
34 
3.2.5 
Organ Function Requirements 
34 
3.2.6 
Exclusion Criteria 
35 
3.2.7 
Regulatory Requirements 
36 
3.3 
Definitions 
36 
4.0 
TREATMENT PLAN 
40 
4.1 
Overview of Treatment Plan 
40 
4.1.1 
TREATMENT ASSIGNMENTS 
41 
4.1.2 
Concomitant Therapy Restrictions 
42 
4.1.3 
Supportive Care for Patients 15 Years and Older 
43 
4.2 
Block 1 (All patients) - 4 Weeks Duration 
44 
4.2.1 
Disease Evaluation Pre-Treatment 
44 
4.2.2 
General Chemotherapy Guidelines 
44 
4.2.3 
Block 1 Chemotherapy 
44 
4.2.4 
Disease Evaluation End Block 1 
46 
4.2.5 
Research Studies Block 1 
46 
4.2.6 
HLA Tissue Typing for Hematopoietic Stem Cell Transplant 
46 
4.2.7 
Evaluation 1 (Risk Assessment following Block 1) 
46 
4.3 
Block 2 (LR Patients: Post-randomization) – 4 weeks duration 
48 
4.3.1 
Criteria to Begin Block 2 Therapy 
48 
4.3.2 
Testicular Radiation Therapy (TRT) 
48 
4.3.3 
General Chemotherapy Guidelines 
48 
4.3.4 
Block 2 Chemotherapy 
49 
4.3.5 
Evaluation 2 (Disease Evaluation End Block 2) 
51 

 
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4.3.6 
Following Completion of Block 2: 
51 
4.4 
Block 3 (LR Patients on Arm C) - 4 weeks 
52 
4.4.1 
Criteria to Begin Block 3 Therapy 
52 
4.4.2 
General Chemotherapy Guidelines 
52 
4.4.3 
Block 3 Chemotherapy 
52 
4.4.4 
Disease Evaluation End Block 3 (HR/IR Patients ONLY): 
54 
4.4.5 
Following completion of Block 3: 
54 
4.5 
Blinatumomab Block: Cycle 1 (HR/IR Patients in Arm B) - 5 weeks 
55 
4.5.1 
Criteria to Begin Blinatumomab Block: Cycle 1 
55 
4.5.2 
Testicular Radiation Therapy (TRT) 
56 
4.5.3 
General Chemotherapy Guidelines 
56 
4.5.4 
Blinatumomab Block: Cycle 1 Chemotherapy 
56 
4.5.5 
Disease Evaluation End-Blinatumomab Block: Cycle 1 
57 
4.5.6 
Following completion of Blinatumomab Block: Cycle 1 (Arm B) 
57 
4.6 
Blinatumomab Block: Cycle 2 (HR/IR Patients in Arm B) - 5 weeks 
58 
4.6.1 
Criteria to Begin Blinatumomab Block: Cycle 2 
58 
4.6.2 
General Chemotherapy Guidelines 
58 
4.6.3 
Blinatumomab Block: Cycle 2 Administration Guidelines 
59 
4.6.4 
Disease Evaluation End-Blinatumomab Block: Cycle 2 
59 
4.6.5 
Following completion of Blinatumomab Block: Cycle 2 (Arm B): 
60 
4.7 
Blinatumomab-S: Cycle 1 (Salvage Therapy) - 5 weeks 
61 
4.7.1 
Criteria to Begin Blinatumomab-S: Cycle 1 
61 
4.7.2 
Testicular Radiation Therapy (TRT) 
61 
4.7.3 
General Chemotherapy Guidelines 
62 
4.7.4 
Blinatumomab-S: Cycle 1 Chemotherapy Guidelines 
62 
4.7.5 
Disease Evaluation End Blinatumomab-S Cycle 1: 
63 
4.7.6 
Following completion of Blinatumomab-S: Cycle 1: 
63 
4.8 
Blinatumomab-S: Cycle 2 (Salvage Therapy) - 5 weeks 
64 
4.8.1 
Criteria to Begin Blinatumomab-S: Cycle 2 
64 
4.8.2 
General Chemotherapy Guidelines 
64 
4.8.3 
Blinatumomab-S: Cycle 2 Chemotherapy 
65 
4.8.4 
Disease Evaluation End-Blinatumomab-S: Cycle 2 
65 
4.8.5 
Following completion of Blinatumomab-S: Cycle 2: 
65 
4.9 
Hematopoietic Stem Cell Transplant 
67 
4.9.1 
Overview 
67 
4.9.2 
Preparative Regimen Administration 
71 
4.9.3 
Preparative Regimen Administration Tables 
71 
4.9.4 
Sanctuary Site Therapy (see Section 14.0) 
73 
4.9.5 
Growth Factor Administration 
73 
4.9.6 
GVHD Prophylaxis 
74 
4.9.7 
Standard Taper of Immune Suppression 
76 
4.9.8 
Accelerated Taper of Immune Suppression 
76 
4.10 
Bridging Maintenance Therapy (All HR/IR Patients, as required) – up to 6 weeks 77 
4.10.1 Criteria to Begin Bridging Maintenance Therapy 
77 

 
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4.10.2 General Chemotherapy Guidelines 
77 
4.10.3 Bridging Maintenance Chemotherapy Guidelines 
77 
4.11 
Continuation 1/Continuation 2 (All LR Patients) - 8 weeks 
78 
4.11.1 Criteria to Begin and During Continuation Therapy 
78 
4.11.2 General Chemotherapy Guidelines 
79 
4.11.3 Continuation 1/Continuation 2 Chemotherapy Guidelines 
79 
4.11.4 Following Continuation 1: 
82 
4.11.5 Following Continuation 2: 
82 
4.12 
Maintenance Cycle 1 (All LR patients) – 12 weeks 
83 
4.12.1 Criteria to Begin Maintenance Therapy 
83 
4.12.2 Duration of Cycles in Maintenance Therapy 
83 
4.12.3 General Chemotherapy Guidelines 
83 
4.12.4 Maintenance Chemotherapy Cycle 1 
84 
4.12.5 Following Maintenance Cycle 1: 
85 
4.13 
Maintenance Chemoradiation - 3 weeks 
86 
4.13.1 Criteria to Begin Maintenance Chemoradiation 
86 
4.13.2 Cranial Radiation Therapy 
86 
4.13.3 General Chemotherapy Guidelines 
86 
4.13.4 Chemotherapy Guidelines for Maintenance Chemoradiation 
86 
4.13.5 Following Maintenance Chemoradiation: 
87 
4.14 
Maintenance-Post Cycle 1 (All LR patients) 
88 
4.14.1 Criteria to Continue Maintenance Therapy 
88 
4.14.2 Duration of Cycles in Maintenance Chemotherapy 
88 
4.14.3 General Chemotherapy Guidelines 
88 
4.14.4 Chemotherapy Guidelines for Maintenance-Post Cycle 1 
88 
4.15 
Blinatumomab Block: Cycle 1 (Patients in Arm D) - 5 weeks 
90 
4.15.1 Criteria to Begin Blinatumomab 
90 
4.15.2 General Chemotherapy Guidelines 
90 
4.15.3 Blinatumomab Block: Cycle 1 (Patients in Arm D) Chemotherapy 
91 
4.15.4  Following Blinatumomab Block: Cycle 1 (Arm D) 
91 
4.16 
Blinatumomab Block: Cycle 2/3 (LR Patients in Arm D) - 5 weeks 
92 
4.16.1 Criteria to Begin Blinatumomab Block: Cycle 2/3 
92 
4.16.2 General Chemotherapy Guidelines 
92 
4.16.3 Blinatumomab Block: Cycle 2/3: Chemotherapy Guidelines 
92 
4.16.4 Following Blinatumomab Block Cycle 2: 
93 
4.16.5 Following Blinatumomab Block Cycle 3: 
93 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
94 
5.1 
Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 
94 
5.2 
Blinatumomab 
95 
5.3 
Cyclophosphamide 
99 
5.4 
Cytarabine (ARAC) 
100 
5.5 
Anthracycline-Mitoxantrone 
100 
5.6 
Etoposide 
101 
5.7 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
101 

 
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5.8 
Intermediate-Dose Methotrexate (ID MTX) and Leucovorin Rescue 
103 
5.8.1 
ID MTX Infusion Guidelines and dose modifications for toxicity 
103 
5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
106 
5.10 
Steroids (Dexamethasone) 
109 
5.11 
PO 6-Thioguanine (TG) 
110 
5.12 
Vincristine 
110 
5.13 
Stem Cell Transplant Regimen Agents 
111 
5.13.1 Tacrolimus 
111 
5.13.2 Cyclosporine 
112 
5.13.3 Methotrexate 
112 
5.13.4 Guidelines for Leucovorin Rescue 
113 
5.13.5 Mycophenolate Mofetil (MMF) 
113 
5.13.6 Adjustment of TBI/chemotherapy During the Preparative Regimen. 
113 
5.13.7 Dose Adjustment of Chemotherapy for Patients Whose Weight Exceeds > 125% 
Ideal Body Weight (IBW) 
113 
6.0 
DRUG INFORMATION 
115 
6.1 
BLINATUMOMAB (11/18/2019) 
115 
6.2 
ASPARAGINASE Erwinia chrysanthemi (05/07/19) 
128 
6.3 
CYCLOPHOSPHAMIDE INJECTION  (03/13/13) 
130 
6.4 
CYCLOSPORINE A  (11/16/17) 
132 
6.5 
CYTARABINE - ALL ROUTES (07/13/15) 
134 
6.6 
DEXAMETHASONE (05/07/19) 
136 
6.7 
ETOPOSIDE – INJECTION (11/15/2016) 
138 
6.8 
FILGRASTIM, TBO-FILGRATIM, FILGRATIM-SNDZ (05/13/2019) 
141 
6.9 
FLUDARABINE (01/10/18) 
142 
6.10 
INTRATHECAL TRIPLES (05/08/12) 
146 
6.11 
LEUCOVORIN CALCIUM (05/07/19) 
147 
6.12 
MERCAPTOPURINE (11/27/17) 
149 
6.13 
METHOTREXATE-ALL ROUTES (05/07/19) 
150 
6.14 
MITOXANTRONE (11/27/17) 
154 
6.15 
MYCOPHENOLATE MOFETIL (12/06/18) 
156 
6.16 
PEGASPARGASE (06/05/17) 
160 
6.17 
TACROLIMUS (11/27/17) 
162 
6.18 
THIOGUANINE (12/05/2016) 
165 
6.19 
THIOTEPA (01/23/18) 
166 
6.20 
VINCRISTINE SULFATE (08/16/12) 
168 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
171 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
171 
7.2 
Research Studies 
174 
7.3 
At Relapse 
175 
7.4 
Follow-up 
175 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
175 

 
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8.1 
Criteria for Removal from Protocol Therapy 
175 
8.2 
Off Study Criteria 
176 
9.0 
STATISTICAL CONSIDERATIONS 
176 
9.1 
Statistical Design 
176 
9.1.1 
Primary Endpoint 
176 
9.1.2 
Secondary Endpoints 
176 
9.1.3 
Exploratory Endpoints 
177 
9.2 
Patient Accrual and Expected Duration of Trial 
177 
9.2.1 
Stratification to be used in the randomization 
177 
9.2.2 
Sample size with power calculation (Activation Protocol) 
178 
9.2.3 
Extension of accrual duration for both the LR cohort and the HR/IR cohort 
(Amendment #8) 
179 
9.3 
Statistical Analysis Methods 
183 
9.3.1 
HR/IR Randomization for HR and IR relapse patients 
183 
9.3.2 
LR Randomization for LR relapse patients 
189 
9.3.3 
Pilot intervention for very high risk subset of HSCT recipients based on MRD 
and aGVHD 
193 
9.3.4 
Treatment Failure (TF) patients who are non-randomly assigned to 
blinatumomab 
195 
9.3.5 
Blinatumomab related reportable adverse event (RAE) 
196 
9.3.6 
Monitoring for infection rate of 96-hour bag changes in Blinatumomab 
administration (Amendment #2) 
196 
9.3.7 
Monitoring for infection rate of 7-day bag changes in Blinatumomab 
administration (Amendment #8) 
196 
9.4 
Gender and Minority Accrual Estimates 
197 
10.0 
EVALUATION CRITERIA 
198 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
198 
10.2 
Response Criteria 
198 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
199 
11.1 
Purpose 
199 
11.2 
Determination of reporting requirements 
199 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
199 
11.4 
Special Situations for Expedited Reporting 
200 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
200 
11.4.2 Persistent or Significant Disabilities/Incapacities 
200 
11.4.3 Death 
200 
11.4.4 Secondary Malignancy 
201 
11.4.5 Second Malignancy 
201 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
201 
11.5.1 Baseline AEs 
202 
11.5.2 Persistent AEs 
202 
11.5.3 Recurrent AEs 
203 
11.6 
Exceptions to Expedited Reporting 
203 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
203 

 
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11.6.2 Special Situations as Exceptions to Expedited Reporting 
203 
11.7 
Reporting Requirements - Investigator Responsibility 
203 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
203 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
205 
11.10 
Protocol Specific Additional Instructions and Reporting Exceptions 
206 
11.11 
Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
206 
11.12 
Routine Adverse Event Reporting 
207 
12.0 
RECORDS AND REPORTING 
209 
12.1 
CDUS 
209 
12.2 
CTA/CRADA 
209 
13.0 
SPECIAL STUDIES AND SPECIMEN REQUIREMENTS 
211 
13.1 
Banking for Future Research (optional) 
211 
13.2 
Local Bone Marrow: Central review of cytogenetics/FISH 
212 
13.3 
Bone Marrow for Central Flow-Immunophenotyping and MRD (required) 
213 
13.4 
Bone Marrow for CRLF2 expression (optional) 
214 
13.5 
Blinatumomab Pharmacodynamics (PD) (optional) 
215 
13.6 
Protein Cell Stress Pathways (optional) 
216 
13.8 
Blinatumomab PK (required) 
218 
14.0 
RADIATION THERAPY GUIDELINES FOR ALL PATIENTS 
219 
14.1 
General Guidelines 
219 
14.1.1 Required Benchmark and Questionnaires 
220 
14.2 
Indications for Radiation Therapy 
220 
14.2.1 Total Body Irradiation 
220 
14.2.2 Cranial Irradiation 
220 
14.2.3 Testicular Irradiation 
221 
14.3 
Timing 
221 
14.3.1 All patients who might require irradiation should be seen in consultation by a 
radiation oncologist in advance of treatment. The purpose of the consultation is 
to participate in planning the sequence of treatment and to determine the need for 
extra medullary (cranial, testicular and other) and supplemental irradiation in 
conjunction with HSCT. 
221 
14.3.2 The timing of TBI and supplemental irradiation will be determined in part by the 
TBI fractionation regimen. Supplemental irradiation should precede TBI and be 
performed during weekdays. 
221 
14.4 
Emergency Irradiation 
221 
14.5 
Equipment and Methods of Delivery 
221 
14.6 
Treatment Volumes 
221 
14.6.1 Total Body Irradiation 
221 
14.6.2 Cranial Irradiation 
222 
14.6.3 Testicular Irradiation 
222 
14.7 
Target Dose 
222 
14.7.1 Dose Definition 
222 
14.7.2 Prescribed Dose, Fractionation and Dose Rate for TBI 
222 

 
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14.7.3 Prescribed Dose and Fractionation for Cranial Irradiation 
222 
14.8 
Treatment Technique 
223 
14.8.1 TBI 
223 
14.8.2 TBI - Lung Shielding 
223 
14.8.3 Cranial Irradiation 
224 
14.8.4 Testicular Irradiation 
224 
14.9 
Organs at Risk 
224 
14.9.1 Normal tissue sparing for TBI 
224 
14.9.2 Normal tissue sparing for cranial irradiation 
224 
14.9.3 Normal tissue sparing for testicular irradiation 
224 
14.10 
Dose Calculation and Reporting 
224 
14.10.1 Dose calculations for TBI 
224 
14.10.2 Dose Uniformity and Treatment Site Coverage 
226 
14.10.3 Tissue heterogeneity 
227 
14.10.4 Interruption of therapy 
227 
14.11 
Quality Assurance Documentation and Review 
227 
14.12 
Definitions of Deviation in Protocol Performance 
227 
14.12.1 TBI 
227 
14.12.2 Deviations for Cranial Irradiation Dose 
228 
14.12.3 Deviations for Testicular Irradiation Dose 
228 
APPENDIX I: SUPPORTIVE CARE 
229 
APPENDIX II:  THERAPY DELIVERY MAPS 
233 
APPENDIX III:  MERCAPTOPURINE DOSING GUIDELINES 
257 
APPENDIX IV:  THIOGUANINE DOSING GUIDELINES 
259 
APPENDIX V: 
 YOUTH INFORMATION SHEETS 
260 
APPENDIX VI: ADDITIONAL INFORMATION FOR BANKING FOR FUTURE 
RESEARCH CORRELATIVE BIOLOGY STUDY 
262 
APPENDIX VII-A: CLINICAL SITE MANAGEMENT OF OUT-PATIENT 
TREATMENT USING CTEP-SUPPLIED BLINATUMOMAB 
264 
APPENDIX VII-B: SHIPMENT OF BLINATUMOMAB IV BAG FROM 
SITE/PHARMACY TO PATIENT’S HOME 
268 
APPENDIX VIII: ADDITIONAL INFORMATION FOR MRD CORRELATIVE 
BIOLOGY STUDY 
269 
APPENDIX IX: ADDITIONAL INFORMATION FOR CRLF2 CORRELATIVE 
BIOLOGY STUDY 
270 
APPENDIX X: ADDITIONAL INFORMATION FOR BLINATUMOMAB 
PHARMACODYNAMICS CORRELATIVE BIOLOGY STUDY 
273 
APPENDIX XI: ADDITIONAL INFORMATION FOR PROTEIN CELL STRESS 
PATHWAYS CORRELATIVE BIOLOGY STUDY 
279 
APPENDIX XII: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT 
VERSUS HOST DISEASE (GVHD) 
285 

 
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APPENDIX XIII: CTEP AND CTSU REGISTRATION PROCEDURES 
291 
APPENDIX XIV: POSSIBLE DRUG INTERACTIONS 
294 
REFERENCES: 
302 
 

 
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Patrick Brown, MD 
Andrew Carroll, PhD. 
Hematology/Oncology 
Cytogenetics 
Johns Hopkins Univ./Sidney Kimmel Cancer Center 
Children’s Hospital of Alabama 
1650 Orleans St. CRB 2M49 
Department of Genetics 
Baltimore, MD. 21231 
1530 3rd Ave. South Kaul Bldg. Rm 314B 
Phone: (410) 614-4915     
Birmingham, AL 35294 
Fax: 
(410) 955-8897     
Phone: (205) 934-0665      
E-mail: pbrown2@jhmi.edu      
Fax: 
(205) 934-1078     
 
E-mail: acarroll@uab.edu      
STUDY VICE CHAIR 
 
James A. Whitlock, MD 
M. Brooke Bernhardt, PharmD 
Hematology/Oncology 
Pharmacy 
Hospital for Sick Children 
Baylor College of Medicine  
555 University Ave, Room 9409 Black 
1102 Bates St. Suite 1025.17 
Toronto, ON M5G 1X8 
Houston, TX 77030 
Phone: (416) 813-8885      
Phone: (832) 824-7702 
Fax: 
(416) 813-5327     
E-mail: mbbernha@txch.org  
E-mail: jim.whitlock@sickkids.ca      
 
 
Kala Kamdar, MD 
STUDY STATISTICIAN 
Hematology/Oncology 
Lingyun Ji, PhD 
Baylor College of Medicine 
Children’s Oncology Group  
6621 Fannin St. CC1410.00 
Statistics and Data Center 
Houston, TX 77030 
222 E. Huntington Drive, #100 
Phone: (832) 824-4163 
Monrovia, CA 91016 
E-mail: kykamdar@txch.org  
Phone: (626) 241-1519 
 
Fax: 
(626) 445-4334 
Mignon Lee-Cheun Loh, MD 
E-mail: lji@childrensoncologygroup.org      
Hematology/Oncology 
 
UCSF Medical Center-Mission Bay 
STUDY COMMITTEE MEMBERS 
Loh Laboratory 
Michael Borowitz, MD PhD 
Helen Diller Family Comprehensive Cancer Center  
Pathology 
1450 3rd Street, Room 284 
Johns Hopkins Univ./Sidney Kimmel Cancer Center  
San Francisco CA 94158 
401 N. Broadway, Weinberg 2237 
Phone: (415) 476-3831 
Baltimore, MD. 21231 
Fax: 
(415) 353-2657 
Phone: (410) 614-2889      
E-mail: mignon.loh@ucsf.edu 
Fax: 
(410) 502-1493     
 
E-mail: mborowit@jhmi.edu      
Lia Gore MD 
 
Hematology/Oncology 
Stephen Hunger, MD 
Children’s Hospital Colorado 
Hematology/Oncology 
Center for Cancer & Blood Disorders 
Children’s Hospital of Philadelphia 
Pediatrics, Mail Stop 8302  
Colket Translational Research Building 
PO Box 6511  
3501 Civic Center Blvd 
Aurora, CO 80045  
Room 3060 
Phone: (720) 777-4159 
Philadelphia, PA 19104 
Fax: 
(720) 777-7279 
Phone: (267) 425-0197 
E-mail: lia.gore@ucdenver.edu 
E-mail: hungers@email.chop.edu 
 
 
 
 
 
 
 

 
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STUDY COMMITTEE MEMBERS 
Fady Mikhail, MD PhD 
Jennifer McNeer, MD 
Cytogenetics 
Hematology/Oncology 
Children’s Hospital of Alabama 
University of Chicago Comprehensive Cancer Center 
Genetics 
Pediatrics 
720 20th Street South, Kaul Bldg. Rm. 314A 
5841 S. Maryland Ave 
Birmingham, AL 35294 
MC 4060 
Phone: (205) 934-9588      
Chicago, IL. 60637 
Fax: 
(205) 934-1078     
Phone: (773) 702-5782  
E-mail: fmikhail@uab.edu      
Fax: 
(773) 702-9881 
 
E-mail: jmcneer@peds.bsd.uchicago.edu 
Julie M. Gastier-Foster, PhD. 
 
Laboratory Science 
Maureen Megan O’Brien, MD 
Nationwide Children’s Hospital 
Hematology/Oncology 
Laboratory Medicine 
Cincinnati Children’s Hospital Medical Center 
700 Children’s Drive, CO988A 
3333 Burnet Avenue 
Columbus, OH. 43205 
MLC 7015 
Phone: (614) 722-2866    
Cincinnati, OH. 45229 
Fax: 
(614) 722-2887     
Phone: (513) 803-1678  
E-mail: Julie.Gastier-Foster@nationwidechildrens.org   
Fax: 
(513) 636-3549 
 
E-mail: maureen.obrien@cchmc.org      
Terzah Horton, MD PhD 
 
Hematology/Oncology  
Michael Pulsipher, MD 
Baylor College of Medicine 
Cellular Therapy 
Pediatrics 
Children’s Hospital of Los Angeles 
1102 Bates Avenue, Suite 750 
Blood and Marrow Transplantation 
Houston, TX. 77030 
4650 Sunset Blvd, MS#54 
Phone: (832) 824-4269     
Los Angeles, CA 90027 
Fax: 
(832) 824-1206     
Phone: (323) 361-2546 
E-mail: tmhorton@txch.org      
Fax: 
(323) 361-8068 
 
E-mail: mpulsipher@chla.usc.edu 
Stephanie Terezakis, MD. 
 
Radiation Oncology 
Susan Rheingold, MD 
Johns Hopkins Univ./Sidney Kimmel Cancer Center 
Hematology/Oncology  
Department of Radiation 
Children’s Hospital of Philadelphia 
401 N. Broadway, Ste 1440 
Division of Oncology 
Baltimore, MD. 21231 
34 & Civic Center Blvd. 
Phone: (443) 287-7889 
Philadelphia, PA. 19104 
Fax: 
(410) 502-1419 
Phone: (215) 590-3079     
E-mail: stereza1@jhmi.edu      
Fax: 
(215) 590-4183     
 
E-mail: Rheingold@email.chop.edu      
Christopher Henchen, BS, CCRP 
 
Clinical Research Associates 
Richard Tower, MD MS 
Children’s Hospital of Wisconsin 
Hematology/Oncology 
8701 Watertown Plank Road 
Children’s Hospital of Wisconsin 
Milwaukee, WI, 53226 
Pediatric/Hematology/Oncology/BMT 
Phone: (414)  266-8913 
MACC Fund Research Center 
E-mail: chenchen@mcw.edu   
8701 Watertown Plank Road. 
 
Milwaukee, WI. 53226 
 
Phone: (414) 955-5653 
 
Fax: 
(414) 955-6543 
 
E-mail: rtower@mcw.edu 
 
 
 
 
 
 
 

 
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14 
Meenakshi Devidas, PhD 
Debra Marie Schissel, RN CCRP CPON 
Statistics 
Nursing 
St. Jude Children’s Research Hospital 
Children’s Hospital Colorado 
Department of Global Pediatric Medicine 
Center for Cancer & Blood Disorders 
262 Danny Thomas Place Mail Stop 721 
13123 East 16th Avenue B115 
Memphis, TN 38105 
Aurora, CO 80218 
Phone:  (904) 595-1764 
Phone: (720) 777-2879 
E-mail: mini.devidas@stjude.org 
Fax: 
(720) 777-7289 
 
Email: Debra.schissel@childrenscolorado.org 
Sarah Tasian, MD 
 
Hematology/Oncology 
Laura Hogan, MD 
Children’s Hospital of Philadelphia 
Hematology/Oncology 
Division of Oncology 
Stony Brook University Medical Center 
3501 Civic Center Blvd 
Pediatrics 
CTRB, 3rd Floor Room 3010 
HSC T11-029, Stony Brook, NY 11794 
Philadelphia, PA 19104 
Phone: (631) 444-7720 
Phone: (267) 425-0118 
Fax: 
(631) 444-2785 
Fax: 
(215) 590-3770 
E-mail: laura.hogan@stonybrookmedicine.edu 
Email: tasians@email.chop.edu 
 
 
Susan Zupanec, MN NP 
Teena Bhatla, MD 
Nursing 
Hematology/Oncology 
Hospital for Sick Children 
Newark Beth Israel Medical Center 
555 University Avenue 
201 Lyons Avenue 
Toronto, ON M5G1X8 
Newark, NJ 07112 
Phone: (416) 813-3488 
Phone:  (973) 926-7161 
Fax: 
(416) 813-5574 
Fax:  (973) 282-0395 
E-mail: sue.zupanec@sickkids.ca 
E-mail: teena.bhatla@rwjbh.org 
 
 
 
COG RESEARCH COORDINATOR  
 
Don Sortillon, MS  
AGENT 
 
 
NSC# 
 
IND# 
Children's Oncology Group Statistics and Data Center  
Blinatumomab 
 
 
765986  
 
222 E. Huntington Drive, Suite 100 
(IND Sponsor: CTEP) 
Monrovia, CA 91016 
Asparaginase E. chrysanthemi 
106977  
Exempt  
Phone: 626-241-1597 
Cyclophosphamide 
 
26271 
 
Exempt  
Fax: 
626-445-4334 
Cyclosporine 
 
 
290193  
Exempt  
E-mail: dsortillon@childrensoncologygroup.org 
Cytarabine 
 
 
63878 
 
Exempt 
 
Dexamethasone  
 
34521 
 
Exempt 
COG PROTOCOL COORDINATOR 
Etoposide 
 
 
141540  
Exempt 
Christine Petrossian 
Filgrastim 
 
 
614629  
Exempt 
Children’s Oncology Group Operations Center 
Fludarabine 
 
 
312887  
Exempt 
Study Development Office 
Hydrocortisone  
 
10483 
 
Exempt 
222 E. Huntington Dr., Suite 100  
Leucovorin 
 
 
003590  
Exempt 
Monrovia, CA 91016 
Mercaptopurine  
 
000755  
Exempt 
Phone: (626) 241-1578 
Methotrexate 
 
 
000740  
Exempt 
Fax: 
(626) 445-4334 
Mitoxantrone 
 
 
301739  
Exempt  
E-mail: cpetrossian@childrensoncologygroup.org 
Mycophenolate Mofetil 
 
724229  
Exempt 
 
Pegaspargase 
 
 
624239  
Exempt 
 
Tacrolimus 
 
 
717865  
Exempt 
 
Thioguanine 
 
 
00752 
 
Exempt 
 
Thiotepa 
 
 
6396 
 
Exempt 
 
Vincristine 
 
 
67574 
 
Exempt 
 
 
 
SEE SECTION 13.0 FOR SPECIMEN SHIPPING ADDRESSES. 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
ABSTRACT 
AALL1331 is a group wide risk-stratified, randomized Phase III study to test whether incorporation of 
blinatumomab into the treatment of patients with childhood B-Lymphoblastic Leukemia (B-ALL) at first 
relapse will improve disease free survival. Blinatumomab is being tested in this population based on its 
demonstrated safety profile and single agent activity (induction of MRD-negative remissions in children 
with multiple relapsed refractory B-ALL). 
 
AALL1331 risk stratification is determined based on site of relapse [marrow versus isolated extramedullary 
(IEM)], time to relapse and minimal residual disease (MRD) status following a uniform first block of 
chemotherapy. High risk (HR) and intermediate risk (IR) patients will be eligible for randomization to 
either a control arm with two additional blocks of chemotherapy, or an experimental arm with two blocks 
of blinatumomab. Both arms will proceed to protocol-specified hematopoietic stem cell transplant (HSCT) 
that includes a rapid taper of immune suppression for patients with residual disease and no graft vs. host 
disease (GVHD). Low risk (LR) patients will be eligible for randomization to either a control arm with two 
blocks of chemotherapy followed by continuation and maintenance chemotherapy, or an experimental arm 
with one block of chemotherapy, 2 blocks of blinatumomab, each followed by continuation and a third 
additional block of blinatumomab followed by maintenance. 
 
AALL1331 includes correlative laboratory studies to refine risk stratification, identify new targets for 
therapy, identify biomarkers to predict response to chemotherapy and blinatumomab, and to link host 
polymorphisms with various disease characteristics and toxicities. 
 
Amendment #10 incorporates the High Risk/Intermediate Risk randomization closure as a result of COG 
DSMC’s recommendation based on data that determined the experimental arm with blinatumomab 
(Arm B) has a significantly more favorable tolerability profile and similar or superior EFS/OS. Effective 
September 18, 2019, accrual and randomization on the HR/IR arms closed. At completion of Block 1, if 
patient is found to be HR/IR the patient comes off protocol therapy. HR/IR patients already assigned 
to Arm A (standard chemotherapy) who are at an appropriate point in their treatment program (prior to 
receiving Day 22 treatment on Block 3) will be offered the opportunity to cross over to Arm B to receive 
blinatumomab.    

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EXPERIMENTAL DESIGN SCHEMA 
HR=High Risk 
R=Randomization 
HSCT=Hematopoietic Stem Cell Transplant 
IR=Intermediate Risk  
CR=Complete response 
LR=Low Risk 
TF: Treatment Failure 
@ See Section 3.3 for definitions of treatment failure and relapse. 
1 End Block 1 Callback (completed via OPEN, see Section 3.1.6-3.1.7) 
2 Randomization and accrual to the HR/IR arms is permanently closed effective 09/18/2019. All HR/IR patients receiving 
treatment on Arm A prior to Amendment #10 will receive blinatumomab in place of standard chemotherapy.  
# CNS3 patients receive chemoradiation post Maintenance Cycles 1  * Patient may receive bridge therapy prior to HSCT  
^ Patients with persistent testicular involvement after Block 1 will receive testicular radiation (TRT) during designated blocks 
% Evaluation pre-HSCT at end of each cycle. See Section 4.7.6 and 4.8.5 for details  
+ Patients who achieve remission at end-Block 1 or 2 but are no longer in remission on a subsequent evaluation will be removed 
from protocol therapy for relapse. 
Arm D 
Arm C
HR/IR 
HR/IR Randomization 
Permanently Closed 2 
Blinatumomab^ 
(1st cycle) 
1st Relapse B-ALL (On Study) 
Evaluation 1 1 
Pre-treatment Evaluation 
Treatment Failure@ 
Maintenance# 
Maintenance# 
Continuation 2 
Continuation 1 
Continuation 1 
Blinatumomab 
(2nd cycle) 
Continuation 2 
Blinatumomab 
(3rd cycle) 
Block 2^ 
Block 3 
Blinatumomab 
(1st cycle)
Evaluation 2 
Off 
Protocol 
Therapy 
Yes 
Off protocol therapy 
Blinatumomab 
(2nd cycle) 
HSCT* 
No 
Prior blinatumomab, or 
CNS disease 
Evaluation pre-HSCT  
Salvage Therapy^ 
(Blinatumomab-S) 
Up to 2 Cycles % 
Evaluation 2 
LR 
LR Randomization 
Block 1 
Arm B 
Arm A 
Relapse@ + 
Eligible 
Ineligible 
Refer to Section 3.1.5 for details 
regarding staged consent 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
1.1.1 
To compare disease free survival (DFS) of HR and IR relapse B-ALL patients who 
are randomized following Induction Block 1 chemotherapy to receive either two 
intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR 
Randomization). (Closed effective September 18, 2019) 
 
1.1.2 
To compare DFS of LR relapse B-ALL patients who are randomized following 
Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus 
blinatumomab (LR Randomization). 
 
1.2 
Secondary Aims 
 
1.2.1 
To compare overall survival (OS) of HR and IR relapse B-ALL patients who are 
randomized following Induction Block 1 chemotherapy to receive either two 
intensive chemotherapy blocks or two 5 week blocks of blinatumomab (HR/IR 
Randomization). (Closed effective September 18, 2019) 
 
1.2.2 
To compare OS of LR relapse B-ALL patients who are randomized following 
Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus 
blinatumomab (LR Randomization). 
 
1.3 
Exploratory Aims 
 
1.3.1 
To compare the rates of MRD ≥ 0.01% at the end of Block 2 and Block 3 for HR 
and IR relapse B-ALL patients in HR/IR randomization. (Closed effective 
September 18, 2019) 
 
1.3.2 
To estimate, for treatment failure (TF) patients not previously receiving 
blinatumomab, the hematologic complete remission rate (CR), rate of MRD 
< 0.01%, and proportion able to proceed to hematopoietic stem cell transplant 
(HSCT) in CR after treatment with blinatumomab. 
 
1.3.3 
To assess the feasibility and safety of rapid taper of immune suppression for the 
subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-HSCT with no acute 
graft versus host disease (aGVHD). 
 
1.3.4 
To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response 
relationships for measures of safety and effectiveness. 
 
 

 
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2.0 
BACKGROUND 
2.1 
Overview 
First relapse of childhood B-ALL is a vexing clinical problem with high rates of subsequent 
relapse and death with current treatment approaches.1 This trial will determine if 
blinatumomab can reduce rates of second relapse, and improve survival. If successful, these 
interventions could become standard of care for this disease. Additionally, success in 
relapsed B-ALL will identify interventions that can subsequently be studied in patients 
with newly diagnosed B-ALL in order to reduce rates of first relapse. 
 
This study also is a paradigm shift away from the non-randomized historical control 
outcome comparisons pursued in recent COG trials for patients with early relapse of B-
ALL (ADVL04P2 and AALL07P1). Those trials were designed to screen promising new 
agents for possible activity in order to identify which agents should be tested further in 
more definitive trials. Because of the remarkable efficacy of blinatumomab in adult trials2-
5 and in the Phase I portion of COG AALL1121,6 this study will directly test the efficacy 
of blinatumomab in two risk groups of relapsed B-ALL in a randomized fashion. 
 
This trial also seeks to enhance accrual to relapse childhood ALL trials within COG. Prior 
to this trial, COG has used a fragmented approach that has required institutions to open a 
different protocol for each of the many subsets of first relapse ALL. This trial will address 
this issue by studying first relapse B-ALL in a single, comprehensive protocol. 
 
Importantly, this study will establish an infrastructure for systematic studies of the 
classification and biology of relapsed childhood B-ALL. Due to the fragmented nature of 
previous trials and poor accrual, these types of studies have not been possible in the COG 
until now. 
 
2.2 
Rationale for Selected Approach and Trial Design 
2.2.1 
Rationale for Consolidated First Relapse B-ALL Trial 
This study alters the approach to clinical investigation of relapsed B-ALL in COG. 
Previous treatment protocols for the 3 major risk groups of first relapse ALL based 
on duration of 1st complete remission (CR1) and site of relapse (see Table 1) have 
been separate.  
Table 1: Risk groups by duration of CR1, and site of relapse. 
Risk group 
CR1 duration and site 
Studies 
Low 
≥ 18 mo isolated extramedullary (Late IEM) 
AALL02P2 
(closed) 
Intermediate 
≥ 36 mo marrow (Late marrow), 
< 18 mo isolated extramedullary (Early IEM) 
AALL0433 
(closed) 
High 
< 36 mo marrow (Early marrow), 
all T-ALL/T-LL relapses 
ADVL04P2 
(completed) 
AALL07P1 
The approach for HR patients has been a series of single arm, limited 
accrual/duration Phase II re-Induction studies of novel agents (epratuzumab for 
ADVL04P2, bortezomib for AALL07P1) added to the 3-block backbone of 
chemotherapy established by AALL01P2 (see Table 2) with the primary endpoint 
being CR2 at end Block 1 as compared to historical control data using the 

 
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backbone alone.7 Use of historical control data is problematic for a number of 
reasons. COG trials for IR and LR patients have each utilized a unique multiagent 
chemotherapy regimen with or without randomized interventions with a 3-year 
event free survival (EFS) endpoint. 
 
Table 2: Backbone Chemotherapy for relapse B-ALL 
Block 1 
Block 2 
Block 3 
PRED 40 mg/m2/day, Days 1-29 
VCR 1.5 mg/m2, Days 1, 7, 15, 21 
PEG 2500 IU/m2, Days 2, 9, 16, 23 
DOXO 60 mg/m2, on Day 1 
IT ARAC Day 1 
IT MTX Days 15, 29 (or ITT if CNS 
positive) 
ETOP Days 1-5 
CPM Days 1-5 
HDMTX Day 22 
with leucovorin 
rescue 
HD ARAC Days 1, 2, 8, 9 
L-ASP Days 2, 9 
IT MTX or ITT Days 1, 22 
 
This fragmented approach has been associated with problems in meeting accrual 
goals and/or completion of studies in a timely and efficient manner. A major 
obstacle to accrual is the reluctance of COG sites to open all of the relapse studies. 
Since relapsed ALL is significantly less common than newly diagnosed ALL, the 
annual accrual to each individual study is expected to be low enough at most COG 
sites that it may not justify the regulatory burden involved in opening several 
studies. This is exacerbated for the HR group by the limited accrual/duration of 
each study, since individual COG sites may be unlikely to enroll any patients 
during the conduct of such a study. For example, major frontline COG ALL trials 
are typically open at 190 - 200 sites. In contrast the HR relapse trials have been 
open in only about 100 sites, and the IR and LR trials at 125 to 150 sites. 
 
We therefore are addressing these issues with a consolidated approach to the 
classification and initial treatment of first relapse B-ALL, in which all patients are 
eligible to enroll in a single trial. This approach has been successful in other 
cooperative groups, including the International Berlin Frankfurt Munster (I-BFM)8 
and 
United 
Kingdom 
Children’s 
Cancer 
and 
Leukemia 
Group 
(UK CCLG)/Australia/New Zealand9 consortia. 
 
2.2.2 
Rationale for Studying Blinatumomab in First Relapse of B-ALL 
Survival for first relapse of B-ALL is suboptimal. Blinatumomab is a promising 
novel agent for the treatment of B-lineage lymphoid malignancies.1-5 
Blinatumomab is a bispecific single-chain antibody that targets the CD19 antigen 
and redirects CD3+ T cells for selective lysis of tumor cells. In a Phase II trial of 
adult B-ALL, patients with MRD persistence or relapse after Induction and 
Consolidation therapy received blinatumomab as a 4 week continuous intravenous 
infusion at a dose of 15 µg/m2/24 hours.5 Of 21 treated patients, 16 patients became 
MRD negative as assessed by quantitative polymerase chain reaction for either 
rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic 
aberrations. Among the 16 responders, 12 patients had been molecularly refractory 
to previous chemotherapy. Probability for relapse-free survival was 78% at a 
median follow-up of 405 days. Blinatumomab was similarly effective and well 
tolerated in an anecdotal report of a small series of pediatric cases.2 
 

 
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Blinatumomab is presently being evaluated in children with relapsed/refractory 
ALL in an Amgen-sponsored Phase I/II study being conducted by COG (MT103-
205/AALL1121) and the I-BFM European childhood leukemia cooperative group 
with extremely promising early results. As of September 2013, 34 patients have 
been treated in the Phase I portion. Across all dose levels, 11 (32%) patients had 
CR, 1 (3%) had hypocellular blast-free bone marrow, and 2 (6%) had partial 
remission within the first two treatment cycles. All patients with CR also 
experienced molecular remission (MRD level < 10-4) after one 4 week block of 
blinatumomab.10 The recommended Phase 2 dose for patients with untreated 
relapse has been determined to be a 4 week continuous IV infusion of 5 µg/m2/day 
for the first week of Cycle 1 and 15 µg/m2/day thereafter (i.e. Weeks 2 - 4 of 
Cycle 1 and Weeks 1 - 4 of all subsequent cycles), with a 2 week break between 
each cycle. The Phase 2 portion of the study is being conducted at 20 COG and 20 
European institutions and began accrual in September 2013. A 2 week rest period 
between 4 week cycles was selected arbitrarily in early studies of blinatumomab. 
To preserve the symmetry of timing between arms as much as possible, in 
AALL1331, a “block” of blinatumomab will be 5 weeks in duration, and will 
consist of a 4 week continuous infusion followed by a 1 week break. AALL1331 
will also use a flat dose of 15 µg/m2/day for all blinatumomab cycles except for 
the first cycle for TF patients (who, like the Phase I/II study patients, will have 
bulk disease at the time of initiating treatment), where the Phase 2 escalating 
dosing strategy will be used. 
 
The level of single agent activity seen with blinatumomab has not been seen in 
recent Phase I ALL studies outside the use of tyrosine kinase inhibitors (TKI) in 
patients with Philadelphia chromosome positive (Ph+) ALL, thus supporting a 
Phase III randomized clinical trial with DFS endpoints. AALL1331 uses a risk-
stratified approach to test whether incorporating blinatumomab into treatment of 
first relapse B-ALL will reduce rates of second relapse and improve DFS. If 
successful, inclusion of blinatumomab could become standard of care for this 
disease. Additionally, success in relapsed B-ALL will provide additional rationale 
to test blinatumomab in newly diagnosed B-ALL patients in order to reduce rates 
of first relapse. 
 
As experience with blinatumomab remains relatively limited, this study will 
include close early monitoring for uncommon but significant adverse events in 
patients receiving blinatumomab. In addition, the potential for adverse effects from 
long term depletion of CD19+ normal lymphocytes following blinatumomab 
treatment is unknown and so monitoring for lymphocyte recovery and for potential 
adverse effects related to delayed recovery are included. 
 
Neurological adverse events have been described with blinatumomab and will be 
closely monitored on this study. One potential concern regards the safety of 
combining blinatumomab with IT chemotherapy. In the current Phase I/II pediatric 
study cited above, IT methotrexate or IT triples are included prior to Cycle 1, at 
Day 15 of Cycle 1 and at Day 29 of each cycle. No unusual or increased CNS side 
effects have been seen in this setting.10 
 
Cytokine release syndrome (CRS) has also been described. This is more prevalent 
in patients with higher leukemia burden, however can occur in any patient treated  

 
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with blinatumomab. Pre-medication with dexamethasone is mandated in the 
protocol, and at the suggestion of the development of CRS, even after the 
premedication doses, additional dexamethasone administration is suggested. There 
is a published case report suggesting that for cases of life-threatening cytokine 
release syndrome for which dexamethasone and supportive care measures are not 
adequate, consideration may be given to the administration of tocilizumab, the 
anti-IL-6 monoclonal antibody.11 
 
2.2.3 
Rationale for Risk Stratification 
Long term survival rates for B-ALL early marrow (15% - 30%) and B-ALL early 
IEM (30% - 50%) relapses are very poor, and HSCT is generally considered to 
provide the best chance for cure.1 This group of patients will be classified as HR 
and will be eligible to participate in HR/IR randomization upon recovery from 
Block 1 unless they meet TF criteria (see Table 6). 
 
Late B-ALL marrow relapse patients have excellent end-reinduction CR2 rates 
(> 95%),7 but long term EFS is suboptimal at about 50 – 60%. For these late 
B – ALL marrow relapse patients, end-Block 1 MRD has been identified in multiple 
studies to be a strong prognostic factor.7,12-14 In AALL01P2, for example, the 
5 year EFS for late marrow/MRD-negative patients (< 0.01% by flow at end-Block 
1, occurring in about 50% of patients) was 57% vs. 24% for those with 
MRD ≥ 0.01%.7 Thus, AALL1331 will use MRD response to stratify late pre-B 
marrow relapse patients into those for whom HSCT is or is not indicated. We will 
use an MRD threshold of 0.1% at end-Block 1 for this HSCT allocation (see 
Table 3 below). This is based on data from AALL01P2 and the ongoing 
AALL0433 trial, in which MRD data (end Blocks 1, 2 and 3) have been collected 
for a large cohort (~150) of late B-ALL marrow relapse patients. The AALL0433 
cohort is especially informative since the post-Block 3 therapy given in the context 
of AALL0433 is uniform (this is not true for AALL01P2). Recent analyses of 
MRD and outcome from patients enrolled on COG AALL0433 with BM or 
combined relapse and available end Induction MRD data (n = 175) showed 3 year 
EFS 80.2 ± 5.2% vs. 40.9 ± 8.4%, and 3year OS of 87.1 ± 4.3% vs. 56.2 ± 9.0% 
for those below (n = 112) or above (n = 63) an MRD cutoff of 0.1%.15 Thus far, 
about 62% of late BM relapse patients enrolled in AALL0433 attain MRD < 0.1% 
by end Block 1. Summarily, for late B-ALL marrow relapse patients, post-Block 
1 treatment will be risk-stratified, based on end-Block 1 MRD. MRD analysis will 
be performed centrally in Dr. Borowitz’s laboratory at Johns Hopkins using flow 
cytometry and a cutoff for MRD positivity of ≥ 0.1% will be used. Patients with 
end-Block 1 MRD levels of ≥ 0.1% will be classified as IR and will be eligible to 
participate in HR/IR randomization. Those with end-Block 1 MRD levels of 
< 0.1% will be classified as LR and will be eligible to participate in LR 
Randomization (see Table 3 below). 
 
For B-ALL IEM relapses, expected outcomes with chemotherapy and radiation for 
those relapsing at least 18 months from diagnosis are similar to those for late 
marrow LR patients.16,17 It is generally agreed that HSCT is not indicated for B-
ALL late IEM relapses. An exception to this will be patients found to have 
detectable minimal marrow disease at study entry that does not clear to < 0.1% by 
the end of Block 1, based on published literature that minimal marrow disease in 
the setting of extramedullary relapse is associated with increased risk of 

 
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subsequent marrow relapse.18,19 Thus, B-ALL late IEM relapses that have 
MRD < 0.1% (or uninterpretable MRD results) at end Block 1 will be classified as 
LR and will be eligible to participate in LR Randomization. B-ALL late IEM/end 
Block 1 MRD ≥ 0.1% relapses will be classified as IR and will be eligible to 
participate in HR/IR randomization. Effective September 18, 2019, accrual and 
randomization on the HR/IR arms closed. With Amendment #10, at completion of 
Block 1, if patient is found to be HR/IR the patient comes off protocol therapy. HR/IR 
patients already assigned to Arm A (standard chemotherapy) who are at an appropriate 
point in their treatment program (prior to receiving Day 22 treatment on Block 3) will 
be offered the opportunity to cross over to Arm B to receive blinatumomab.    
 
Table 3: Risk Classification on AALL1331 
Risk Group 
Definition 
Randomization 
Eligibility 
HSCT Treatment 
Low 
• Late (≥ 36 months) marrow, 
end-Block 1 MRD < 0.1% 
• Late (≥ 18 months) Isolated 
extramedullary (IEM), 
end-Block 1 MRD < 0.1% 
LR 
Randomization 
No HSCT 
(Treatment includes 
Continuation and 
Maintenance) 
Intermediate 
• Late (≥ 36 months) marrow, 
end-Block 1 MRD ≥ 0.1% 
• Late (≥ 18 months) IEM, 
end-Block 1 MRD ≥ 0.1% 
HR/IR 
Randomization  
HSCT 
High 
• Early (< 36 months) 
marrow 
• Early (< 18 months) IEM 
HR/IR 
Randomization 
HSCT 
Treatment 
Failure 
Failure to achieve the 
following at end Block 1: 
• 
M2 or better 
• 
CNS remission 
(clearance of CSF 
blasts, i.e. CNS1) 
None (Possible 
treatment 
assignment to 
Salvage 
Therapy) 
HSCT 
 
2.2.4 
Rationale for Backbone Chemotherapy Treatment (Blocks 1, 2 and 3) 
AALL1331 adopts the chemotherapy used in the recently published international 
collaborative United Kingdom Medical Research Council ALLR3 study 
(mitoxantrone arm).9 These results are the most promising for relapsed childhood 
ALL published to date, and need to be confirmed using data from the standard 
arms of this trial. In addition, adopting ALLR3 will pave the way for the 
international collaboration that we know will be necessary as we begin to test 
agents targeted to small molecularly-defined subsets of patients (i.e., JAK2 
mutant). The first 3 blocks of therapy will serve as the control arm for all patients 
on this study. These 3 blocks are quite similar to the AALL01P2 Blocks (Table 4).  
Table 4: Comparison of AALL01P2 and AALLR3 
 
COG AALL01P2 
ALLR3 (mitoxantrone arm) 
Block 1 
 
PRED 40 mg/m2/day, Day 1-29 
VCR 1.5 mg/m2, Days 1, 8, 15, 22 
PEG 2500 IU/m2 Days 2, 9, 16, 23 
DOXO 60 mg/m2 on Day 1 
IT ARAC Day 1 
DEX 20 mg/m2/day Days 1-5, 15-19 
VCR1.5 mg/m2 Days 3, 10, 17, 24 
PEG 1000 IU/m2 Day 3 of weeks 1 & 3 
Mitoxantrone 10 mg/m2 Days 1, 2 

 
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IT MTX Days 15, 29 (or ITT if 
CNS positive)  
IT MTX Days 1, 8 (or weekly if CNS 
positive until 2 clear samples are 
obtained) 
Block 2 
ETOP 100 mg/m2 Days 1-5 
CPM 440 mg/m2 Days 1-5 
MTX 5 g/m2 Day 22 
IT MTX Days 1, 8 
DEX 6 mg/m2/day Days 1-5 
VCR 1.5 mg/m2 Day 3 
MTX 1 g/m2 Day 8 
PEG 1000 IU/m2 Day 9 
CPM 440 mg/m2 Days 15-19 
ETOP 100 mg/m2 Days 15-19 
IT MTX Day 8 
Block 3 
ARAC 3000 mg/m2 q12h 
Days 1, 2, 8, 9 
L-ASP 6000 IU/m2 Days 2, 9 
DEX 6 mg/m2/day Days 1-5 
VCR 1.5 mg/m2 Day 3 
ARAC 3000 mg/m2 q12 Days 1, 2, 8, 9 
Erwinia asparaginase 20,000 IU/m2 
Days 2, 4, 9, 11, 23 
MTX 1 g/m2 Day 22 
IT MTX Days 1, 22 
CR2 end 
Block 1 
96% for IR, 67% for HR (31% for 
CR1 < 18 mo), 29% for T-ALL 
92% for IR, 58% for HR 
MRD+ 
end 
Block 1 
51% for IR, 75% for HR 
59% for IR, 100% for HR  
(small numbers) 
Survival 
12 month EFS: 80% for IR, 35% 
for HR  
3-year EFS: 55% for IR, 15% for 
HR 
3-year PFS: 65% for mitoxantrone arm 
(includes HR and IR patients) 
The ALLR3 trial randomized patients to mitoxantrone versus idarubicin in 
Block 1, and found that the mitoxantrone arm with a 3 year progression free 
survival (PFS) of 65% was superior to the idarubicin arm in both 3 year PFS 
(65% vs. 36%, p = 0.0004) and 3 year overall survival (69% vs. 45%, p = 0.004). 
The major differences between Block 1 in ALLR3 and in the COG AALL01P2 
backbone are the replacement of doxorubicin with mitoxantrone and 28 days of 
prednisone with two 5-day pulses of high-dose dexamethasone. Dexamethasone 
was used in ALLR3 based on evidence in prior studies of superior CNS activity 
and survival when compared with prednisone.20-22 For Block 2, the major 
differences are the inclusion of a “prophase” week of dexamethasone and 
vincristine, a lower dose of methotrexate (MTX; 1 g/m2 vs. 5 g/m2), and the 
inclusion of a dose of PEG asparaginase in combination with MTX. For Block 3, 
the major differences are the addition of dexamethasone and vincristine to the first 
week of high dose cytarabine, the addition of intravenous (IV) MTX (1 g/m2) and 
2 doses of intrathecal (IT) MTX, the use of Erwinia asparaginase instead of E.coli 
asparaginase and the inclusion of 3 additional doses of Erwinia asparaginase. 
AALL1331 differs from ALLR3 in several ways: 
• 
AALL1331 administers vincristine beginning on Day 1 of Block 1, rather 
than beginning on Day 3. 
• 
The pegaspargase preparation utilized in the ALLR3 trial, which is supplied 
by Medac, differs from that utilized in North America, which is supplied by 
Sigma Tau. Thus, it is possible that the pharmacokinetics (PK) and/or activity 
profiles of the pegaspargase preparation utilized in Europe differ from that 

 
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used in North America. As the Medac pegaspargase product is not available 
for use in North America, AALL1331 will use the COG standard dose 
(2,500 IU/m2) of intravenous Oncospar pegaspargase given on the same 
schedule utilized in ALLR3. Recent and ongoing COG relapse ALL trials 
utilize 4 doses of pegaspargase (2,500 IU/m2) given weekly in Block 1, and 
the most recent and current UKALL 2003/2011 trials and current frontline 
AIEOP-BFM 2009 ALL trial use 2 doses of pegaspargase during a 4-drug 
Induction, so this change is expected to be safe. 
 
2.2.5 
Rationale for Backbone Chemotherapy Treatment (post-Block 3) 
One attractive aspect of the post-Block 3 chemotherapy given in the ALLR3 
protocol is that it is significantly less intensive than that given to similar patients 
on the current COG study, AALL0433 (Table 5), affording us an opportunity to 
decrease short and long term toxicity for relapsed patients with a relatively good 
prognosis. 
 
Table 5* Comparative Cumulative Dosing 
Drug 
AALL0433 
ALLR3 
Intravenous methotrexate (IV MTX) 
40 
--- 
Cytarabine (ARAC) 
48 
0.6 
Etoposide (ETOP) 
2.4 
0.6 
Cyclophosphamide (CPM) 
10 
1.2 
Vincristine (VCR) 
0.0525 
0.030 
Mercaptopurine (MP) 
18 
44 
Dexamethasone (DEX) 
0.39 
0.24 
Doxorubicin (DOXO) 
0.075 
--- 
Pegaspargase (PEG) 
6 doses (2500 IU/m2) 
--- 
Intrathecal methotrexate (IT MTX) - CNS 
negative 
15 doses 
10 doses 
Oral Methotrexate (PO MTX) 
1.2 
1.7 
*Units are cumulative grams/m2 of indicated drug unless otherwise indicated. 
 
2.2.6 
Therapy for CNS3 Patients 
The majority of patients with isolated CNS relapse on the ALLR3 trial proceeded 
to HSCT, so data regarding the efficacy of ALLR3 chemotherapy and radiation 
alone are lacking. However, Pediatric Oncology Group (POG) studies 
demonstrated excellent outcomes for late isolated CNS relapse with the 
incorporation of drugs with both systemic and CNS efficacy (intermediate-dose 
MTX 1 g/m2 and high-dose ARAC 3 g/m2) and delayed CNS-directed 
radiation.16,17 On these trials, coordinated systemic and intrathecal therapy (IT) 
were given early in therapy to target both the CNS relapse and the high risk for 
subsequent marrow relapse. On POG 9061, radiation therapy (cranial 24 Gy, spinal 
15 Gy) was given after 6 months of intensive chemotherapy and then followed by 
maintenance chemotherapy, resulting in 84% EFS for late EM relapse patients. 
The chemotherapy used on POG 9061 was similar to the proposed backbone for 
this study but included additional CNS-directed therapy.17 The successor trial, 
POG 9412, successfully reduced radiation to 18 Gy cranial and eliminated spinal 
radiation for late CNS relapse patients but included maximal intensity 
chemotherapy for 12 months prior to radiation.16  
 

 
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On AALL1331, the backbone described above will be modified to include 
increased CNS-directed therapy. Throughout therapy, intrathecal triples (ITT) will 
replace IT MTX. During Block 1, two additional ITT doses will be given. During 
Block 2, one additional ITT dose will be given. Late B-ALL isolated CNS or late 
B-ALL CNS3 combined relapse patients with MRD < 0.1% after Block 1 will be 
LR and eligible for randomization to receive either standard Block 3, Continuation 
and 
Maintenance 
or 
Blinatumomab, 
Continuation/Blinatumomab 
and 
Maintenance. We will further intensify CNS-directed therapy for these patients by 
replacing lower dose oral MTX (25 mg/m2 every 6 hours x 4 doses) with 
intermediate-dose IV MTX (1,000 mg/m2 over 36 hours) during the each of the 2 
continuation phases. All of these patients will then receive 1800 cGy cranial 
radiation and concurrent chemotherapy (including high-dose dexamethasone) 
between and the first and second 12 week blocks of Maintenance. Radiation will 
be administered later on the current study (approximately Week 40 for the control 
arm and Week 54 for the experimental arm) as compared to the ALLR3 trial 
(Week 14) to maximize delivery of early intensive chemotherapy; this is similar to 
the timing of radiation in POG 9412 (Week 51).  
 
All other CNS3 relapse patients that meet IR or HR criteria will proceed to total 
body irradiation (TBI) based HSCT as described in Section 14.5. In addition to the 
TBI, these patients will also receive a protocol-specified cranial radiation boost as 
part of their HSCT preparative regimen. 
 
2.2.7 
Treatment of Testicular Relapse 
Although historically testicular irradiation has been used for patients with 
testicular leukemia at relapse, there are no studies that prove the necessity of this 
approach. Studies conducted by St. Jude and the European Organization for 
Research and Treatment of Cancer (EORTC) show that the prognostic significance 
of overt testicular disease at first diagnosis of ALL has declined on modern 
treatment protocols.23,24 The EORTC no longer irradiates any of these patients.24 
The Dutch Childhood Oncology Group has shown that it is possible to effectively 
treat patients with isolated testicular relapse without radiation.25,26 The COG has 
been steadily decreasing the percentage of newly diagnosed and relapsed patients 
with testicular leukemia that receive testicular irradiation due to the intensified 
chemotherapeutic regimens and the associated long-term morbidity of testicular 
irradiation. The findings described above, along with those that show testicular 
relapses have decreased as chemotherapy regimens for newly diagnosed ALL have 
intensified, patients with testicular relapse often have detectable disease in the 
bone marrow, and patients with initial testicular disease usually relapse in the bone 
marrow, suggest that cure of patients with testicular leukemia is a systemic control 
problem, not a local control problem. Much of the decrease in testicular relapse 
has been attributed to intermediate and high-dose MTX.27-29 Patients will receive 
intermediate-dose MTX in Blocks 2 and 3 of AALL1331. Since the ALLR3 
protocol has shown superior outcomes to previous relapsed leukemia therapies, we 
believe the improved chemotherapy backbone on this protocol will allow the 
elimination of testicular irradiation (beyond that which may be used in the HSCT 
preparative regimen) for those patients that have a complete response of testicular 
leukemia by end Block 1. 
 

 
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2.2.8 
Treatment Failure (TF) 
Recent COG early marrow relapse ALL studies have defined TF as not achieving 
M1 marrow by Day 15 of Block 2. In both ALLR3 and in this study, the order of 
Block 2 chemotherapy differs from that of prior COG studies and non-cross-
resistant therapy is not given until Day 15; thus in this study, TF is assessed at the 
Blocks 1 and 2. 
 
Patients failing to achieve pre-defined response criteria at end-Block 1, 
end – Block 2/Blinatumomab Cycle 1 (Table 6) will be categorized as having TF 
(an event). Such patients will be eligible to receive up to 2 blocks of blinatumomab 
if they had not previously received it on study and do not have residual CNS 
disease, and will be eligible to continue on study to HSCT if they achieve a CR. 
Otherwise they will be removed from protocol therapy. Patients who achieve 
remission at end of Block 1 or Block 2 but are no longer in remission on a 
subsequent evaluation will be removed from protocol therapy for relapse and will 
not be eligible to receive blinatumomab. TF is assessed at the end of Blocks 1 
and 2. 
 
Table 6: Response criteria required to continue on study 
 
Marrow 
CNS 
Testicular 
End-Block 1  
(All patients) 
M2 or 
better 
Remission 
(clearance of CSF 
blasts) 
None; patients with 
persistent testicular 
disease will receive 
testicular radiation in 
Block 2 (LR and HR/IR 
randomized to the 
control arm) or during 
Blinatumomab Block: 
Cycle 1 (HR/IR 
randomized to the 
experimental arm) 
End-Block 2 or End 
Blinatumomab Block: 
Cycle 1(HR/IR only) 
M1 
Continued remission 
Remission (clearance of 
testicular disease) 
 
2.2.9 
Additional non-randomized Pilot Intervention for Very High Risk Subset of HSCT 
Recipients based on MRD and aGVHD 
Relapse rates for patients with relapsed B-ALL who are MRD+ immediately prior 
to HSCT or are MRD+ in the first 100 days post HSCT are exceedingly high, 
particularly if there is no aGVHD.30-33 Table 7 below shows the relative risk of 
relapse in the recently closed COG ASCT0431 trial according to MRD (using 
0.01% as a threshold) and aGVHD status by Day +55.33 
 
Table 7 Relapse risk on ASCT0431 per MRD and aGVHD status 
Factor  
RR (95% CI)  
Pre-MRD+ vs Pre-MRD-  
1.9 (0.9-4.1)  
aGVHD Yes vs No  
0.29 (0.12-0.72)  
Any post-MRD+  
2.8 (1.2-6.5)  
 

 
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Patients who were MRD+ pre-HSCT who did not develop acute GVHD and patients 
with any MRD+ detected after HSCT had a relapse rate of 83%. Given this 
unacceptably high relapse rate, including a post-HSCT immunological intervention 
for such patients could potentially address this high relapse rate, and should help 
standardize post-HSCT interventions and decrease dropout of MRD+ patients prior 
to HSCT. While the optimal immunological intervention is not known, AALL1331 
will include a relatively simple intervention (accelerated taper of immune 
suppression as detailed in Section 4.9) that is designed to gather additional data to 
set the stage for more definitive interventions in future trials (e.g. post-HSCT 
blinatumomab, moxetumomab or other immunotherapy). Trials both in Europe and 
the US have shown that patients defined as high risk for relapse based upon 
increasing recipient chimerism (i.e., increased percentage of recipient DNA 
markers) can successfully undergo withdrawal of immune suppression (IS) without 
excessive toxicity, and their survival is improved. Out of 46 patients with increasing 
recipient chimerism (a group at very high risk for relapse), Bader et al intervened 
in 31 patients with immune suppression (IS) withdrawal, donor lymphocyte 
infusions (DLI), or both. Three-year EFS was 37% vs. 0% in the intervention vs. 
non-intervention groups (p < 0.001).34 Of the 31 patients, 11 received IS withdrawal 
alone; 2 relapsed and 1 died of TRM with 8/11 surviving. Three, 2, and 2 patients 
developed Grades 1, 2, and 3 aGHVD respectively, with no Grade IV or chronic 
GVHD. A smaller portion of patients responded to DLI (4/17) or a combination of 
both (1/3). Follow up publications by the Bader group and American groups have 
shown that patients defined at high risk for relapse by chimerism can safely undergo 
immune withdrawal with a survival benefit to the patient.35,36 It is reasonable, 
therefore, to hypothesize that IS withdrawal may provide benefit, and it is necessary 
to do this in a standardized manner in the context of this trial. In addition, 
understanding the proportion of high risk patients who can successfully discontinue 
IS vital to future trial planning, as many interventions to prevent relapse under 
consideration require patients to be on no or minimal IS. 
 
2.2.10 Rationale for closure of the HR/IR Randomization (Amendment #10) 
The DSMC decision was made in the interest of current and future patients despite 
the monitoring rule for DFS in the AALL1331 protocol not being crossed. The 
DSMC decision was made based on following four key points: 
• 
The profound difference in toxicity between Arm A chemotherapy and 
blinatumomab as given on Arm B. 
• 
The DFS and OS results favoring Arm B (blinatumomab) that make it highly 
likely that Arm B (blinatumomab) has an impact on DFS and OS that is as 
good as or better than that achieved with the chemotherapy of Arm A. 
• 
The highly significant difference in MRD levels favoring Arm B 
(blinatumomab) over the chemotherapy of Arm A that support high level 
anti-leukemia activity for blinatumomab as given on Arm B. 
• 
The comparison of DFS and OS for Arm A and B of the original AALL1331 
protocol can still be made with longer follow-up. The original comparison 
was based on 170 patients. As a result of an amendment to the protocol in 
2018, accrual was extended to a target enrollment of 220 patients. The 
number of patients randomized as of the June 30, 2019 report was 208.  
 
 

 
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3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
Note: This study is not on the CTSU Menu (i.e. it is not posted to the CTSU web site) but 
is supported by the CTSU Regulatory Office, OPEN and Rave. 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix XIII for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 

 
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For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements 
(i.e., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 

 
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Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
See Section 3.1.6 below for details regarding randomization and treatment 
assignment for patients. 
 
3.1.4 
Timing 
Informed consent: Except for administration of intrathecal chemotherapy 
(methotrexate strongly preferred) administered at the time of the required 
diagnostic lumbar puncture to establish baseline CNS status, informed 
consent/parental permission MUST be signed before protocol therapy begins. See 
Section 3.1.5 for summary of time points to obtain informed consent.  
 
Study enrollment: Study enrollment must take place no later than five (5) calendar 
days after beginning protocol therapy. If study enrollment takes place before 
starting protocol therapy, the date that protocol therapy is projected to start must 
be no later than five (5) calendar days after enrollment.  
 
Eligibility studies: Patients must meet all eligibility criteria prior to the start of 
protocol therapy or enrollment, whichever occurs first. All clinical and laboratory 
studies to determine eligibility must be performed within 7 days prior to 
enrollment. 
 
3.1.5 
Staged Consent 
Informed consent will be obtained at critical stages of treatment for the different 
groups of patients on this study (see summary table below). Informed consent that 
describes Block 1 therapy (common to all patients on study) will be obtained before 
starting treatment, with the exception of intrathecal chemotherapy (methotrexate 
strongly preferred) administered at the time of the required diagnostic lumbar 
puncture to establish baseline CNS status. At the end of Block 1 therapy, after risk 
groups have been assigned, subsequent informed consent that describes further 
therapy will be obtained at the various time points detailed in Table 8 below. Also see 
Experimental Design Schema 
 
Effective September 18, 2019 the HR/IR randomization closed. Patients who meet 
criteria for HR/IR randomization should not be approached for post-Induction 
therapy on AALL1331 and will be removed from protocol therapy at the 
completion of Block 1. 
 
 
 
 

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Table 8: Summary of required consents for AALL1331 
Consent Form 
Time point to Obtain Consent 
Population for 
Consent 
Consent 5 – Consent for collection 
of additional marrow 
Before study entry (prior to 
collection of bone marrow) 
All potential 
subjects 
Consent 1 – Re-induction (block 1) 
therapy for all subjects  
 
Study Entry (Prior to shipment 
of 
bone 
marrow 
sample, 
enrollment, and initiation of 
therapy) 
All subjects  
Consent 2: All High-Risk and 
Intermediate-Risk patients eligible 
to take part in HR/IR  
randomization  
Closed effective 09/18/2019 
 
Evaluation 1 (prior to HR/IR 
randomization) 
HR/IR subjects 
Consent 3: All low-risk patients 
eligible to take part in LR 
randomization  
Evaluation 1 (prior to start of LR 
randomization) 
LR subjects 
Consent 4: Patients who did not 
respond to therapy after Block 1 (all 
patients) or Block 2 (HR/IR Patients 
on Treatment Arm A) 
Prior to start of Salvage 
Therapy (Blinatumomab-S): 
⚫End Block 1  
⚫End Block 2 
Treatment Failures 
(TF) 
 
 
3.1.6 
Risk Assignment, Randomization, and Treatment Assignment 
• 
Evaluation 1 (detailed in Section 4.2.7). 

 
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Evaluation 1 must occur no earlier than Day 29 (± 1 day); the evaluation may be 
delayed until no later than Day 36 (± 1 day) if ANC < 500 and/or 
platelets < 50,000 on Day 29. 
 
Completion of risk group/stratum assignment must occur within 5 calendar days 
of Evaluation 1. 
o Step 1: site enters results of local morphologic assessment 
(marrow/CSF/testes) using Block 1 RP form (form may be saved while 
incomplete) 
o Step 2: central lab enters marrow flow MRD result using Block 1 MRD form 
o Step 3: Study chair confirms risk group/stratum assignment using SC 
Risk Assignment form (using criteria outlined in Section 3.3) 
 
Submission of end-Block 1 callback form must occur within 5 calendar days of 
risk group/stratum assignment. 
 
Components of callback 
1) Risk group/stratum 
2) Confirmation that patient does not have severe residual toxicities 
3) Confirmation that consent has been signed 
 
Upon submission, site receives treatment assignment: Consenting LR patients 
will be randomized according to LR Randomization; HR/IR patients are not 
eligible for post-Induction treatment on AALL1331 and are removed from 
protocol therapy following completion of Block 1; patients deemed Treatment 
Failure at Evaluation 1 who are eligible for and consent to Salvage Therapy will 
be assigned to Salvage Therapy. 
 
NOTE: Patients with residual non-heme toxicities that are likely to prevent 
beginning post-Block 1 treatment within required time frames should NOT 
submit the End-Block 1 callback. 
 
3.1.7 
Callbacks 
Callback is performed using the Oncology Patient Enrollment Network (OPEN). 
Callback 
Timing 
Population for 
Callback 
Purpose 
End Block 1 
Callback 
(ALL 
patients 
continuing to 
post-Block 1 
therapy) 
Evaluation 1* 
Consenting LR 
patients not off 
protocol therapy 
after completion of 
Block 1 therapy. 
 
 
Treatment Failure 
patients who are 
eligible for and 
consent to Salvage 
Therapy  
Randomize LR patients to 
either of 2 treatment 
arms:  
Arm C (Control Arm) or  
Arm D (Experimental 
Arm). 
 
Assign patients to 
Salvage Therapy 
(Blinatumomab-S) 
*See Section 3.1.6 for timing details 

 
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3.1.8 
Drug Preparation and Administration 
Blinatumomab must be prepared in an ISO Class 5 containment device, ideally in an 
ISO Class 7 room as described in USP <797>, but ISO Class 7 is not required. US 
sites must attest that their drug preparation and administration guidelines comply with 
the USP 797. Documentation of participating site training with regard to the 
preparation and administration of blinatumomab must be submitted via RSS as 
protocol specific requirement at the time of site activation for participation on the 
trial. 
 
3.1.9 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study. To 
allow non-English speaking patients to participate in the study, bilingual health care 
services will be provided in the appropriate language. 
 
 
  
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the 
time of audit. 
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, if applicable, must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
3.2.1 
Age 
Patients ≥1 year and < 31 years of age at the time of relapse will be eligible. 
 
3.2.2 
Diagnosis 
First relapse of B-ALL, allowable sites of disease include isolated bone marrow, 
combined bone marrow and CNS and/or testicular, and isolated CNS and/or 
testicular.  
 

 
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Extramedullary sites are limited to the CNS and testicles. Please refer to Section 3.3 
for definitions of relapse and criteria for risk classification. 
 
3.2.3 
Prior Therapy 
Please see Section 4.1.2 for the concomitant therapy restrictions for patients during 
treatment.  
 
3.2.3.1 
No waiting period for patients who relapse while receiving standard 
Maintenance therapy 
 
3.2.3.2 
Patients who relapse on frontline therapy in phases other than 
Maintenance must have fully recovered from the acute toxic effects of 
all prior chemotherapy, immunotherapy, or radiotherapy prior to 
entering this study. 
 
3.2.3.3 
Cytotoxic therapy: At least 14 days since the completion of cytotoxic 
therapy with the exception of hydroxyurea, which is permitted up to 
24 hours prior to the start of protocol therapy, or Maintenance 
chemotherapy (see Section 3.2.3.1), or intrathecal chemotherapy 
(methotrexate strongly preferred) administered at the time of the required 
diagnostic lumbar puncture to establish baseline CNS status. 
 
3.2.3.4 
Biologic (anti-neoplastic) agent: At least 7 days since the completion of 
therapy with a biologic agent. For agents that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur. 
 
3.2.3.5 
Stem cell transplant or rescue: Patient has not had a prior stem cell 
transplant or rescue. 
 
3.2.3.6 
Patient has not had prior treatment with blinatumomab. 
 
3.2.3.7 
With the exception of intrathecal chemotherapy (methotrexate strongly 
preferred; cytarabine is permissible) administered at the time of the 
required diagnostic lumbar puncture to establish baseline CNS status, 
patient has not received prior relapse-directed therapy (i.e., this protocol 
is intended as the INITIAL treatment of first relapse). 
 
3.2.4 
Performance Status 
Patients must have a performance status corresponding to ECOG scores of 0, 1, 
or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 
years of age. Please refer to performance status scale at: 
https://members.childrensoncologygroup.org/_files/protocol/Standard/Performan
ceStatusScalesScoring.pdf 
 
3.2.5 
Organ Function Requirements 
3.2.5.1 
Adequate Renal Function Defined As: 

 
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- Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR utilizing child length and stature data published 
by the CDC.37 
 
3.2.5.2 
Adequate liver function defined as a direct bilirubin < 3.0 mg/dL. 
 
3.2.5.3 
Adequate Cardiac Function Defined As: 
- Shortening fraction of  27% by echocardiogram, or 
- Ejection fraction of  50% by radionuclide angiogram.  
 
3.2.6 
Exclusion Criteria 
 
3.2.6.1 
Patients with Philadelphia chromosome positive/BCR-ABL1+ ALL are 
not eligible 
 
3.2.6.2 
Patients with Burkitt Leukemia/Lymphoma or mature B-cell leukemia 
are not eligible 
 
3.2.6.3 
Patients with T-Lymphoblastic Leukemia (T-ALL)/Lymphoblastic 
Lymphoma (T- LL) are not eligible 
 
3.2.6.4 
Patients with B-Lymphoblastic Lymphoma (B-LL) are not eligible 
 
3.2.6.5 
Patients with known optic nerve and/or retinal involvement are not 
eligible. Patients who are presenting with visual disturbances should 
have an ophthalmologic exam and, if indicated, an MRI to determine 
optic nerve or retinal involvement. 
 
3.2.6.6 
Patients known to have one of the following concomitant genetic 
syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, 
Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any 
other known bone marrow failure syndrome. 
 
3.2.6.7 
Patients with known HIV infection. 
 
3.2.6.8 
Patients with known allergy to mitoxantrone, cytarabine, or both 
etoposide and etoposide phosphate (Etopophos). 
 

 
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3.2.6.9 
Lactating females who plan to breastfeed. 
 
3.2.6.10 Patients who are pregnant since fetal toxicities and teratogenic effects 
have been noted for several of the study drugs. A pregnancy test is 
required for female patients of childbearing potential. 
 
3.2.6.11 Sexually active patients of reproductive potential who have not agreed 
to use an effective contraceptive method for the duration of their study 
participation. 
 
3.2.6.12  
a) Patients with pre-existing significant central nervous system 
pathology that would preclude treatment with blinatumomab, 
including: history of severe brain injury, dementia, cerebellar 
disease, 
organic 
brain 
syndrome, 
psychosis, 
coordination 
/movement disorder, or autoimmune disease with CNS involvement 
are not eligible. Patients with a history of cerebrovascular 
ischemia/hemorrhage with residual deficits are not eligible.  
(Patients with a history of cerebrovascular ischemia/hemorrhage 
remain eligible provided all neurologic deficits have resolved)  
 
b) Patients with uncontrolled seizure disorder are not eligible.  
(Patients with seizure disorders that do not require antiepileptic 
drugs, or are well controlled with stable doses of antiepileptic drugs 
remain eligible.) 
 
3.2.7 
Regulatory Requirements  
 
3.2.7.1 
All patients and/or their parent or legal guardian must sign a written 
informed consent. 
 
3.2.7.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
3.3 
Definitions 
Acute Lymphoblastic Leukemia (ALL) 
Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow). Patients with > 25% L3 
marrow lymphoblasts and/or evidence of c-myc translocation are considered to have 
Burkitt or mature B-cell leukemia and are ineligible for this study. 
 
Definitions of Relapse  
• 
RELAPSE: Any recurrence of disease whether in marrow or extramedullary. For the 
purposes of eligibility for this trial, extramedullary sites are limited to the CNS and 
testicles. Relapse should be confirmed by pathology examination of appropriate 
tissue. 
 
• 
ISOLATED BONE MARROW RELAPSE: Patients with an M3 marrow at any point 
after achieving remission without involvement of the CNS and/or testicles. Every effort 

 
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should be made to confirm morphologic relapse using flow cytometry, FISH and/or 
cytogenetics. 
 
• 
CNS RELAPSE: Positive cytomorphology and WBC ≥ 5/µL OR clinical signs of CNS 
leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome 
that are, in the opinion of the investigator, more likely due to recurrent CNS leukemia 
than to alternative causes (e.g., viral infection or chemotherapy toxicity). If any CSF 
evaluation shows positive cytomorphology and WBC < 5/µL, a second CSF evaluation is 
recommended within 2 - 4 weeks. While identification of a leukemic clone in CSF by 
flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic karyotypic abnormality 
may be useful, definitive evidence of CNS involvement (i.e. WBC ≥ 5/µL OR clinical 
signs of CNS leukemia) is required for the diagnosis of a CNS relapse. Note that 
AALL1331 excludes patients with known optic nerve and/or retinal involvement 
(Section 3.2.6.5). 
 
• 
TESTICULAR RELAPSE: Must be documented by testicular biopsy, if not associated 
with a marrow relapse. 
 
• 
ISOLATED EXTRAMEDULLARY (IEM) RELAPSE: CNS and/or testicular relapse 
with an M1 marrow. The presence of MRD in the bone marrow does NOT exclude 
IEM. 
 
• 
COMBINED RELAPSE: M2 or M3 marrow at any point after achieving remission 
with concomitant CNS and/or testicular relapse.  
 
CNS Status: 
NOTE: in this protocol “CNS-positive” means meeting the criteria for CNS Relapse 
(whether isolated CNS or combined relapse) at the time of AALL1331 study entry as listed 
in the Definitions of Relapse above. CNS 2 status first noted at the time of enrollment for 
concurrent relapse at another site (i.e. bone marrow) will not be considered ‘CNS-positive’. 
 
CNS 1: 
In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of white blood cells (WBCs). 
 
CNS 2: 
In CSF, presence < 5/L WBCs and cytospin positive for blasts, or ≥ 5/L 
WBCs but negative by Steinherz/Bleyer algorithm: 
 
CNS 2a: 
< 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; 
CNS 2b: 
≥ 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; and 
CNS 2c: 
≥ 10/L RBCs; ≥ 5/L WBCs and cytospin positive for blasts but negative 
by Steinherz/Bleyer algorithm (see below). 
 
CNS3: 
In CSF, presence of ≥ 5/µL WBCs and cytospin positive for blasts and/or 
clinical signs of CNS leukemia: 
 
CNS 3a: 
< 10/L RBCs; ≥ 5/µL WBCs and cytospin positive for blasts; 
CNS 3b: 
≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer algorithm 
(see below);  
CNS 3c: 
Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome). 

 
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Method of Evaluating Initial Traumatic Lumbar Punctures: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains  5 WBC/L and blasts, the following algorithm should be used to 
distinguish between CNS 2 and CNS 3 disease: 
 
CSF WBC   > 2X   Blood WBC 
CSF RBC               Blood RBC 
 
A patient with CSF WBC  5/L blasts, whose CSF WBC/RBC is 2X greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis. Example: CSF WBC = 60/L; CSF RBC = 
1500/L; blood WBC = 46000/L; blood RBC = 3.0 X 106/L: 
 
  60    = 0.04  >  2X     46,000      = 0.015 
1,500                          3.0 X 106 
 
Bone Marrow Status: 
M1 Marrow: < 5% blasts in a bone marrow aspirate with at least 200 cells counted. 
 
M2 Marrow: 5% - 25% blasts in a bone marrow aspirate with at least 200 cells counted. 
 
M3 Marrow: > 25% blasts in a bone marrow aspirate with at least 200 cells counted. 
 
For initial remission an M1 marrow must be achieved. 
 
Treatment Failure: Failure to achieve the following: 
 
Marrow 
CNS 
Testicular 
End-Block 1  
(All patients) 
M2 or 
better 
Remission  
(clearance of CSF 
blasts, i.e. CNS1) 
None; patients with persistent 
testicular disease will receive 
testicular radiation in Block 2 (LR and 
HR/IR randomized to the control arm) 
or during Blinatumomab Block: Cycle 
1 (HR/IR randomized to the 
experimental arm) 
End-Block 2, or  
End Blinatumomab 
Block, Cycle 1 
(HR/IR only) 
M1 
Continued 
remission 
Remission (clearance of testicular 
disease) 
NOTE: Patients who achieve remission (M1 marrow and clearance of extramedullary 
disease) at end-Block 1 or Block 2 but are no longer in remission on a subsequent 
evaluation will be removed from protocol therapy for relapse. 
 
 
 
Risk Assessment-End Block 1*: 
Low Risk 
• 
Late marrow (≥ 36 months), end-Block 1 MRD < 0.1%  
• 
Late (≥ 18 months) Isolated Extramedullary (IEM), end-Block 1 MRD < 0.1% (or 
indeterminate MRD) 

 
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Intermediate Risk 
• 
Late (≥ 36 months) marrow, end-Block 1 MRD ≥ 0.1% 
• 
Late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1% 
 
High Risk 
• 
Early (< 36 months) marrow 
• 
Early (< 18 months) IEM 
 
* 
The timing of relapse (duration of first remission) is measured from the date of initial 
diagnosis to the date of relapse. 
 
Complete Remission 
Complete remission (CR) is defined as an M1 marrow (< 5% blasts) with no evidence of 
circulating blasts or extramedullary disease and with peripheral count recovery, defined as 
absolute neutrophil count higher than or equal to 500/µL and platelet count higher than or 
equal to 50,000/µL. 
 
 
 

 
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4.0 
TREATMENT PLAN 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
All eligible patients with first relapse B-ALL who are enrolled on AALL1331 will receive 
standard chemotherapy during Block 1. All patients will then be risk assessed at the end of 
Block 1 as either HR, IR, LR or TF. Risk assessment is based on site of relapse, time to 
relapse, end Block 1 bone marrow morphology and MRD levels. Effective September 18, 
2019, HR and IR patients are no longer eligible for post-Induction therapy on AALL1331 
due to closure of the HR/IR randomization and will be removed from protocol therapy 
following completion of Block 1. LR patients will be eligible to participate in LR 
Randomization. See summary table below. Treatment failures are those patients whose 
disease status fails to meet pre-defined response criteria at end-Block 1 or end-Block 2. 
These patients are eligible to receive up to 2 blocks of blinatumomab if they have not 
previously received it on study and have no evidence of persistent CNS disease. These 
patients will also be eligible to continue on to HSCT if they achieve a CR. Otherwise, they 
will be removed from protocol therapy. See Section 3.3 for response definitions of TF CR. 
 
Risk Stratification at end Block 1 
Risk Group 
Definition 
Randomization 
Eligibility 
Treatment Arms 
High 
• Early (< 36 months) marrow 
• Early (< 18 months) IEM 
HR/IR  
Closed 09/18/2019 
• Arm A (Control) 
• Arm B (Experimental) 
Intermediate 
• Late (≥ 36 months) marrow, 
end-Block 1 MRD ≥ 0.1% 
• Late (≥ 18 months) IEM, 
end-Block 1 MRD ≥ 0.1% 
HR/IR  
Closed 09/18/2019 
• Arm A (Control)  
• Arm B (Experimental) 
Low 
• Late (≥ 36 months) marrow, 
end-Block 1 MRD < 0.1% 
• Late (≥ 18 months) IEM, 
End-Block 1 MRD < 0.1% 
LR 
• Arm C (Control) 
• Arm D (Experimental) 
Treatment 
Failure at 
end Block 1 
Failure to achieve the 
following: 
• 
M2 or better 
• 
CNS remission 
(clearance of CSF 
blasts, i.e. CNS1) 
None (treatment 
assignment) 
• Salvage therapy 
(Blinatumomab-S) 
 
CNS Leukemia 
All patients with CNS3 involvement at the time of relapse will receive intrathecal triples 
(ITT) instead of IT MTX beginning on Day 8. During Block 1 these patients will receive 
two additional ITT doses (Days 15 and 22) and during Block 2 they will receive one 
additional ITT dose (Day 22). For LR patients with CNS3 involvement, AALL1331 will 

 
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further intensify CNS-directed therapy by replacing lower dose oral MTX (25 mg/m2 every 
6 hours x 4 doses) with intermediate dose IV MTX (1 g/m2 over 24 hours) during the each 
of the 2 continuation phases. All of these patients will then receive 1800 cGy cranial 
radiation and concurrent chemotherapy (including high dose dexamethasone) between and 
the first and second 12 week blocks of Maintenance. IR and HR patients will proceed to 
TBI-based HSCT and these patients will also receive a protocol-specified cranial radiation 
boost as part of their HSCT preparative regimen. 
 
Testicular Leukemia 
Patients with suspected isolated testicular relapse or equivocal testicular enlargement with 
concurrent bone marrow/CNS relapse must have a testicular biopsy performed at baseline. 
Patients with persistent or equivocal testicular enlargement at the end of Block 1 must have 
a testicular biopsy. Patients with persistent testicular leukemia at the end of Block 1 are 
eligible to continue on study and will receive 2400 cGy of testicular radiation during either 
Block 2 chemotherapy (for LR patients and HR/IR patients randomized to the control arm) 
or during blinatumomab (for HR/IR patients randomized to the experimental arm and TF.) 
Patients with extramedullary testicular leukemia that has resolved by end Block 1 will NOT 
receive testicular irradiation, with the exception of that which may be used in the HSCT 
preparative regimen for HR/IR patients. 
 
HSCT 
All patients enrolled on this protocol, their parents and full siblings should undergo 
HLA tissue typing as soon as possible after diagnosis of relapse, and should have 
transplantation consultation and initiation of a donor search. For HR/IR patients, 
and for TF patients who achieve CR with Salvage Therapy (Blinatumomab-S), the 
goal of this protocol is to move to transplant within 2 weeks of recovery from the last 
block/cycle of therapy prior to transplant. Because unrelated donor acquisition can 
take 8 - 12 weeks, centers must expedite the donor search process to meet this 
deadline. 
 
Patient Pill Diary 
It is recommended that patients use a Patient Pill Diary to keep track of oral medications. 
 
4.1.1 
TREATMENT ASSIGNMENTS 
IMPORTANT NOTE: 
In order to continue to receive protocol therapy, patients will need to begin 
post-Block 1 therapy within a specified time frame (see Section 4.2.7). If a 
patient has residual severe non-hematologic toxicities from Block 1 that are 
likely to preclude beginning post-Block 1 therapy within this time frame, 
please DO NOT complete end-Block 1 Callback for the patient. This is 
important to minimize the number of patients who are randomized/assigned 
but are unable to receive post-callback treatment. 
 
4.1.1.1 HR/IR Randomization 
Effective 09/18/2019, HR/IR patients are not eligible for post-Induction 
therapy on AALL1331 and will be removed from protocol therapy. 
Patients receiving therapy on Arm A prior to Amendment #10 who have 
not yet received Day 22 treatment on Block 3 will be offered the 
opportunity to cross over to Arm B to receive blinatumomab.  
 

 
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• 
Arm A (Control Arm): Patients receive Block 2 and Block 3 of standard 
therapy followed by HSCT. Closed effective September 18, 2019. 
 
• 
Arm B (Experimental Arm): Patients receive two 5 week blocks of 
Blinatumomab, followed by HSCT. 
 
4.1.1.2 LR Randomization 
Following submission of the end-Block 1 callback form LR patients will 
be randomized to receive treatment on either of 2 treatment arms (see 
Experimental Design Schema and Section 3.1.6): 
 
• 
Arm C (Control): Patients receive Block 2 and Block 3 of standard 
therapy followed by Continuation 1, Continuation 2, and 
Maintenance. 
 
• 
Arm D (Experimental): Patients receive Block 2 of standard therapy 
followed by a 5 week Blinatumomab Block, Continuation 1, a 5 week 
Blinatumomab Block, Continuation 2, a 5 week Blinatumomab Block, 
and Maintenance. 
 
4.1.1.3 Salvage Therapy (Blinatumomab-S) 
Following submission of the end-Block 1 or End-Block 2 callback form, 
eligible Treatment Failure patients will be assigned to Salvage Therapy 
(see Experimental Design Schema and Section 3.1.6).  
 
4.1.2 
Concomitant Therapy Restrictions 
 
4.1.2.1 Cytochrome P450 Interactions with Antileukemic Drugs. 
Since concurrent use of enzyme inducing anticonvulsants (e.g., phenytoin, 
phenobarbital, and carbamazepine) with anti-leukemic therapy has 
recently been associated with inferior EFS, every effort should be made to 
avoid these agents, as well as rifampin, which also induces many drug 
metabolizing enzymes.38 Neither gabapentin nor levetiracetam induce 
hepatic drug metabolizing enzymes and may be suitable alternative 
anticonvulsants. Azole antifungals (listed in the table below) and the 
macrolide group of antibiotics (listed in the table below) may have potent 
inhibitory effects on drug-metabolizing enzymes. Patients receiving some 
anti-leukemic drugs (e.g., vincristine, anthracyclines, etoposide) may 
experience excess toxicity when these agents are given concomitantly; 
alternate antifungal and antibacterial therapy should be used where 
possible (see table below). 
 
DRUGS 
POTENTIAL 
INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug 
metabolizing enzymes 
Lowered EFS 
AVOID phenytoin, 
phenobarbital, carbamazepine 
Consider gabapentin or 
levetiracetam as alternative 
Rifampin 
Induction of drug 
metabolizing enzymes  
DO NOT USE 

 
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Azole Antifungals 
(fluconazole, 
itraconazole*, 
posaconazole 
voriconazole, 
ketoconazole) 
Inhibition of drug 
metabolizing enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
May need dose reductions of 
vincristine*, anthracyclines, 
etoposide, steroids 
Macrolide Antibiotics 
(erythromycin, 
clarithromycin, 
azithromycin, 
roxithromycin, 
telithromycin) 
Inhibition of drug 
metabolizing enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
May need dose reductions of 
vincristine, anthracyclines, 
etoposide, steroids 
* 
Itraconazole should NOT be used in patients who are receiving vincristine 
due to a serious drug-drug interaction leading to severe neurotoxicity.39,40  
 
This is not an inclusive list. Because the lists of these agents are constantly 
changing, it is important to regularly consult frequently updated medical 
references. 
 
4.1.2.2 Possible Drug Interactions with Intermediate Dose Methotrexate: 
Avoid 
non-steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
trimethoprim/sulfamethoxazole (TMP/SMX), penicillins, probenecid, IV 
contrast media, proton pump inhibitors, phenytoin and fosphenytoin. 
Urinary acidifiers can cause methotrexate to precipitate in the urinary tract. 
 
For COG Supportive Care Guidelines see 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.p
df 
 
4.1.3 
Supportive Care for Patients 15 Years and Older 
It is recommended that adolescent and young adult (AYA) patients enrolled on this 
protocol (defined as patients between the ages of 15 and 31 years) be monitored in 
the hospital during Block 1, Block 2 and Block 3 of chemotherapy until they show 
signs of bone marrow recovery (specifically until they show evidence that the 
absolute neutrophil count (ANC) is rising for 2 successive days) and the patient is 
afebrile and clinically stable. If a patient should experience profound 
myelosuppression at any other time, there should also be a very low threshold to 
hospitalize AYA patients, and to continue inpatient management until there is 
evidence of bone marrow recovery. Antibiotic prophylaxis against Gram-positive 
and Gram-negative organisms (e.g. levofloxacin) may be considered during these 
hospitalizations until patients meet the criteria for discharge. If the patient should 
develop febrile neutropenia while on antibiotic prophylaxis, the patient should be 
started 
on 
broad-spectrum 
intravenous 
antibiotics 
per 
institutional 
guidelines. Antifungal prophylaxis may also be considered during periods of 
myelosuppression. Options include an echinocandin such as caspofungin or 
micafungin, or an azole. Azole antifungal agents (i.e., fluconazole, itraconazole, 
posaconazol, voriconazole) given concurrently with vincristine may increase 
the risk of neurotoxicity. Investigator caution is advised if azole antifungals 
are used. If antibiotic and/or antifungal prophylaxis is utilized, consultation with 
Infectious Disease may be considered. 
 

 
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4.2 
Block 1 (All patients) - 4 Weeks Duration 
Block 1 therapy is common to all patients on study. See Experimental Design Schema. 
The therapy delivery map (TDM) for Block 1 is in APPENDIX II-A. 
 
NOTE: The risks of significant morbidity and mortality, including sudden death in 
patients with relapsed leukemia, are sufficient to strongly recommend hospitalization 
during remission Induction, until patients show consistent neutrophil recovery and 
transfusion needs that are deemed to be manageable in the outpatient setting. Please see 
Appendix I for additional details. 
 
4.2.1 
Disease Evaluation Pre-Treatment 
See Section 7.0, Evaluations/Material and Data to be Accessioned 
 
4.2.2 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 
4.2.3 
Block 1 Chemotherapy 
Dexamethasone: PO (may be given IV) 
Days: 1 - 5, 15 - 19 
Dose: 10 mg/m²/dose (Total daily dose: 20 mg/m²/day, divided BID; dose capped 
at 40 mg per day) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 8, 15, 22 
Dose: 1.5 mg/m²/dose (maximum dose: 2 mg) 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 

 
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Pegaspargase: IV over 1 - 2 hours 
Days: 3, 17 
Dose: 2,500 International Units/m²/dose 
Administer through the tubing of a rapidly infusing solution of D5W or 
0.9% NaCl 
 
Special precautions: 
1. Pegaspargase is contraindicated with a history of severe pancreatitis with any 
prior asparaginase therapy. Caution should be used if serious thrombosis or 
hemorrhagic events have occurred with any prior asparaginase therapy (see 
Section 5.1) 
2. Pegaspargase may affect coagulation factors and predispose to bleeding and/or 
thrombosis. Caution should be used when administering any concurrent 
anticoagulant therapy. 
3. Suggested monitoring during and after administration: Because pegaspargase 
is long acting, hypersensitivity reactions may not appear for hours after drug 
administration. Monitor vital signs, for signs of fever, chills, or acute allergic 
reactions including anaphylaxis. Have medications to treat hypersensitivity 
reactions readily available at each administration (e.g., epinephrine, IV 
corticosteroids, antihistamines). Consider prescribing an EpiPen® for home 
use. 
 
MitoXANTRONE: IV over 15 - 30 minutes, administered through the tubing of 
a rapidly infusing solution of D5W or 0.9% NaCl. 
Days: 1, 2 
Dose: 10 mg/m² 
 
Methotrexate: Intrathecal (IT) - ALL PATIENTS 
Days: 1 
 
Note: If intrathecal chemotherapy (methotrexate strongly preferred; 
cytarabine permissible) was given at the time of the diagnostic lumbar 
puncture, and if the treatment was given less than 7 days prior to the 
beginning of Day 1 systemic therapy, then the Day 1 IT treatment can be 
omitted at the discretion of the investigator. Otherwise, Day 1 intrathecal 
methotrexate must be given. 
 
Age-based dosing: 
Age (yrs) 
Dose (mg) 
1 - 1.99  
8 
2 - 2.99  
10 
3 - 8.99  
12 
≥ 9 
 
15 
 
Methotrexate: Intrathecal (IT) - CNS 1/2 PATIENTS ONLY 
Days: 8  
Note: For CNS2 patients continue weekly IT until 2 clear CSF samples 
(CNS1) are obtained. 
 

 
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Age-based dosing: 
Age (yrs) 
Dose (mg) 
1 - 1.99  
8 
2 - 2.99  
10 
3 - 8.99  
12 
≥ 9 
 
15 
 
Intrathecal Triple Therapy (ITT) - ANY PATIENT WITH CNS3 AT THE 
TIME OF RELAPSE 
Days 8, 15, and 22.  
 
Age-based dosing: 
Age (yrs) 
Dose (mg) 
1 - 1.99 
MTX: 8 
HC: 8 
ARAC: 16 
2 - 2.99 
MTX: 10 
HC: 10 
ARAC: 20 
3 - 8.99 
MTX: 12 
HC: 12 
ARAC: 24 
≥ 9 
MTX: 15 
HC: 15 
ARAC: 30 
 
4.2.4 
Disease Evaluation End Block 1 
• 
The end-Induction evaluation should occur no earlier than Day 29 (± 1 day).  
• 
The evaluation may be delayed no later than Day 36 (± 1 day) if 
ANC < 500/µL and platelets < 50,000/µL on Day 29. 
• 
The evaluation includes a bone marrow aspirate for all patients, a diagnostic 
lumbar puncture should be performed for CNS2 or CNS3 patients for whom 
clearance of CSF blasts has not yet been documented, and a testicular biopsy 
for patients with definite or equivocal residual testiculomegaly at end of Block 
1. 
• 
See Sections 7.1 and 13.0 for details on specimen acquisition, handling and 
shipping. 
 
4.2.5 
Research Studies Block 1 
See Section 7.2 for a full list of research studies. 
 
4.2.6 
HLA Tissue Typing for Hematopoietic Stem Cell Transplant 
All patients enrolled on this protocol, their parents and full siblings should undergo 
HLA tissue typing as soon as possible after diagnosis of relapse, and should have 
transplantation consultation and initiation of a donor search. The goal of this 
protocol is to initiate transplantation within 2 weeks of recovery from Block 3. 
Since unrelated donor acquisition can take 8 - 12 weeks, centers must expedite the 
search process to meet this timeframe. 
 
4.2.7 
Evaluation 1 (Risk Assessment following Block 1) 
Following completion of Block 1, patients will be risk assessed based on end-
Block 1 criteria outlined in Section 3.3, and according to procedures in 
Section 3.1.6, as HR, IR, LR, or TF.  
 
 

 
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IMPORTANT NOTE: 
In order to continue to receive protocol therapy, patients will need to begin 
post-Block 1 therapy within a specified time frame (see below). If a patient 
has residual severe non-hematologic toxicities from Block 1 that are likely to 
preclude beginning post-Block 1 therapy within this time frame, please DO 
NOT complete end-Block 1 Callback for the patient. This is important to 
minimize the number of patients who are randomized/assigned but are 
unable to receive post-callback treatment. 
 
Post-Block 1 treatment should begin after submission of end-Block 1 Callback and 
receipt of treatment assignment as soon as clinically acceptable to the treating 
institution. Patients should have time for full or partial recovery (judged by the 
treating institution) from any toxicities experienced in the prior course(s) of 
therapy before proceeding to the next course. However, treatment must begin 
according to time frames below for patients to continue to receive protocol therapy. 
 
HR B-ALL or IR B-ALL patients  
Effective 09/18/2019, HR/IR patients are not eligible for post-Induction therapy 
on AALL1331 and will be removed from protocol therapy.  
 
LR B-ALL Eligible for the LR Randomization 
• 
All LR B-ALL patients (Arm C and Arm D) will receive Block 2 therapy 
(Section 4.3, APPENDIX II-B) and should proceed with Day 1 vincristine and 
dexamethasone without awaiting count recovery (no later than 5 calendar days 
after callback). It is recommended, but not required, that proceeding with 
Day 8 IV methotrexate treatment await count recovery to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL. Day 8 treatment must begin no later than 14 calendar 
days after giving the Day 1 vincristine and dexamethasone to continue to 
receive protocol therapy. 
 
Treatment failures Post-Block 1 (see Section 3.3 for definition) have the option 
to receive up to two 5 week cycles of Blinatumomab (Sections 4.7, 4.8 and 
APPENDIX II-F, and II-G respectively) and continue on to HSCT after achieving 
CR. 
• 
TF patients with residual CNS disease (CNS2/3) regardless of marrow status 
should be removed from protocol therapy. 
• 
TF patients with M3 marrow disease and no residual CNS disease (CNS1) 
should proceed to Blinatumomab-S Cycle 1 without awaiting count recovery 
(no later than 5 calendar days after callback). 
 
NOTE: If residual non-hematologic toxicities prevent a patient from beginning 
post Block-1 treatment within the time frames noted above, then the patient should 
be removed from protocol therapy. 

 
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4.3 
Block 2 (LR Patients: Post-randomization) – 4 weeks duration 
Block 2 therapy is for all LR patients post LR randomization (Arm C and Arm D). See 
Experimental Design Schema. 
 
The Therapy Delivery Map (TDM) for Block 2 is in APPENDIX II-B. 
 
END-BLOCK 1 CALLBACK OCCURS PRIOR TO STARTING BLOCK 2 THERAPY. 
PLEASE SEE SUMMARY TABLE IN SECTION 3.1.5 FOR DETAILS ON STAGED 
CONSENT, AND APPROPRIATE TIMING TO OBTAIN INFORMED CONSENT. 
 
4.3.1 
Criteria to Begin Block 2 Therapy 
Block 2 should begin after submission of the appropriate end-Block 1 Callback 
and receipt of treatment assignment as soon as clinically acceptable to the treating 
institution. Patients should have time for full or partial recovery (judged by the 
treating institution) from any toxicities experienced in the prior course(s) of 
therapy before proceeding to the next course. To continue to receive protocol 
therapy, however, Block 2 must begin no later than 5 calendar days after callback. 
Count recovery is not required to proceed to Block 2. 
 
4.3.2 
Testicular Radiation Therapy (TRT) 
Patients with persistent testicular leukemia at the end of Block 1 are eligible to 
continue on study and will receive 2400 cGy of testicular radiation during either 
Block 2 chemotherapy (all LR patients) or during the first cycle of Blinatumomab 
(for HR/IR patients). 
 
• 
Patients with extramedullary testicular leukemia that has resolved by end 
Block 1 will NOT receive testicular irradiation with the exception of that 
which may be used in the HSCT preparative regimen.  
• 
See Section 14.2 for detailed testicular radiation guidelines 
 
4.3.3 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration Guidelines (CAGs) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 
 
 

 
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4.3.4 
Block 2 Chemotherapy  
Dexamethasone: PO (may be given IV) 
Days: 1-5 
Dose:  3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day: 
1 
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Intermediate Dose Methotrexate (ID MTX): IV over 36 hours 
Day: 
8 
Dose: 1,000 mg/m²/dose 
Given as a 100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over 
35.5 hours. 
 
Be certain that the ID MTX infusion is completed in the 36 hour period. Even if 
the infusion is not complete at this time point, it must be stopped. 
 
Leucovorin rescue: See below. 
 
Suggested hydration and alkalinization for IDMTX: Prehydrate with D5 ¼ NS 
with 30 mEq NaHCO3/L at 125 mL/m2/hour to achieve a urine specific gravity 
≤ 1.010 and pH between 7 and 8.  Ringers Lactate may be used as the initial fluid 
if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium 
bicarbonate to maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A 
bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH 
relatively quickly; a normal saline bolus may also be helpful in facilitating 
hydration. Continue hydration using D 5 ¼ NS with 30 mEq NaHCO3/L at 
125 mL/m2/hour throughout IDMTX infusion after its completion until the last 
dose of leucovorin has been given.  
 
Timing of ID MTX: 
• 
For patients beginning Block 2 with M1 marrow, it is recommended to await 
count recovery to an ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to 
beginning Day 8 IV methotrexate.  

 
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• 
Patients beginning Block 2 with M2 marrow should proceed without awaiting 
count recovery.  
 
Leucovorin: PO/IV 
Day: 
10, 11 
Dose: 15 mg/m2/dose every 6 hours beginning 48 hrs after the START of ID 
MTX infusion.  
 
• 
If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two 
doses of leucovorin (48 and 54 hours).  
• 
If MTX level at 48 hours is > 0.5 μM, then continue hydration and 
leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours until MTX 
levels are < 0.1 μM. 
 
See Section 5.8 for ID MTX/LCV rescue and infusion guidelines. 
 
Methotrexate: Intrathecal (IT) – CNS1/2 PATIENTS ONLY 
Day: 
8 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
When IT therapy and ID MTX are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Days: 8, 22 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
When ITT therapy and ID MTX are scheduled for the same day, deliver the ITT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Pegaspargase: IV over 1-2 hours  
Administer 4 hours after completion of Day 8 IV MTX. (Day 9 or 10) 
Dose: 2,500 International Units/m2/dose 
 

 
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Special precautions: 
1. Pegaspargase is contraindicated with a history of severe pancreatitis with any 
prior asparaginase therapy. Caution should be used if serious thrombosis or 
hemorrhagic events have occurred with any prior asparaginase therapy (see 
Section 5.1) 
2. Pegaspargase may affect coagulation factors and predispose to bleeding and/or 
thrombosis. Caution should be used when administering any concurrent 
anticoagulant therapy. 
3. Suggested monitoring during and after administration: Because pegaspargase 
is long acting, hypersensitivity reactions may not appear for hours after drug 
administration. Monitor vital signs, for signs of fever, chills, or acute allergic 
reactions including anaphylaxis. Have medications to treat hypersensitivity 
reactions readily available at each administration (e.g., epinephrine, IV 
corticosteroids, antihistamines). Consider prescribing an EpiPen® for home 
use. 
 
Cyclophosphamide: IV over 15-30 minutes (see note below) 
Days: 15-19 
Dose: 440 mg/m²/dose 
 
Etoposide: IV over 1-2 hours (see note below) 
Days: 15-19 
Dose: 100 mg/m²/dose 
 
NOTE: Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior 
to beginning Day 15 IV cyclophosphamide and etoposide. 
 
4.3.5 
Evaluation 2 (Disease Evaluation End Block 2) 
• 
Evaluation 2 should not be done earlier than Day 29 (± 1 day);  
• 
The evaluation may be delayed no later than Day 36 (± 1 day) if ANC 
< 500/µL and platelets < 50,000/µL on Day 29.  
• 
See Sections 7.1 and 13.0 for details on specimen acquisition, handling and 
shipping. 
 
4.3.6 
Following Completion of Block 2: 
 
 
For LR B-ALL patients post-Block 2:  
• 
Arm C, Block 3 (Section 4.4, APPENDIX II-C) starts when ANC ≥ 
500/µL and platelets ≥ 50,000/µL.  
• 
Arm D, therapy with Blinatumomab Block Cycle 1 (Section 4.15, 
APPENDIX II-M) starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL.  
 
 

 
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4.4 
Block 3 (LR Patients on Arm C) - 4 weeks 
Block 3 therapy is for LR patients randomized to the control arm (Arm C). See 
Experimental Design Schema. 
 
The Therapy Delivery Map (TDM) for Block 3 is in APPENDIX II-C. 
 
4.4.1 
Criteria to Begin Block 3 Therapy 
Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL 
 
4.4.2 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 
4.4.3 
Block 3 Chemotherapy 
Dexamethasone: PO (may be given IV) 
Days: 1-5 
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day: 1 
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
 
 

 
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Cytarabine: IV over 3 hours 
Days: 1, 2, 8, 9 
Dose: 3000 mg/m2/dose every 12 hours 
Administer steroid eye drops (0.1% dexamethasone or 1% prednisolone 
ophthalmic solution), 2 drops to each eye every 6 hours, beginning 
immediately before the first dose of cytarabine and continuing for 24 hours 
after the last dose. If patient does not tolerate steroid eye drops, may 
administer artificial tears on an every 2-4 hour schedule. 
 
Asparaginase (Erwinia): IM (may be given IV over 1 hour) 
Day: 2, 4, 9, 11, 23 
Dose: 25, 000 International Units/m2/dose 
 
• 
Asparaginase (Erwinia) should be given 4 hours after the completion of the 
last cytarabine infusion on Days 2 and 9.  
• 
Asparaginase (Erwinia) should be given 4 hours after the MTX infusion is 
complete on Day 23.  
• 
If Asparaginase (Erwinia) is not available, a single dose of Pegaspargase 
should be substituted 4 hours after the last cytarabine dose is complete on Day 
9, and no asparaginase is given on Day 23. 
 
Methotrexate: Intrathecal (IT)  
Day: 1  FOR ALL PATIENTS 
Day 22: CNS1/2 PATIENTS ONLY 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
When IT therapy and ID MTX are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
NOTE: Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior 
to beginning Day 22 IV Methotrexate and intrathecal chemotherapy. 
 
Triple Intrathecal Therapy (ITT) -  
CNS3 PATIENTS ONLY 
Day: 22 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 to < 1.99 
MTX: 8 mg 
HC: 8 mg 
ARAC: 16 mg 
2 to < 2.99 
MTX: 10 mg 
HC: 10 mg 
ARAC: 20 mg 
3 to < 8.99 
MTX: 12 mg 
HC: 12 mg 
ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg 
HC: 15 mg 
ARAC: 30 mg 
 

 
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When IT therapy and ID MTX are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Intermediate Dose Methotrexate: IV over 36 hours 
Day: 22 
Dose 1000 mg/m²/dose 
 
See Sections 4.3.4 and 5.8 for ID MTX/LCV rescue and infusion guidelines 
 
Leucovorin: PO/IV 
Days: 24, 25 
Dose: 15 mg/m2/dose beginning 48 hrs after the START of ID MTX infusion. 
 
• 
If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two doses of 
leucovorin (48 and 54 hours).  
• 
If MTX level at 48 hours is > 0.5 μM, then continue hydration and leucovorin 
rescue at 15 mg/m2/dose po/IV every 6 hours until MTX levels are < 0.1 μM. 
 
See Section 5.8 for ID MTX/LCV rescue and infusion guidelines. 
 
4.4.4 
Disease Evaluation End Block 3 (HR/IR Patients ONLY):  
• 
The End Block 3 disease evaluation should not be done earlier than Day 29 
(± 1 day);  
• 
The evaluation may be delayed no later than Day 36 (± 1 day) if ANC 
< 500/µL and platelets < 50,000/µL on Day 29.  
• 
See Sections 7.1 and 13.0 for details on specimen acquisition, handling and 
shipping. 
 
Notes regarding End Block 3 Disease Assessment:  
• 
BM assessment should be coordinated so that patients begin their preparative 
regimens no later than 2 weeks from BM documentation of M1.  
• 
If delays > 14 days are required for donor timing or other reasons, patients may 
receive up to 6 weeks of bridging maintenance therapy as described in 
Section 4.10.  
• 
For patients who receive bridging therapy, a repeat BM assessment is required 
to document remission and MRD status within 14 days of starting the HSCT 
preparative regimen.  
• 
Patients who are unable to begin the transplant preparative regimen within 
8 weeks of initial BM assessment are off protocol therapy. 
 
4.4.5 
Following completion of Block 3: 
 
For LR B-ALL patients:  
Arm C, Continuation 1 (Section 4.11, APPENDIX II-I) starts when ANC 
≥ 500/µL and platelets ≥ 50,000/µL.  
 
 

 
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4.5 
Blinatumomab Block: Cycle 1 (HR/IR Patients in Arm B) - 5 weeks  
With Amendment #10, HR/IR patients already assigned to Arm A (standard 
chemotherapy) who are at an appropriate point in their treatment program (prior to 
receiving Day 22 treatment on Block 3) will be offered the opportunity to cross over to 
Arm B to receive blinatumomab.    
 
The therapy described in this section is for the 1st cycle of therapy with Blinatumomab for 
HR/IR patients. See Experimental Design Schema.  
 
The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 1 (Arm B) is in 
APPENDIX II-D. 
 
NOTE: Hospitalization is STRONGLY recommended during the first 9 days of this cycle 
in case of a cytokine reaction. Manifestations of cytokine release syndrome include fever, 
headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased 
aspartate aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC). Corticosteroids should be administered for severe or life threatening 
cytokine release syndrome.  
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. Administration of 
the premedication (dexamethasone) described in Section 4.5.4, is recommended. If 
possible, the infusion time before and after a break should sum up to 28 days treatment per 
cycle. 
 
END BLOCK 1 CALLBACK OCCURS PRIOR TO STARTING BLINATUMOMAB 
BLOCK: CYCLE 1 THERAPY. PLEASE SEE SUMMARY TABLE IN SECTION 3.1.5 
FOR DETAILS ON STAGED CONSENT, AND APPROPRIATE TIMING TO OBTAIN 
INFORMED CONSENT. 
 
4.5.1 
Criteria to Begin Blinatumomab Block: Cycle 1 
Blinatumomab Cycle 1 should begin after submission of end- Block 1 Callback 
and receipt of treatment assignment and as soon as clinically acceptable to the 
treating institution. Patients should have time for full or partial recovery (judged 
by the treating institution) from any toxicities experienced in the prior course(s) of 
therapy before proceeding to the next course. 
 
For patients beginning Blinatumomab Cycle 1 with M1 marrow, it is 
recommended 
to 
await 
count 
recovery 
to 
ANC 
≥ 
500/µL 
and 
platelets ≥ 50,000/µL. To continue to receive protocol therapy, M1 patients must 
begin Blinatumomab Cycle 1 no later than 14 calendar days after callback. 
 

 
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For patients beginning Blinatumomab Cycle 1 with M2 marrow, it is 
recommended to proceed without awaiting count recovery. To continue to receive 
protocol therapy, M2 patients must begin Blinatumomab Cycle 1 no later than 
5 calendar days after Callback. 
 
4.5.2 
Testicular Radiation Therapy (TRT) 
• 
Patients with persistent testicular leukemia at the end of Block 1 are eligible 
to continue on study and will receive 2400 cGy of testicular radiation during 
the 1st cycle of Blinatumomab (for HR/IR patients).  
• 
Patients with extramedullary testicular leukemia that has resolved by end-
Block 1 will NOT receive testicular irradiation with the exception of that 
which may be used in the HSCT preparative regimen. 
• 
See Section 14.2 for detailed testicular radiation guidelines. 
 
4.5.3 
General Chemotherapy Guidelines 
See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral 
Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 
 
Dosing should be based on actual BSA. There is no maximum dosing 
 
4.5.4 
Blinatumomab Block: Cycle 1 Chemotherapy 
 
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1-28 
Dose: 15 micrograms/m²/day 
 
*IV bag will be changed every 24 - 96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
 
Dexamethasone: PO/IV 
Day: 
1 
Dose: Prior to day 1 therapy -  
• 
A single dose of 5 mg/m2/dose (maximum 20 mg/dose) will be 
administered 30 to 60 minutes prior to the start of the blinatumomab 
infusion and when restarting an infusion after an interruption of 4 or 
more hours in the first cycle.  
 

 
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If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY 
Day: 15, 29 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Days: 15, 29 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
4.5.5 
Disease Evaluation End-Blinatumomab Block: Cycle 1  
• 
The end block disease staging should be performed no earlier than Day 29 (± 1 
day);  
• 
The evaluation may be delayed to no later than Day 36 (± 1 day) if 
ANC < 500/µL and platelets < 50,000/µL on Day 29.  
• 
Two (2 mL) of bone marrow will be collected and shipped to the flow 
cytometry laboratory for MRD determination  
• 
See Sections 7.1 and 13.0 for details on specimen handling and shipping. 
 
4.5.6 
Following completion of Blinatumomab Block: Cycle 1 (Arm B) 
 
a. For HR/IR B-ALL patients assigned to Arm B: 
Blinatumomab Block Cycle 2 (Section 4.6, APPENDIX II-E) starts when 
ANC ≥ 500/µL and platelets ≥ 50,000/µL. 
 
b. Treatment Failures post-Blinatumomab Block:  
Patients with a TF post Blinatumomab Block: Cycle 1 (see Section 3.3 for 
definition) will be taken off protocol therapy. 
 
 
 

 
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4.6 
Blinatumomab Block: Cycle 2 (HR/IR Patients in Arm B) - 5 weeks  
With Amendment #10, HR/IR patients already assigned to Arm A (standard 
chemotherapy) who are at an appropriate point in their treatment program (prior to 
receiving Day 22 treatment on Block 3) will be offered the opportunity to cross over to 
Arm B to receive blinatumomab.    
 
The therapy described in this section is for the 2nd cycle of therapy with blinatumomab on 
Arm B. See Experimental Design Schema.  
 
The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 2 (Arm B) is in 
APPENDIX II-E. 
 
NOTE: Hospitalization is STRONGLY recommended during the first 2 days of this cycle 
in case of a cytokine reaction. Manifestations of cytokine release syndrome include fever, 
headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased 
aspartate aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC). Corticosteroids should be administered for severe or life threatening 
cytokine release syndrome. 
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. (NOTE: 
Administration of the premedication (dexamethasone) is NOT RECOMMENDED for the 
second cycle of blinatumomab.) If possible, the infusion time before and after a break 
should sum up to 28 days treatment per cycle. 
 
4.6.1 
Criteria to Begin Blinatumomab Block: Cycle 2 
• Do not start Blinatumomab Cycle 2 before Day 36 after beginning of Cycle 1.  
• Begin Blinatumomab Block: Cycle 2 therapy when ANC ≥ 500/µL and 
platelets ≥ 50,000/µL. 
 
4.6.2 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 

 
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Dosing should be based on actual BSA. 
 
 
 
 
 
 
 
 
4.6.3 
Blinatumomab Block: Cycle 2 Administration Guidelines 
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1-28 
Dose: 15 micrograms/m²/day 
 
*IV bag will be changed every 24 - 96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
 
(NOTE: Administration of the premedication (dexamethasone) is NOT 
RECOMMENDED for the second cycle of blinatumomab.) 
 
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY 
Days: 8, 29 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Days: 8, 29 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg 
HC: 8 mg 
ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg 
HC: 10 mg 
ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg 
HC: 12 mg 
ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg 
HC: 15 mg 
ARAC: 30 mg 
 
4.6.4 
Disease Evaluation End-Blinatumomab Block: Cycle 2 
• 
The end block disease staging should be performed no earlier than Day 29 (± 1 
day);  
• 
The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC 
< 500/µL and platelets < 50,000/µL on Day 29.  
• 
Two (2 mL) of bone marrow will be collected and shipped to the flow 
cytometry laboratory for MRD determination  
• 
See Sections 7.1 and 13.0 for details on specimen handling and shipping. 
 

 
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Notes regarding End-Blinatumomab Block: Cycle 2 Disease Assessment:  
• 
BM assessment should be coordinated so that patients begin their preparative 
regimens no later than 2 weeks from BM documentation of M1.  
• 
If delays > 14 days are required for donor timing or other reasons, patients may 
receive up to 6 weeks of bridging maintenance therapy as described in 
Section 4.10. 
• 
For patients who receive bridging therapy, a repeat BM assessment is required 
to document remission and MRD status within 14 days of starting the HSCT 
preparative regimen.  
• 
Patients who are unable to begin the transplant preparative regimen within 
8 weeks of initial BM assessment are off protocol therapy. 
 
4.6.5 
Following completion of Blinatumomab Block: Cycle 2 (Arm B): 
• 
Patients will continue on to HSCT (See Section 4.9).Patients may receive up 
to 6 weeks of bridging maintenance therapy prior to HSCT as described in 
Section 4.10. 
• 
Treatment Failures post-Blinatumomab Block: Cycle 2 (see Section 3.3 for 
definition) will be taken off protocol therapy. 
 

 
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4.7 
Blinatumomab-S: Cycle 1 (Salvage Therapy) - 5 weeks  
Patients classified as treatment failures after Block 1 or Block 2 treatment (see Section 3.3 
for definitions) who have not previously received blinatumomab on study and who are 
without evidence of CNS disease will have the option to be non-randomly assigned 
treatment with up to 2 blocks of salvage blinatumomab (Blinatumomab-S), and continue 
on study with HSCT therapy if a CR is achieved. Eligible patients should complete the 
appropriate callback (Section 3.1.7) before initiating Salvage Therapy treatment. Note that 
blinatumomab dosing in Blinatumomab-S cycles differs from dosing in 
Blinatumomab Block cycles (See Section 4.7.4.) The schedule below describes treatment 
for the 1st cycle only. See Experimental Design Schema. 
 
The Therapy Delivery Map (TDM) for the Blinatumomab-S: Cycle 1 is in 
APPENDIX II – F. 
 
NOTE: Hospitalization is STRONGLY recommended during the first 9 days of this cycle 
in case of a cytokine reaction. Manifestations of cytokine release syndrome include fever, 
headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased 
aspartate aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC). Corticosteroids should be administered for severe or life threatening 
cytokine release syndrome. 
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. Administration of 
the premedication (dexamethasone) described in Section 4.5.4, is recommended. If 
possible, the infusion time before and after a break should sum up to 28 days treatment per 
cycle. 
 
OBTAIN INFORMED CONSENT PRIOR TO INITIATING THE FIRST CYCLE OF 
SALVAGE THERAPY. PLEASE SEE THE SUMMARY TABLE IN SECTION 3.1.5 
FOR DETAILS ON TIMING TO OBTAIN INFORMED CONSENT. CALLBACK 
OCCURS PRIOR TO STARTING BLINATUMOMAB-S: CYCLE 1 THERAPY (See 
Section 3.1.7 for appropriate callback). 
 
4.7.1 
Criteria to Begin Blinatumomab-S: Cycle 1 
• 
None 
 
4.7.2 
Testicular Radiation Therapy (TRT) 
• 
All Treatment Failures on the basis of M3 marrow at the end of Block 1 who 
also have persistent testicular leukemia will receive 2400 cGy of testicular 
radiation during the 1st cycle of Salvage Therapy (Blinatumomab-S: Cycle 1).  
• 
Patients with extramedullary testicular leukemia that has resolved by end 
Block 1 will NOT receive testicular irradiation with the exception of that 
which may be used in the HSCT preparative regimen for HR/IR patients. 

 
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• 
See Section 14.2 for detailed radiation guidelines. 
 
4.7.3 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 
 
Dosing should be based on actual BSA.  
 
4.7.4 
Blinatumomab-S: Cycle 1 Chemotherapy Guidelines 
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1-28 
Dose: 5 micrograms/m²/day (Days 1-7) followed by 15 micrograms/m²/day 
(Days 8-28) 
 
*IV bag will be changed every 24 - 96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
 
Dexamethasone: PO/IV 
Dose: Prior to day 1 and day 8 of therapy -  
• 
A single dose of 5 mg/m2/dose (maximum 20 mg/dose) will be 
administered 30 to 60 minutes prior to the start of the blinatumomab 
infusion on Day 1, prior to a step dose (such as Cycle 1 Day 8), and 
when restarting an infusion after an interruption of 4 or more hours in 
the first cycle.  
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
Methotrexate: Intrathecal (IT) 
Day: 15 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 

 
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4.7.5 
Disease Evaluation End Blinatumomab-S Cycle 1:  
• 
The end block disease staging should be performed no earlier than Day 29 
(± 1 day);  
• 
The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC 
< 500/µL and platelets < 50,000/µL on Day 29.  
• 
Two (2 mL) of bone marrow will be collected and shipped to the flow 
cytometry laboratory for MRD determination  
• 
See Sections 7.1 and 13.0 for details on specimen handling and shipping. 
 
4.7.6 
Following completion of Blinatumomab-S: Cycle 1: 
 
a. Patients with M1 marrow after Blinatumomab-S Cycle 1: 
• 
If 
patient 
has 
recovered 
counts 
to 
ANC 
≥ 
500/µL 
and 
platelets ≥ 50,000/µL (i.e., have achieved a CR), then proceed to HSCT 
on study as soon as possible. See Section 4.9.  
• 
If patient has NOT recovered counts to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL at the time of the marrow evaluation, but recovers 
counts within 1 week of the marrow evaluation, then this will be 
considered a CR and the patient should proceed to HSCT as soon as 
possible. 
• 
If patient has NOT recovered counts to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL at the time of the marrow evaluation, and does NOT 
recover counts within 1 week of the marrow evaluation, a repeat marrow 
every 1 - 2 weeks until either patient meets definition of CR (in which case 
the patient may proceed to HSCT) or develops an M2/M3 marrow (in 
which case proceed as detailed in Section 4.7.6.b). 
• 
Patients should begin their preparative regimens no later than 2 weeks 
from BM documentation of M1.  
• 
If patient achieves a CR but delays > 14 days are required for donor timing 
or other reasons, patients may receive Blinatumomab-S Cycle 2 as 
described in Section 4.8 or up to 6 weeks of bridging maintenance therapy 
as described in Section 4.10.  
• 
For patients who receive bridging therapy, a repeat BM assessment will 
be needed to document remission and MRD status within 14 days of 
starting the HSCT preparative regimen.  
• 
Patients who are unable to begin the transplant preparative regimen within 
8 weeks of initial BM assessment are off protocol therapy. 
 
b. Patients with M2/M3 marrow after Blinatumomab-S: Cycle 1  
Such patients proceed to Blinatumomab-S: Cycle 2 (Section 4.8, 
APPENDIX II-G) without awaiting count recovery. 
 
 
 

 
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4.8 
Blinatumomab-S: Cycle 2 (Salvage Therapy) - 5 weeks 
Blinatumomab-S: Cycle 2 is for patients with M2/M3 marrow after completion of 
Blinatumomab-S: Cycle 1. Patients who are M1 after completion of Blinatumomab-S: 
Cycle 1 and have delays >14 days before initiating HSCT may also receive treatment on 
Blinatumomab-S: Cycle 2 (See Section 4.7.6). Note that blinatumomab dosing in 
Blinatumomab-S cycles differs from dosing in Blinatumomab Block cycles (See 
Section 4.8.3.)  
 
The schedule below describes treatment for the 2nd cycle only. See Experimental Design 
Schema. 
 
The Therapy Delivery Map (TDM) for the Blinatumomab-S: Cycle 2 is in 
APPENDIX II - G. 
 
NOTE: Hospitalization is STRONGLY recommended during the first 2 days of this cycle 
in case of a cytokine reaction. Manifestations of cytokine release syndrome include fever, 
headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased 
aspartate aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC). Corticosteroids should be administered for severe or life threatening 
cytokine release syndrome. 
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. NOTE: 
Administration of the premedication (dexamethasone) is NOT RECOMMENDED for the 
second cycle of blinatumomab.) If possible, the infusion time before and after a break 
should sum up to 28 days treatment per cycle. 
 
4.8.1 
Criteria to Begin Blinatumomab-S: Cycle 2 
Do not start Blinatumomab-S: Cycle 2 before Day 36 after beginning of Cycle 1. 
 
4.8.2 
General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 

 
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Dosing should be based on actual BSA.  
 
 
4.8.3 
Blinatumomab-S: Cycle 2 Chemotherapy 
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1-28 
Dose: 15 micrograms/m²/day (Days 1-28) 
 
*IV bag will be changed every 24-96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
 
(NOTE: Administration of the premedication (dexamethasone) is NOT 
RECOMMENDED for the second cycle of blinatumomab.)  
 
Methotrexate: Intrathecal (IT) 
Day: 8 & 29 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
4.8.4 
Disease Evaluation End-Blinatumomab-S: Cycle 2 
• 
The end block disease staging should be performed no earlier than Day 29 (± 
1 day);  
• 
The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC 
< 500/µL and platelets < 50,000/µL on Day 29.  
• 
Two (2 mL) of bone marrow will be collected and shipped to the flow 
cytometry laboratory for MRD determination  
• 
See Sections 7.1 and 13.0 for details on specimen handling and shipping. 
 
4.8.5 
Following completion of Blinatumomab-S: Cycle 2: 
 
a. Patients with M1 marrow after Blinatumomab-S Cycle 2:  
• 
If 
patient 
has 
recovered 
counts 
to 
ANC 
≥ 
500/µL 
and 
platelets ≥ 50,000/µL (i.e., have achieved a CR), then proceed to HSCT 
on study as soon as possible. See Section 4.9.  
• 
If patient has NOT recovered counts to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL at the time of the marrow evaluation, but recovers 
counts within 1 week of the marrow evaluation, then this will be 
considered a CR and the patient should proceed to HSCT as soon as 
possible. 
• 
If patient has NOT recovered counts to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL at the time of the marrow evaluation, and does NOT 
recover counts within 1 week of the marrow evaluation, a repeat marrow 

 
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every 1-2 weeks until either patient meets definition of CR (in which case 
the patient may proceed to HSCT) or develops an M2/M3 marrow (in 
which case proceed as detailed in Section 4.8.5.b). 
• 
Patients should begin their preparative regimens no later than 2 weeks from 
BM documentation of M1.  
• 
If patient achieves CR but delays > 14 days are required for donor timing 
or other reasons, patients may receive up to 6 weeks of bridging 
maintenance therapy as described in Section 4.10.  
• 
For patients who receive bridging therapy, a repeat BM assessment will be 
needed to document remission and MRD status within 14 days of starting 
the HSCT preparative regimen.  
• 
Patients who are unable to begin the transplant preparative regimen within 
8 weeks of initial BM assessment are off protocol therapy. 
 
b. Patients with M2/M3 marrow after Blinatumomab-S Cycle 2  
Remove from protocol therapy. 
 
 
 

 
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4.9 
Hematopoietic Stem Cell Transplant 
All transplants performed on COG trials must occur at FACT-accredited HSCT programs with 
the exception of adolescents/adults being treated on COG trials who are referred to an adult 
transplant facility. See the COG Administrative Policy 3.3 regarding the agreement 
requirements for these cases. 
 
4.9.1 
Overview 
Stem cell transplantation in this study will be utilized in patients with HR/IR 
relapse ALL (see Section 3.3 for risk definitions). 
 
All patients enrolled on this protocol and their full siblings should undergo 
HLA tissue typing as soon as possible after diagnosis of relapse. All high-risk 
patients should have transplantation consultation and initiation of a donor 
search early while undergoing their initial Block 1 therapy. It is recommended 
that all intermediate-risk patients also undergo transplantation consultation 
as soon as possible after Block 1 therapy, so that a donor search can be 
initiated immediately if they are noted to be MRD+ after initial induction. The 
goal of this protocol is to move to transplantation within 2 weeks of recovery 
from the final consolidation cycle or completion of Salvage Therapy 
(Blinatumomab-S). As unrelated donor acquisition can take 8 - 12 weeks, to 
meet this deadline centers must expedite the search process. Please see 
Section 7.1c for details of required evaluations. 
 
Patients going on to HSCT will undergo an extensive pre-transplant 
evaluation to assess remission status, assure adequate organ system function, 
and document freedom from active viral, bacterial, and fungal infection. 
Patients should begin their preparative regimen no later than 2 weeks after 
obtaining the BM aspiration scheduled after recovery from their final 
consolidation cycle or completion of Salvage Therapy (Blinatumomab-S). If 
transplantation is delayed by 14 days for donor timing or other reasons, 
patients may receive up to 6 weeks of bridging maintenance therapy as 
described in Section 4.10, Appendix II-H. For patients who receive bridging 
therapy, a repeat BM assessment will be needed to document remission and 
MRD status within 14 days of starting the HSCT preparative regimen. 
Patients who are unable to begin the transplant preparative regimen within 8 
weeks of initial BM assessment are off protocol therapy. 
 
Patients 
will 
receive 
1 
of 
3 
designated 
preparative 
regimens 
(cyclophosphamide/total body irradiation (TBI) [cy/TBI] alone or with thiotepa or 
etoposide). Fludarabine will be added to cy/TBI for cord blood recipients. GVHD 
prophylaxis varies slightly according to stem cell source. 
 Patients who are high risk for relapse (MRD+ pre-HSCT with no evidence of 
GVHD by Day +55, or with + MRD post BMT) are eligible for early taper of 
immune suppression. The intent of the protocol will be for patients to undergo TBI-
based myeloablative conditioning. If patients are not eligible for a myeloablative 
regimen and either do not undergo HSCT or undergo a reduced intensity 
procedure, limited data will be collected regarding post transplant survival and 
relapse. 
 

 
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In the recent COG ASCT0431 trial some variability was allowed in lung shielding 
with total body irradition. Review of ASCT0431 data showed that lung irradiation 
doses above 800 cGy were significantly associated with an increased risk of 
treatment-related mortality and relapse, largely due to toxicity (Pulsipher and Lu, 
unpublished data November 2014). Accordingly, AALL1331 mandates lung 
shielding with total body irradiation to limit the lung dose to less than 800 cGy 
(See Section 14.0 for Radiation Therapy Guidelines). 
 
4.9.1.1 Eligibility Criteria for Hematopoietic Stem Cell Transplant (HSCT) 
Patients who have an appropriately matched stem cell source (see 
Section 4.9.1.5) and who meet one of the following criteria: 
 
1. Patients with HR relapse: 
• 
Early (< 36 months) marrow 
• 
Early (< 18 months) IEM 
 
2. Patients with IR relapse with persistent MRD: 
• 
Late (≥ 36 months) marrow, end-Block 1 MRD ≥ 0.1% 
• 
Late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1% 
 
3. Patients with treatment failure (TF) who achieve a CR after receiving 
blinatumomab. 
 
NOTE: Patients must maintain an M1 marrow (< 5% blasts) through 
the BM assessment prior to transplant. (Patients who achieve a 
remission and relapse prior to HSCT can go to HSCT later, but as they 
have met a study endpoint (relapse), this procedure will be as per 
center preference and the patient will only be followed for survival.) 
 
4.9.1.2 Exclusion Criteria for Hematopoietic Stem Cell Transplant (HSCT) 
Interval development of significant pathology that would preclude HSCT 
including the following infectious and organ system pathologies: 
 
1. Infections 
Patients with uncontrolled fungal, bacterial or viral infections are 
excluded. 
 
Patients acquiring fungal disease during Induction therapy may 
proceed if they have a significant response to antifungal therapy with 
no or minimal evidence of active disease remaining by CT evaluation. 
 
2. Organ Function Requirements for HSCT 
Must meet the criteria for renal, biliary and cardiac function as 
outlined in Section 3.2.4. In addition, must have adequate pulmonary 
function defined as anFEV1, FVC, and DLCO (corrected for Hgb) 
≥ 60% by pulmonary function tests (PFTs). 
 
For children who are unable to cooperate for PFTs, the criteria are: no 
evidence of dyspnea at rest, no exercise intolerance, and not requiring 
supplemental oxygen therapy. 

 
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3. Performance Status 
Patients must have a performance status corresponding to ECOG 
scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and 
Lansky for patients ≤ 16 years of age. Please refer to performance 
status scale at: 
https://members.childrensoncologygroup.org/_files/protocol/Standar
d/PerformanceStatusScalesScoring.pdf 
 
4.9.1.3 Eligibility for Accelerated Taper of Immune Suppression 
a. Patients who are MRD+ (≥ 0.01%) within 2 weeks of beginning HSCT 
preparative regimen who do not have any evidence of aGVHD by 
Day +55 post HSCT (pre-MRD+ group) 
 
b. Patients who are MRD- (< 0.01%) within 2 weeks of beginning HSCT 
preparative regimen but are found to be MRD+ (≥ 0.01%) on peri-
engraftment (Day +28-55) or Day +100 marrow who do not have any 
evidence of aGVHD by Day +55 (peri-engraftment group) or 
Day +100 (Day +100 group) 
 
4.9.1.3.1 Adjustment of TBI/chemotherapy During the Preparative 
Regimen 
The full dose of preparative regimen TBI and chemotherapy 
agents will be administered unless patients have a life 
threatening reaction thought likely to occur again with 
continued administration and an appropriate substitution cannot 
be made (i.e. etopophos for etoposide). 
 
4.9.1.4 Dose Adjustment of Chemotherapy for Patients Whose Weight Exceeds 
> 125% Ideal Body Weight (IBW) 
Chemotherapy given during the preparative regimen (thiotepa, 
cyclophosphamide, and etoposide) will be dosed based on actual weight 
for patients ≤ 125% IBW. Those > 125% IBW will be dosed based upon 
adjusted ideal body weight as follows: 
 
Adjusted ideal body weight = IBW + 0.25 (Actual weight – IBW). 
 
The following formulas for pediatric and adult IBW calculations are 
recommended, but IBW may be calculated according to institutional 
standard operating procedures (SOPs). 
 
Recommended Ideal Body Weight Calculation for Children Age 1 - 17 
years 
IBW = Height (cm)2 x 1.65 
 
 
1000 
 
Recommended Ideal Body Weight Calculation for Adults (Height 
> 5 feet/60 inches) 
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg 
 

 
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IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg  
 
4.9.1.5 Stem Cell Source Requirements 
Molecular typing at high resolution of HLA A, B, C, and DRB1 is 
required, and DQB1 suggested, for all bone marrow or peripheral blood 
stem cell (PBSC) donors who are either unrelated or related but not 
matched siblings (i.e. matched parent, partially mismatched sibling, etc.). 
For matched sibling donors and cord blood units, intermediate level 
matching of class I antigens is acceptable, but allele level typing is 
required for DRB1 and encouraged for class I antigens and DQB1.  
 
Hierarchy of stem cell choices is as follows: 
 
1) Preferred: Genotypically HLA matched siblings 
 
2) If genotypically matched sibling is not available, the following are 
equally acceptable: 
 
a) Unrelated or “other” related (non-genotypically matched) 
donors must be matched at 8/8 or 7/8 alleles (HLA-A, B, C and 
DRB1 at high resolution). 
 
b) Unrelated cord blood units must be matched at 4/6, 5/6, or 6/6 
antigens (HLA A, B [intermediate), and DRB1 [high resolution]). 
Published data show lower non-relapse mortality when patients 
receive units matched at 8/8, 7/8, or 6/8 alleles (HLA-A, B, C and 
DRB1 at high resolution), therefore allele-level typing is strongly 
encouraged. Use of cords matched at 5/8 or 4/8 alleles leads to 
more TRM, but are acceptable if better matches are not available. 
It is recommended that units matching at the 3/8 allele level be 
avoided if possible. Minimum pre-thaw cell dose of 3x107 
nucleated cells/kg recipient weight is required. Two cords may be 
used if this cell dose is not achieved with a single unit. The two 
units must each match the recipient at a minimum of 4/6 antigens 
and must match each other at a minimum of 3/6 antigens. 
 
NOTE: Centers using unlicensed cord blood must consent the 
patient on the NMDP cord blood IND protocol or other cord blood 
IND protocols as appropriate in order to use such units on this 
study 
 
3) Use of Peripheral Blood Stem Cells (PBSC) 
Bone marrow should be requested from allogeneic donors. PBSC is 
allowed only if the donor is unable or unwilling to give marrow. 
 
4.9.1.5.1 Recommended minimum cell doses: 
HPC-M cell dose should be at least 1 x 108 TNC/kg 
HPC-A cell dose should be at least 2 x 106 CD34/kg 
 

 
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4.9.1.6 Preparative Regimens 
Preparative regimens allowed on this protocol are standard regimens used 
in ASCT0431 for related and unrelated BM/PBSC recipients and BMT 
CTN 0501 for cord blood recipients. ASCT0431 designated TBI 
1200cGy/thiotepa/cyclophosphamide, but also allowed a variation 
substituting etoposide for thiotepa and a second variation substituting a 
slightly higher TBI dose (1320cGy) for thiotepa. BMT CTN 0501 used 
TBI 1320/cyclophosphamide/fludarabine for all patients. 
 
4.9.2 
Preparative Regimen Administration 
4.9.2.1 TBI Administration 
Fractionated TBI will be administered according to protocol guidelines 
(see Section 14.5 for radiotherapy guidelines). TBI may be delivered from 
either linear accelerator or Cobalt sources. 
 
4.9.2.2 Thiotepa Administration (for centers choosing the thiotepa-containing 
regimen).  
• 
Thiotepa will be administered intravenously over 3 hours. To 
minimize skin toxicity, frequent bathing (minimum 2 - 3x daily) is 
required on the days of thiotepa administration as per center standard. 
• 
See above for dose modification if weight exceeds 125% of IBW 
 
4.9.2.3 Cyclophosphamide Administration  
• 
Cyclophosphamide will be administered intravenously over 1-6 hours.  
• 
Hyperhydration, maintenance of significant urine output after 
administration, and the use of Mesna is required. 
• 
Recommended mesna dosing: 360 mg/m2 during cyclophosphamide 
followed by 120 mg/m2/hour for 12 hours after each dose. Institutional 
standards or protocols for mesna administration may also be used. 
• 
See above for dose modification if weight exceeds 125% of IBW 
 
4.9.2.4 Etoposide Administration (for centers choosing etoposide regimen) 
• 
Etoposide will be administered intravenously at a maximum infusion 
rate of 300 mg/m2/hour for a minimum of 5 hours or per institutional 
standard. 
• 
Patients should be given 1.5X maintenance fluids during etoposide 
administration to minimize the risk of hypotension.  
• 
Etopophos substitution is allowed.  
• 
See above for dose modification if weight exceeds 125% of IBW 
 
4.9.2.5 Fludarabine Administration 
• 
Fludarabine will be administered intravenously over 30 - 60 minutes 
each day. 
• 
Fludarabine will not be adjusted for body weight. 
 
4.9.3 
Preparative Regimen Administration Tables 
4.9.3.1 TBI 1200/thiotepa/cyclophosphamide Regimen (related and unrelated 
BM/PBSC) 

 
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Treatment 
Route 
Dose 
Days 
Notes 
TBI 
 
200 cGy 
BID 
Day -8, -
7, & -6  
May deliver 
1200 cGy 
fractionated TBI 
over 4 days per 
center preference 
Thiotepa 
IV over 3 
hours daily 
5 
mg/kg/day 
Day -5 & 
-4 
 
Cyclophosphamide 
IV over 1-6 
hours daily 
60 
mg/kg/day 
Day -3 & 
-2 
 
Rest 
 
 
Day -1 
 
Infusion of 
allogeneic HSCT 
 
 
Day 0 
 
 
4.9.3.2 TBI 1200/etoposide/cyclophosphamide Regimen (related and unrelated 
BM/PBSC) 
 
Drug/Treatment 
Route 
Dose 
Days 
Notes 
TBI 
 
200 cGy 
BID 
Day -7, -
6, & -5  
May deliver 
1200 cGy 
fractionated TBI 
over 4 days per 
center 
preference 
Etoposide 
IV over a 
minimum 
of 5 hours 
or per 
institutional 
standard 
1500 mg/m2 
Day -4 
maximum rate 
of infusion is 
300 mg/m2/hour 
or per 
institutional 
standard 
 
Cyclophosphamide 
IV over 1-6 
hours daily 
60 
mg/kg/day 
Day -3 & 
-2 
 
Rest 
 
 
Day -1 
 
Infusion of 
allogeneic HSCT 
 
 
Day 0 
 
 
4.9.3.3 TBI 1320/cyclophosphamide Regimen (related and unrelated BM/PBSC) 
Treatment 
Route 
Dose 
Days 
Notes 
TBI 
 
165 cGy 
BID 
Day -7, -6, 
-5, & -4  
Total dose must 
be  
1320 cCy 
Cyclophosphamide 
IV over 
1-6  
hours 
daily 
60 
mg/kg/day 
Day -3 & 
- 2 
 
Rest 
 
 
Day -1 
 
Infusion of 
allogeneic HSCT 
 
 
Day 0 
 
 

 
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4.9.3.4 TBI 1320/fludarabine/cyclophosphamide Regimen (related and unrelated 
cord blood) 
Treatment 
Route 
Dose 
Days 
Notes 
Fludarabine 
IV over 
30 - 60 
minutes 
daily 
25 mg/m2/day 
Day -10, -9, -8 
 
TBI 
 
165 cGy BID 
Day -7, -6, -5, 
& -4  
Total dose 
must be  
1320 cCy 
Cyclophosphamide 
IV over 
1-6 
hours 
daily 
60 mg/kg/day 
Day -3 & -2 
 
Rest 
 
 
Day -1 
 
Infusion of 
allogeneic HSCT 
 
 
Day 0 
 
 
4.9.4 
Sanctuary Site Therapy (see Section 14.0) 
Prior to transplant, designated patients with extramedullary relapse must receive 
cranial or testicular radiotherapy boosting in addition to the doses of TBI 
associated with the preparative regimen. The cranial boost and/or testicular boosts 
should be given over 3 days prior to the beginning of TBI. 
 
4.9.4.1 Radiotherapy boost for patients with CNS leukemia (CNS3) at 
relapse: 
Patients with CNS3 involvement at the time relapse with or without a 
history of prior CNS leukemia and/or radiotherapy will receive a cranial 
radiotherapy boost just prior to TBI (3 doses, maximum 200 cGy daily: 
total dose to cranial axis = 1800 cGy (unless alternative TBI dose given in 
which case the dose will be 1920 cGy). If the patient is ≤ 3 years at the 
time of transplant, centers may elect not to give a boost because of 
developmental concerns. If the patient has CNS1 or CNS2 status at 
relapse, no boost will be given. 
 
4.9.4.2 Testicular boost for patients with testicular leukemia at relapse: 
The only patients that will receive a testicular boost prior to TBI (3 daily 
doses, 200 cGy fractions, total 600 cGy) are IR/HR/TF patients with 
extramedullary testicular leukemia at the time of relapse that DID resolve 
by end Block 1, since those without resolution have already received 
2400 cGy of testicular radiation. 
 
4.9.4.3 Prophylactic testicular boosting: 
Prophylactic testicular boosting of 400 cGy for patients without testicular 
relapse is allowed, but not part of the designated therapy. 
 
4.9.5 
Growth Factor Administration 
Filgrastim (G-CSF) at a dose of 5 micrograms/kg/day given IV or subcutaneously 
is required for recipients of cord blood starting at Day +1 and continuing until 

 
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patients are fully engrafted. G-CSF is generally not necessary for BM/PBSC 
recipients and is not recommended, unless engraftment is delayed. 
 
4.9.6 
GVHD Prophylaxis 
GVHD prophylaxis will consist of tacrolimus/methotrexate (TAC/MTX) for 
recipients of related and unrelated donor BM/PBSC and cyclosporine and 
mycophenolate mofetil (CYA/MMF) for cord blood recipients. Substitution of 
CYA for TAC or TAC for CYA according to center preference is allowed. 
 
Drug 
Route* Dose  
Days 
Important Notes 
BM Recipient 
 
 
 
 
Tacrolimus 
(TAC) 
IV 
0.02 mg/kg/day 
cont infusion 
Begin Day -3 
Target 
concentration 
8 - 12 ng/mL 
Methotrexate 
(MTX) 
IV 
5 mg/m2 sib donor 
10 mg/m2 URD^ 
+1, +3, &+6 
sibs 
+1, +3, +6, 
+11 URD 
 
Cord Recipient 
 
 
 
 
Cyclosporine A 
(CYA) 
IV 
Varies by age, 
adjusted to target 
Begin Day -3 
Target 
concentration 
200 - 400 ng/mL 
Mycophenolate 
mofetil (MMF) 
IV 
≥ 50 kg: 1000 mg 
q8h 
< 50kg: 15 mg/kg 
q8h 
Begin Day -3 
 
* All drugs may be switched to PO after engraftment when patients are able to tolerate and 
absorb PO medications. 
^ URD, unrelated donor 
 
4.9.6.1 Tacrolimus Administration, Monitoring and Dose Adjustments 
(related or unrelated BM/PBSC)  
Tacrolimus should be administered by continuous IV infusion until 
patients are able to take PO. Serum tacrolimus troughs and serum 
magnesium, potassium, and creatinine should be drawn at least twice per 
week while hospitalized, then as per good clinical practice thereafter 
unless a change in medication (e.g. use of concomitant CYP3A4 
inhibitors) or renal function might result in an acute change in level. 
 
At that point, concentrations will be measured as clinically indicated. 
Concentrations sent when dosing by continuous infusion are not true 
trough concentrations, however, the same target range of drug 
concentration will be used for both continuous IV and bolus PO routes of 
administration. 
 
When converting patients at a therapeutic tacrolimus level from IV to PO 
formulation, multiply total daily IV dose times 4 and administer in 2 
divided oral doses per day, every 12 hours (e.g., 1 mg of IV tacrolimus per 

 
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day equates to 4 mg of PO tacrolimus per day). Younger children (eg. 
< 6 years of age) may require more frequent PO tacrolimus dosing (every 
8 hours) to maintain target trough concentrations. The oral dose should be 
administered 8 - 12 hours after the end of the tacrolimus continuous 
infusion.41 
 
The target serum trough concentration for tacrolimus is 8 - 12 ng/mL. 
Dose adjustments are based on clinical judgment of the treating physician 
after considering clinical toxicity, serum levels, GVHD, concomitant drug 
use and the rate of rise or decline of the serum level.  
 
4.9.6.2 Methotrexate Administration, Monitoring and Dose Adjustments 
(related or unrelated BM/PBSC) 
For patients receiving sibling donors, methotrexate should be given at a 
dose of 5 mg/m2 on Days +1, 3, and 6 after transplant. For patients 
receiving unrelated BM or PBSC, methotrexate should be given at a dose 
of 10 mg/m2 on Days +1, 3, and 6, and 11. All doses of methotrexate 
should be administered as scheduled if possible, but centers may modify 
or hold methotrexate for significant toxicity (see Section 5.8 for 
methotrexate dose modification guidelines). 
 
4.9.6.3 Leucovorin Administration 
Leucovorin may be given at the physician’s discretion for patients at risk 
for methotrexate toxicity. Patients at risk for methotrexate toxicity include 
those with extravascular fluid collections (ascites, pleural effusions) or 
with decreased renal function (see Section 5.8). 
 
4.9.6.4 Cyclosporine Administration, Monitoring and Dose Adjustments 
(related and unrelated cord blood) 
Cyclosporine should be administered by IV infusion until patients are able 
to take PO. Cyclosporine levels as well as serum magnesium, potassium, 
and creatinine levels should be drawn at least twice per week while 
hospitalized, then weekly or monthly thereafter unless a change in 
medication (e.g. use of concomitant CYP3A4 inhibitors) or renal function 
might result in an acute change in level. At that point, levels will be 
measured as clinically indicated. When converting patients at a therapeutic 
tacrolimus level from IV to PO formulation, multiply the IV dose times 
2.5 if using the modified formulation (i.e., Neoral or Gengraf) or times 3 
if using the non-modified formulation (i.e., SandIMMUNE). 
 
The target serum trough concentration for cyclosporine is 
200 – 400 ng/mL. Variations in dosing levels based upon laboratory 
methodology (e.g. tandem mass-spec analysis) allowed. Dose adjustments 
are based on clinical judgment of the treating physician after considering 
clinical toxicity, serum levels, GVHD, concomitant drug use and the rate 
of rise or decline of the serum level.  
 
4.9.6.5 Mycophenolate Mofetil (MMF) Administration and Dose 
Adjustments (related and unrelated cord blood) 

 
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MMF should be given at a dose of 1 gram IV q8 hours for patients ≥ 50kg 
or 15 mg/kg IV q8 hours for patients < 50 kg beginning the morning of 
Day -3. MMF should be given IV until patient can tolerate oral 
medications. MMF should be dosed upon actual body weight. 
 
The FDA has determined that a REMS (Risk Evaluation and Mitigation 
Strategy) program is necessary to ensure the benefits of mycophenolate 
outweigh the risks of first trimester pregnancy loss and congenital 
malformations associated with mycophenolate use during pregnancy. 
Mycophenolate REMS is a program to tell doctors, nurses, pharmacists 
and patients about the risks of taking mycophenolate during pregnancy. 
The program also contains important information about patient education 
and reporting details for pregnancy. Please refer to the website for 
additional 
information 
(https://www.mycophenolaterems.com/). 
If 
≤ Grade 1 acute GVHD, MMF will be discontinued by Day +30. For 
patients with > Grade 1 acute GVHD, the MMF taper will be per 
institutional protocols. Patients may transition to PO formulations at a 1:1 
IV to PO conversion when clinically appropriate. Refer to Section 5.13 for 
dose adjustments based upon clinical and laboratory findings. 
 
4.9.7 
Standard Taper of Immune Suppression 
This applies to all patients who are MRD negative pre- and at all times post-
transplant who have not developed aGVHD requiring systemic therapy. (Patients 
who develop significant aGVHD will be tapered at the discretion of the transplant 
center.) 
Drug 
Stem Cell Source 
Taper Schedule 
Tacrolimus 
Matched Sibling 
BM/PBSC 
Start Day +42 over 8 weeks, off by 
Day +98 
Tacrolimus 
Unrelated Donor 
BM/PBSC 
Start Day +100 off by Day +180 
Cyclosporine 
Unrelated Cord 
Start Day +100 off by Day +180 
Mycophenolate 
Mofetil 
Unrelated Cord 
Continue until Day +45 or 7 days after 
engraftment, whichever day is later. 
Stop without a taper. 
 
4.9.8 
Accelerated Taper of Immune Suppression 
See Section 4.9.1 for eligibility requirements. 
 
4.9.8.1 Taper for patients who are MRD positive pre-HSCT with no aGVHD by 
Day +55 and for patients who are MRD positive > 0.01% by flow 
cytometry at their peri-engraftment BM test (approx. Day +30) 
Drug 
Stem Cell Source 
Taper Schedule 
Tacrolimus 
Matched Sibling 
BM/PBSC 
Taper already started by Day +42. At 
Day +55 increase rate of taper to 
complete taper by Day +70  
Tacrolimus 
Unrelated Donor 
BM/PBSC 
Start Day+55 off by Day +100 
Cyclosporine  
Unrelated Cord 
Start Day+55 off by Day +100 

 
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Mycophenolate 
Mofetil 
Unrelated Cord 
Continue until Day +45 or 7 days after 
engraftment, whichever day is later. 
Stop without a taper. 
 
4.9.8.2 Taper for patients who are MRD negative pre- HSCT with no aGVHD by 
Day +55 who are MRD positive > 0.01% by flow cytometry at their Day 
+100 test. 
Drug 
Stem Cell Source 
Taper Schedule 
Tacrolimus 
Matched Sibling 
BM/PBSC 
Taper already started by Day +42 and 
pt should be off immune suppression. 
Stop tacrolimus without taper if still 
on medication.  
Tacrolimus 
Unrelated Donor 
BM/PBSC 
Taper over 2-3 weeks as soon as MRD 
report is received. 
Cyclosporine  
Unrelated Cord 
Taper over 2-3 weeks as soon as MRD 
report is received. 
Mycophenolate 
Mofetil 
Unrelated Cord 
 
Should be off this medication. 
 
4.10 
Bridging Maintenance Therapy (All HR/IR Patients, as required) – up to 6 weeks 
This therapy is for all HR/IR patients who have completed either Blocks 2 and 3 of 
chemotherapy or both cycles of blinatumomab and due to stem cell source or facility 
scheduling issues have a lag time > 2 weeks after count recovery prior to starting HSCT 
therapy. Patients should start bridging therapy when clinically able after meeting count 
requirements and continue until approximately one week prior to beginning the transplant 
preparative regimen. 
 
The Therapy Delivery Map (TDM) for Bridging therapy is in Appendix II-H. 
 
4.10.1 Criteria to Begin Bridging Maintenance Therapy 
Start when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50,000/µL. 
 
4.10.2 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
Dosing should be based on actual BSA. 
 
4.10.3 Bridging Maintenance Chemotherapy Guidelines 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 22  

 
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Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Mercaptopurine: PO 
Days: 1 - 42 
Dose: 75 mg/m²/dose* once daily 
 
Other Considerations: 
• 
*See Section 5.9 for suggested starting dose based on TPMT status (if 
status is known) 
• 
Mercaptopurine should be taken consistently at the same time every day. 
• 
The liquid or tablet formulation may be used. If using tablets, adjust daily 
dose using the dosing nomogram in Appendix III to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible 
 
Methotrexate: PO 
Days: 1, 8, 15, 22, 29, 36  
Dose: 20 mg/m2/dose 
 
Administer on an empty stomach (at least 1 hour before or 2 hours after food or 
drink except water). 
4.11 
Continuation 1/Continuation 2 (All LR Patients) - 8 weeks 
The therapy described in this section is for all LR patients in either Arm C or Arm D and 
represents therapy given during Continuation 1 and Continuation 2. See Experimental 
Design Schema. 
 
The therapy delivery map for Continuation 1 and Continuation 2 is in APPENDIX II-I. 
 
 
4.11.1 Criteria to Begin and During Continuation Therapy 
a. Begin Continuation when ANC ≥ 500/µL and platelets ≥ 50,000/µL.  
b. All Patients should have ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to 
starting therapy on Days 22 and 43.  
• 
If at Day 22 the ANC is < 500/µL and platelets < 50,000/µL, it is 
permissible to delay the divided dose oral methotrexate (ddMTX) 
(25 mg/m2/dose for  CNS1/2) or ID MTX (for CNS3) by until counts 
recover.  

 
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• 
If counts are not recovered after one (1) week, then omit the Day 22 
ddMTX or ID MTX for this cycle. After counts recover, resume with the 
Day 29 standard dose MTX.  
 
4.11.2 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 
4.11.3 Continuation 1/Continuation 2 Chemotherapy Guidelines 
Dexamethasone: PO (may be given IV) 
Days: 1 - 5 
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day: 
1 
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Methotrexate: Intrathecal (IT) –CNS1/2 PATIENTS ONLY 
Days: 1, 43 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  

 
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When IT therapy and ID MTX are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Days: 1, 43  
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
When ITT therapy and ID MTX are scheduled for the same day, deliver the ITT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Mercaptopurine: PO 
Days: 1 - 42 
Dose: 75 mg/m²/dose* once daily 
 
Other Considerations: 
• 
*See Section 5.9 for suggested starting dose based on TPMT status, if 
known 
• 
Mercaptopurine should be taken consistently at the same time every 
day.  
• 
The liquid or tablet formulation may be used. If using tablets, adjust 
daily dose using the dosing nomogram in Appendix III to attain a 
weekly cumulative dose as close to 525 mg/m2/week as possible 
 
Methotrexate: PO 
Days: 8, 15, 29, 36 
Dose: 20 mg/m2/dose 
Administer on an empty stomach (at least 1 hour before or 2 hours after 
food or drink except water).  
 
Divided Dose Methotrexate (dd MTX): PO - CNS1/2 PATIENTS ONLY 
Day: 
22 
Dose: 25 mg/m2/dose Q6H x 4 doses 
 
Other Considerations: 
• 
ANC must be ≥ 500/µL and platelets must be ≥ 50,000/µL prior to 
Day 22 therapy. 
• 
Administer on an empty stomach (at least 1 hour before or 2 hours 
after food or drink except water).  
 
Leucovorin: PO CNS 1 AND 2 PATIENTS ONLY 
Day: 
24 

 
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Dose: 10 mg/m2/dose for 2 doses 6 hours apart beginning 48 hrs after the 
START of Day 22 Methotrexate 
 
Intermediate Dose Methotrexate (ID MTX): IV over 36 hours - CNS3 
PATIENTS ONLY 
Day: 
22 
Dose: 1000 mg/m²/dose 
Given as a 100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over 
35.5 hours. 
Be certain that the ID MTX infusion is completed in the 36 hour period. Even if 
the infusion is not complete at this time point, it must be stopped. 
 
Leucovorin rescue: See below. 
 
Suggested hydration and alkalinization for IDMTX: Prehydrate with D5 ¼ NS 
with 30 mEq NaHCO3/L at 125 mL/m2/hour to achieve a urine specific gravity ≤ 
1.010 and pH between 7 and 8.  Ringers Lactate may be used as the initial fluid if 
a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium 
bicarbonate to maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A 
bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH 
relatively quickly; a normal saline bolus may also be helpful in facilitating 
hydration. Continue hydration using D 5 ¼ NS with 30 mEq NaHCO3/L at 
125 mL/m2/hour throughout IDMTX infusion, and until the last dose of leucovorin 
has been given. In patients with delayed MTX clearance, continue hydration until 
the plasma MTX concentration is < 0.1 μM. 
 
Timing of ID MTX 
ANC must be ≥ 500/µL and platelets must be ≥ 50 000/µL prior to ID MTX. 
 
Leucovorin: PO/IV CNS 3 PATIENTS ONLY 
Days: 24, 25 
Dose: 15 mg/m2/dose every 6 hours beginning 48 hrs after the START of ID 
MTX infusion.  
• 
If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two 
doses of leucovorin (48 and 54 hours).  
• 
If MTX level at 48 hours is > 0.5 μM, then continue hydration and 
leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours until MTX 
levels are < 0.1 μM. 
 
See Section 5.8 for ID MTX/LCV rescue and infusion guidelines. 
 
Cyclophosphamide: IV over 15 - 30 minutes 
Days: 43, 50 
Dose: 300 mg/m²/dose (see note below) 
 
Etoposide: IV over 1 - 2 hours 
Days: 43, 50 
Dose: 150 mg/m²/dose 
 

 
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Note: ANC must be ≥ 500/µL and platelets must be ≥ 50,000/µL prior to Day 43 
therapy. Once the Day 43 cyclophosphamide/etoposide is given, the Day 50 
cyclophosphamide/etoposide doses should be given regardless of blood counts 
(hold only for presumed or proven significant infection). 
 
Thioguanine: PO 
Days: 43 - 49. 
Dose: 40 mg/m2/dose once daily 
 
Other Considerations: 
• 
Administer consistently at the same time every day. 
• 
Adjust daily dose using the dosing nomogram in Appendix IV to attain 
a weekly cumulative dose as close to 280 mg/m2/week as possible.  
• 
An oral suspension can also be compounded for patients who cannot 
swallow pills. The compounded oral suspension is recommended for 
patients with a BSA between 0.27 and 0.48 m2. (see Section 6.18) 
 
Cytarabine: IV over 1 - 30 minutes or SQ 
Days: 44 - 47, 51 -54 
Dose: 50 mg/m2/dose once daily 
 
4.11.4 Following Continuation 1: 
a. LR B-ALL patients randomized to the control arm (Arm C) will receive 
Continuation 2 (Section 4.11, APPENDIX II-I) when ANC ≥ 500/µL and 
platelets ≥50,000/µL. 
b. LR B-ALL patients randomized to the experimental arm (Arm D) will receive 
Blinatumomab Block: Cycle 2 (Arm D) - (Section 4.16, APPENDIX II-N) 
when ANC ≥ 500/µL and platelets ≥50,000/µL. 
 
4.11.5 Following Continuation 2: 
a. LR B-ALL patients randomized to the control arm (Arm C) will receive 
Maintenance Cycle 1 therapy (Section 4.12, Appendix II-J) when ANC 
≥ 500/µL and platelets ≥ 50,000/µL. 
b. LR B-ALL patients randomized to the experimental arm (Arm D) will receive 
Blinatumomab Block: Cycle 3 (Arm D) - (Section 4.16, APPENDIX II-N) 
when ANC ≥ 500/µL and platelets ≥ 50,000/µL. 
 
 

 
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4.12 
Maintenance Cycle 1 (All LR patients) – 12 weeks 
Maintenance Cycle 1 therapy is for common for all LR B-ALL patients randomized to 
either Arm C or Arm D. See Experimental Design Schema. 
 
The Therapy Delivery Map (TDM) for Maintenance Cycle 1 is in Appendix II-J. 
 
CNS3 patients ONLY are to be given Chemoradiation (Section 4.13, Appendix II-K) 
BETWEEN Maintenance Cycle 1 and subsequent Maintenance cycles (Maintenance-
Post Cycle 1, Section 4.14, Appendix II-L).  
 
All other patients receive Maintenance-Post Cycle 1 treatment (Section 4.14, 
Appendix II-L) immediately following Maintenance Cycle 1. 
 
4.12.1 Criteria to Begin Maintenance Therapy 
• Maintenance begins when peripheral counts recover to ANC ≥ 500/μL and 
platelets ≥ 50,000/μL, whichever occurs later. This count recovery applies to 
Maintenance Cycle 1 only.  
• For subsequent Maintenance cycles, please follow the dose modifications for 
low ANC or low platelets (Section 5.9).  
• Only oral mercaptopurine and methotrexate will be interrupted for 
myelosuppression as outlined in Section 5.9. Triple Intrathecal therapy (ITT), 
vincristine and prednisone will be delivered as scheduled, despite 
myelosuppression. 
 
4.12.2 Duration of Cycles in Maintenance Therapy 
• Maintenance consists of 12 week cycles repeated until total duration of 
therapy is 2 years from start of Block 1 therapy for both male and female 
patients.  
• Therapy may be stopped on anniversary date if the 5-day dexamethasone is 
completed for the cycle (i.e. complete all 5 days of dexamethasone before 
ending therapy). Otherwise continue current cycle through dexamethasone 
administration. 
 
4.12.3 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 

 
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4.12.4 Maintenance Chemotherapy Cycle 1 
Dexamethasone: PO (may be given IV) 
Days: 1 - 5, 29 - 33, & 57 - 61 
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 29, 57 
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Mercaptopurine: PO 
Days: 1 - 84  
Dose: 75 mg/m²/dose* once daily 
Other Considerations: 
• 
*See Section 5.9 for suggested starting dose based on TPMT status, if 
known 
• 
Mercaptopurine should be taken consistently at the same time every 
day.  
• 
The liquid or tablet formulation may be used. If using tablets, adjust 
daily dose using the dosing nomogram in Appendix III to attain a 
weekly cumulative dose as close to 525 mg/m2/week as possible 
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Day: 1 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY 
Day: 1 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 

 
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3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
Methotrexate: PO 
Days: 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78  
Dose: 20 mg/m2/dose 
 
4.12.5 Following Maintenance Cycle 1: 
• 
ONLY 
CNS3 
will 
receive 
Chemoradiation 
(see 
Section 
4.13, 
APPENDIX II-K) prior to moving on to subsequent Maintenance cycles 
(Maintenance-Post Cycle 1, Section 4.14, APPENDIX II-L). 
• 
All other patients in both Arm C and Arm D will continue on to 
Maintenance-Post Cycle 1 (Section 4.14, APPENDIX II-L). 
 
 

 
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4.13 
Maintenance Chemoradiation - 3 weeks 
The CNS-directed therapy described in this section is for LR B-ALL CNS3 Patients 
ONLY (Patients with late B-ALL isolated CNS3 or CNS3 combined relapse).  
 
The Therapy Delivery Map for this additional CNS-directed therapy during Maintenance 
is in APPENDIX II-K. 
 
4.13.1 Criteria to Begin Maintenance Chemoradiation 
Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL. 
 
4.13.2 Cranial Radiation Therapy 
Cranial radiation will be administered during this phase of therapy, which is 
between the 1st and 2nd cycles of Maintenance therapy. Patients with CNS3 and 
isolated CNS relapse will receive 1800 cGy cranial radiation to the brain in 
10 daily fractions along with concurrent chemotherapy. See Section 14.1 for 
details on cranial irradiation. 
 
4.13.3 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA. 
 
4.13.4 Chemotherapy Guidelines for Maintenance Chemoradiation 
Dexamethasone: PO (may be given IV) 
Days: 1 - 7, 15 - 21 
Dose: 5 mg/m²/dose (Total daily dose: 10 mg/m²/day, divided BID; dose capped 
at 40 mg per day) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 8, and 15 
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 

 
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Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Pegaspargase: IV over 1-2 hours  
Day: 
1 
Dose: 2,500 International Units/m2/dose 
 
Special precautions: 
1. Pegaspargase is contraindicated with a history of severe pancreatitis with any 
prior asparaginase therapy. Caution should be used if serious thrombosis or 
hemorrhagic events have occurred with any prior asparaginase therapy (see 
Section 5.1) 
2. Pegaspargase may affect coagulation factors and predispose to bleeding and/or 
thrombosis. Caution should be used when administering any concurrent 
anticoagulant therapy. 
3. Suggested monitoring during and after administration: Because pegaspargase 
is long acting, hypersensitivity reactions may not appear for hours after drug 
administration. Monitor vital signs, for signs of fever, chills, or acute allergic 
reactions including anaphylaxis. Have medications to treat hypersensitivity 
reactions readily available at each administration (e.g., epinephrine, IV 
corticosteroids, antihistamines). Consider prescribing an EpiPen® for home 
use. 
 
4.13.5 Following Maintenance Chemoradiation: 
• 
All patients will continue on to Maintenance-Post Cycle 1 (see Section 4.14, 
APPENDIX II-L). 
 

 
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4.14 
Maintenance-Post Cycle 1 (All LR patients) 
Maintenance-Post Cycle 1 therapy is common for all LR B-ALL patients randomized to 
either Arm C or Arm D. See Experimental Design Schema. 
 
NOTE: CNS3 and Isolated CNS Relapse ONLY are to be given Chemoradiation (see 
Section 4.13, APPENDIX II-K) between Maintenance Cycle 1 and subsequent 
Maintenance cycles (Maintenance-Post Cycle 1). All other patients receive 
Maintenance-Post Cycle 1 immediately following Maintenance Cycle 1. 
 
4.14.1 Criteria to Continue Maintenance Therapy 
Maintenance continues based on the dose modifications for low ANC or low 
platelets (see Section 5.9). Only oral mercaptopurine and methotrexate will be 
interrupted for myelosuppression as outlined in Section 5.9. Triple Intrathecal 
therapy, vincristine and prednisone will be delivered as scheduled, despite 
myelosuppression. 
 
4.14.2 Duration of Cycles in Maintenance Chemotherapy 
• 
Maintenance consists of 12 week cycles repeated until total duration of 
therapy is 2 years from start of Block 1 therapy for both male and female 
patients.  
• 
Therapy may be stopped on anniversary date if the 5 day dexamethasone is 
completed for the cycle (i.e. complete all 5 days of dexamethasone before 
ending therapy). Otherwise continue current cycle through dexamethasone 
administration. 
 
4.14.3 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA.  
 
4.14.4 Chemotherapy Guidelines for Maintenance-Post Cycle 1 
Dexamethasone: PO (may be given IV) 
Days: 1 - 5, 29 - 33, & 57 - 61 
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID) 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed. 
 
 
 

 
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VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 29, 57  
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). Use conventional vinCRIStine 
only; the conventional and liposomal formulations are NOT interchangeable. 
 
Mercaptopurine: PO 
Days: 1 - 84 
Dose: 75 mg/m²/dose* once daily 
 
Other Considerations: 
• 
*See Section 5.9 for suggested starting dose based on TPMT status (if 
status is known) 
• 
Mercaptopurine should be taken consistently at the same time every 
day.  
• 
The liquid or tablet formulation may be used. If using tablets, adjust 
daily dose using the dosing nomogram in Appendix III to attain a 
weekly cumulative dose as close to 525 mg/m2/week as possible 
 
Methotrexate: PO - CNS3 PATIENTS ONLY 
Day: 
1 
Dose: 20 mg/m²/dose 
 
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY 
Day: 
1 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
Methotrexate: PO 
Days: 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78  
Dose: 20 mg/m2/dose 
 
 

 
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4.15 
Blinatumomab Block: Cycle 1 (Patients in Arm D) - 5 weeks  
The therapy described in this section is for the 1st cycle of therapy with Blinatumomab on 
Arm D. See Experimental Design Schema.  
 
The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 1 (Arm D) is in 
APPENDIX II-M. 
 
NOTE: Hospitalization is STRONGLY recommended during the first 9 days of this cycle 
in case of a cytokine reaction. Manifestations of cytokine release syndrome include fever, 
headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased 
aspartate aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC). Corticosteroids should be administered for severe or life threatening 
cytokine release syndrome. 
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. Administration of 
the premedication (dexamethasone) described in Section 4.5.4, is recommended. If 
possible, the infusion time before and after a break should sum up to 28 days treatment per 
cycle. 
 
4.15.1 Criteria to Begin Blinatumomab 
Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL 
 
4.15.2 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I 
for Supportive Care Guidelines.  
 
Dosing should be based on actual BSA. There is no maximum dosing. 
 
 
 
 

 
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4.15.3 Blinatumomab Block: Cycle 1 (Patients in Arm D) Chemotherapy 
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1 - 28 
Dose: 15 micrograms/m²/day 
 
*IV bag will be changed every 24 - 96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
 
Dexamethasone: PO/IV 
Day: 
1  
Dose: Prior to day 1 therapy -  
• 
A single dose of 5 mg/m2/dose (maximum 20 mg/dose) will be 
administered 30 to 60 minutes prior to the start of the blinatumomab 
infusion and when restarting an infusion after an interruption of 4 or 
more hours in the first cycle.  
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions 
are acceptable and intravenous preparations may be used on a temporary 
basis, if needed 
 
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY 
Day: 
8, 29 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg  
 
Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY 
Days: 8, 29 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 – 2.99 
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
4.15.4  Following Blinatumomab Block: Cycle 1 (Arm D)  
The next phase of therapy is Continuation 1 (Section 4.11, APPENDIX II-I). 
 
 

 
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4.16 
Blinatumomab Block: Cycle 2/3 (LR Patients in Arm D) - 5 weeks  
The therapy described in this section is therapy given during Blinatumomab Block Cycle 2 
and Blinatumomab Block Cycle 3. Do not start Blinatumomab Cycle 2 before Day 56 after 
beginning of Continuation 1. Do not start Blinatumomab Cycle 3 before Day 56 after 
beginning of Continuation 2. See Experimental Design Schema.  
 
NOTE: Hospitalization is STRONGLY recommended during the first 2 days of these 
cycles in case of a cytokine reaction. Manifestations of cytokine release syndrome include 
fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, 
increased aspartate aminotransferase, increased total bilirubin, and disseminated 
intravascular coagulation (DIC). Corticosteroids should be administered for severe or life 
threatening cytokine release syndrome. 
 
The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 2/3 (Arm D) is in 
APPENDIX II-N. 
 
Blinatumomab infusion interruptions for technical reasons: 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption due to any technical or logistic reason the interruption should be as short as 
possible and the infusion continued at the earliest time possible. Every interruption longer 
than one hour should be documented. If the interruption is longer than four hours, re- start 
of the infusion should be performed in the hospital, under supervision of the investigator. 
The patient should be observed overnight for possible side effects after the re-start in the 
hospital and can be discharged the following day if no difficulties arise. If possible, the 
infusion time before and after a break should sum up to 28 days treatment per cycle. 
 
4.16.1 Criteria to Begin Blinatumomab Block: Cycle 2/3 
Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL 
 
4.16.2 General Chemotherapy Guidelines 
See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy 
Administration 
Guidelines 
(CAGs) 
on 
the 
COG 
website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf 
for 
special 
precautions 
associated 
with 
chemotherapy 
administration. As applicable, also see the CAGs for suggestions on hydration, or 
hydrate according to institutional guidelines. 
 
See Appendix VII-A for the management options of blinatumomab in the 
outpatient setting. 
 
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for 
Supportive Care Guidelines.  
 
Dosing should be based on actual BSA. There is no maximum dosing. 
 
4.16.3 Blinatumomab Block: Cycle 2/3: Chemotherapy Guidelines  
Blinatumomab: IV; Continuous Infusion over 28 days* 
Days: 1 - 28 

 
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Dose: 15 micrograms/m²/day 
 
*IV bag will be changed every 24 - 96 hours or every 168 hours (7 days), 
depending on the details of the infusion preparation 
(NOTE: Administration of the premedication (dexamethasone) is NOT 
RECOMMENDED for the second or third cycle of blinatumomab.) 
 
4.16.4 Following Blinatumomab Block Cycle 2: 
LR B-ALL patients randomized to the experimental arm (Arm D) will receive 
Continuation 2- (Section 4.11, APPENDIX II-I) 
 
4.16.5 Following Blinatumomab Block Cycle 3: 
LR B-ALL patients randomized to the experimental arm (Arm D) will receive 
Maintenance Cycle 1 therapy- (Section 4.12, Appendix II-J.) 
 
 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
Notify the Study Chair at the time of removing a patient from protocol therapy for toxicity. The 
drugs are listed in alphabetical order. 
 
5.1 
Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 
Systemic Allergic Reactions/Anaphylaxis:  
For severe allergic reaction, discontinue pegaspargase and substitute Erwinia. Erwinia 
therapy should begin within 72 hours of the pegaspargase reaction or as soon as possible. 
Erwinia dosing: 25,000 international units (IU)/m2 IM M-W-F for six doses substituted for 
each dose of pegaspargase.  If Erwinia is given IV it should be given as a 1-2 hour infusion. 
Note that the M-W-F schedule documenting acceptable activity was established using IM 
not IV Erwinia; thus consideration should be given to administer IV Erwinia at the above 
dose every other day for 2 weeks (7 total doses).     
For mild-moderate reversible reaction: 
1. If the infusion was completed, consider sending an asparaginase activity 
level.  Note that a therapeutic level of asparaginase of at least 0.1 IU/mL 14 days 
after administration is considered therapeutic.  Please see the table below for 
guidance on using levels to switch to Erwinia asparaginase. Management decisions 
for levels obtained on other days are up to the treating physician. 
2. If the infusion was discontinued early, consider re-challenging with pegaspargase 
after premedication and send asparaginase levels as above.   
Premedication with antihistamines in the absence of prior hypersensitivity has been 
discouraged in the past since antihistamine use may mask the appearance of systemic 
allergy and fail to alert the provider of the presence of asparaginase neutralizing antibodies. 
The use of asparaginase activity assays, as described above, are commercially available 
and may help determine if neutralizing antibodies are present.   
If there is a question of silent inactivation, check levels as described above between 1 hour 
and 7 days after the dose. Change to Erwinia based on activity levels described above. Of 
note, Erwinia asparaginase is recommended only for pegaspargase hypersensitivity 
reactions and/or in the presence of silent antibody. It is not recommended as a substitute 
for pancreatitis, hepatitis, coagulation abnormalities, or other non-hypersensitivity 
toxicities associated with pegaspargase. To best suit the needs of each individual patient, 
additional modifications to these recommendations may be made at the discretion of the 
treating physician. 
 
Coagulopathy: If symptomatic, hold asparaginase until symptoms resolve, then resume with 
the next scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do 
not withhold dose for abnormal laboratory findings without clinical symptoms.  
 
Hyperbilirubinemia: asparaginase may need to be withheld in patients with an elevated 
direct bilirubin, since asparaginase has been associated with hepatic toxicity. No specific 
Time point after completion of 
pegaspargase infusion 
Asparaginase activity level 
Action 
1 hour – 1 day 
< 0.5 IU/mL 
Substitute Erwinia asparaginase 
7 days 
< 0.3 IU/mL 
Substitute Erwinia asparaginase 
14 days 
< 0.1 IU/mL 
Substitute Erwinia asparaginase 

 
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dose adjustment guidelines are provided in the manufacturer’s labeling. Below are proposed 
dose adjustment guidelines from published literature:42 
 
Direct Bilirubin 
Dose Modification 
< 3.0 mg/dl 
Full dose 
3.1 – 5.0 mg/dl 
Hold pegaspargase and resume when direct bilirubin is < 2 mg/dl; consider 
switching to alternate asparaginase product 
>5.0 mg/dl 
Hold the dose of pegasparagase; do not substitute other asparaginase products; 
do not make up the missed dose 
 
Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically indicated. 
 
Hyperlipidemia: Do not modify dose  
 
Ketoacidosis: Hold asparaginase until blood glucose can be regulated with insulin. 
 
Pancreatitis: Discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the 
case of asymptomatic Grade 2 pancreatitis (enzyme elevation or radiologic findings only), 
asparaginase should be held until symptoms and signs subside, and amylase/lipase levels 
return to normal and then resumed.  
 
Thrombosis (including CNS and non-CNS events): Withhold asparaginase until resolved, and 
treat with appropriate antithrombotic therapy and consider repletion of AT-III, as indicated. 
Upon resolution of symptoms consider resuming asparaginase, while continuing low 
molecular weight heparin (LMWH) or antithrombotic therapy. Do not withhold dose for 
abnormal laboratory findings without clinical correlate. Consider measurement and repletion 
of AT-III during subsequent courses of asparaginase if unable to achieve therapeutic Anti-Xa 
levels. For significant thrombosis, which is not catheter-related, consider evaluation for 
inherited predisposition to thrombosis.  
 
5.2 
Blinatumomab 
The most frequent serious adverse events noted in patients treated with 
blinatumomab to date are disorders of the nervous system, both peripheral and 
central, and systemic cytokine release syndrome (CRS), though both are less likely to 
occur in patients with lower burden of disease at the time of administration. Both 
categories of events are more likely to occur within the first week of treatment with 
blinatumomab, and both categories of events are usually reversible and able to be 
managed with attentive supportive care. 
 
AEs related to blinatumomab that require treatment interruption (according to table below) 
and do not resolve to CTCAE ≤ Grade 1 within 14 days will require permanent 
discontinuation of blinatumomab treatment. If the patient is otherwise eligible to continue 
protocol therapy (standard chemotherapy and/or HSCT), then the patient may, at the 
discretion of the investigator and family, continue to receive protocol therapy.  
 
In the case that the AE(s) DO resolve within 14 days, blinatumomab treatment may 
resume at a reduced dose of 5 mcg/m2/day to complete the 28 day course (not counting 
the duration of treatment interruption). NOTE: For Grade 4 Central Nervous 

 
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System/Psychiatric, Grade 4 thromboembolic or Grade 4 CRS AEs, blinatumomab 
must be permanently discontinued.  
 
For patients who had experienced a ≥ Grade 2 Neurologic Systems and Psychiatric AE 
related to blinatumomab, no dose escalation beyond 5 mcg/m2/day will be permitted for 
subsequent cycles. For patients who experienced other AEs related to blinatumomab, 
subsequent cycles will begin at the reduced dose of 5 mcg/m2/day, but may escalate to 
15 mcg/m2/day after 7 days if there are no significant blinatumomab-related AEs.  
 
A second occurrence of the same AE that requires interruption will require permanent 
discontinuation of blinatumomab. If the patient is otherwise eligible to continue protocol 
therapy (standard chemotherapy, and or HSCT), then the patient may, at the discretion of 
the investigator and family, continue to receive protocol therapy. 
 
The resumption of the infusion at the reduced dose should be accompanied by 
dexamethasone premedication as indicated in the relevant subsection of Section 4.0, and 
should be performed in the hospital under supervision of the investigator. Patients should 
be observed for at least 72 hours after the start of the next infusion at the reduced dose 
before considering discharge to the outpatient setting. 
 
Table: Dose modifications for Adverse Events (AE) Possibly, Probably or Definitely Related to 
Blinatumomab:  
Category: AE  
(CTCAE v4.03) 
AE 
Grade 
Stop 
Infusion? 
Supportive 
Care (in 
addition to 
institutional 
guidelines)* 
Restart 
allowed (with 
dex premeds) 
if  
Gr 1 within 
14 days? 
Restarting 
dose 
(mcg/m2/day) 
Escalation to  
15 mcg/m2/day 
after 7 days 
(with dex 
premed) in 
subsequent 
cycle allowed? 
Nervous system/ 
Psychiatric1: (Confusion, 
Hallucination, Delerium, 
Psychosis), Dysarthria, 
Tremor 
 
1 
N 
CNS 
- 
- 
- 
2 
N 
CNS 
- 
- 
- 
3 
Y 
CNS, DEX 
Y 
5 
N 
4 
Y 
CNS, DEX 
N 
- 
- 
Central Nervous system: 
Seizure 
1, 2, 3 
Y 
SZ, CNS, DEX 
Y 
5 
N 
4 
Y 
SZ, CNS, DEX 
N 
- 
- 
Immune system: 
Cytokine release 
syndrome- NOTE that it 
is NOT recommended to 
use the CTCAE grading3  
1 
N 
- 
- 
- 
- 
2 
N, unless 
patient is 
unable to 
tolerate 
symptoms 
(e.g. due 
to other 
comorbidi
ties) 
TOCI,DEX 
only if patient is 
unable to 
tolerate 
symptoms (e.g. 
due to other 
comorbidities) 
Y 
5 
Y 
3 
Y 
TOCI, DEX 
Y 
5 
Y 
4 
Y 
DEX 
N 
- 
- 

 
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Blood and lymphatic 
system4: Disseminated 
intravascular 
coagulation, hemolysis, 
hemolytic uremic 
syndrome, thrombotic 
thrombocytopenic 
purpura 
1, 2 
N 
- 
- 
- 
- 
3, 4 
Y 
- 
Y 
5 
Y 
Blood and lymphatic 
system5: All others 
(lymphopenia, 
neutropenia, anemia, 
thrombocytopenia, etc.) 
1, 2, 3, 4 
N 
- 
- 
- 
- 
Vascular: 
Thromboembolic event 
1 
N 
- 
- 
- 
- 
2, 3 
Y 
- 
Y 
5 
Y 
4 
Y 
- 
N 
- 
- 
Investigations6,7 
Metabolism and 
Nutrition: All  
(if not considered 
clinically relevant or 
responding to routine 
medical management) 
1, 2, 3, 4 
N 
- 
- 
- 
- 
Investigations6,7 
Metabolism and 
Nutrition: All  
(if clinically relevant 
and not responding to 
routine medical 
management) 
1,2 
N 
- 
- 
- 
- 
3,4 
Y 
- 
Y 
5 
Y 
All other AE  
1,2 
N 
- 
- 
- 
- 
3,4 
Y 
- 
Y 
5 
Y 
Table Footnotes: 
1 Most neurologic AEs associated with blinatumomab are central in nature (e.g. dysarthria, 
encephalopathy, tremor). Peripheral neurologic AEs are very unlikely to be secondary to 
blinatumomab, and are far more likely to be secondary to other causes such as vincristine. 
Discontinuation of blinatumomab secondary to peripheral neurologic AEs should be avoided 
when possible. Most AEs in the psychiatric disorders category are unlikely to be caused by 
blinatumomab and generally require supportive care rather than dose modification or 
discontinuation of blinatumomab (e.g., Insomnia, Depression, Anxiety). Psychiatric AEs that 
may reflect underlying central nervous system toxicity (e.g., Confusion, Delirium, Hallucinations, 
Psychosis) are of greater interest, particularly if accompanied by other AEs in the nervous system 
disorders category. 
2 Close monitoring of fluid status by intake and output should be undertaken for the first 48 hours 
of blinatumomab infusion. Efforts to keep patients balanced between intake and output should 
be maintained, even if diuretic therapy (furosemide or similar) is needed to do this. Careful 
attention to fluid status may prevent deterioration from capillary leak, however even with 
meticulous attention some patients may experience pulmonary edema and require more 
aggressive respiratory support. Treating physicians should use their clinical judgment and 
institutional standards for whatever supportive care measures are needed during this period of 
time. 

 
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3 Grading of cytokine release syndrome (CRS) severity should be performed according to that of 
Lee et al (see below table).43 As many of the symptoms of CRS overlap with those of other medical 
complications such as infection, attribution should be carefully considered. Accurate application 
of this grading system requires clinical judgment to confirm that the symptoms are most likely 
due to CRS rather than to another medical condition. In all grades of CRS, aggressive supportive 
care is required. In grade 2 or 3 CRS, careful monitoring of cardiac function is strongly 
suggested. 
 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only, eg. 
fever, nausea, fatigue, headache 
Grade 2 
Symptoms require and respond to moderate intervention 
Oxygen requirement <40%, or 
Hypotension responsive to fluids or low dose of one vasopressor, or 
Grade 2 organ toxicity 
Grade 3 
Symptoms require and respond to aggressive intervention 
Oxygen requirement >=40%, or 
Hypotension requiring high dose of one vasopressor or multiple vasopressors, or 
Grade 3 organ toxicity or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms 
Requirement for ventilator support, or 
Grade 4 organ toxicity (excluding transaminitis) 
 
4 In the first days of treatment, transient DIC-like pictures may develop. Because patients are at 
risk for capillary leak syndrome and cytokine release syndrome, appropriate supportive care 
with dexamethasone (described above), blood products and factors (packed red cells, platelets, 
cryoprecipitate, fresh frozen plasma), vitamin K, and/or albumin should be considered according 
to institutional standards of care.  Particularly in the first week of infusion, when the risk of 
capillary leak and cytokine release is more prominent, appropriate use of blood products and 
factors is preferred if laboratory indications suggest the need for replacement, as large volumes 
of crystalloid fluids tend to exacerbate the capillary leak. 
5 In the first days of treatment, a rapid transient drop in platelets, neutrophils and/or hemoglobin 
may be observed. These effects are not necessarily cytokine-mediated. Counts typically recover 
to baseline during treatment, and usually within two weeks of starting blinatumomab. 
Transfusion of blood and platelets should be performed according to appropriate institutional 
standards. 
6 In the first days of treatment, transient increases in transaminases up to over 1000 U/L may 
develop. These have generally returned to baseline in the 1st week of treatment. 
7 Decrease in serum immunoglobulins have been observed in patients treated with blinatumomab. 
Intravenous immunoglobulin should be administered according to institutional standards, but is 
recommended for any patient with a total IgG level below 400. Immunoglobulin must not be 
administered through the line through which blinatumomab is actively being infused. 
 
* 
Definitions of supportive care abbreviations: 
DEX: Given its potential to interfere with the efficacy of blinatumomab, the use of dexamethasone 
should be reserved for serious side effects that are unresponsive to other treatments (supportive care, 
discontinuation of blinatumomab infusion, tocilizumab) and for clinically significant neurologic 
toxicity. If required, dexamethasone should be administered at a total daily dose of at least 0.2 - 0.4 
mg/kg/day (maximum 24 mg per day) administered preferably intravenous divided 3 - 4 times daily for 
at least 1 day but no more than 4 days. The dose should then be stopped or tapered as clinically 
indicated. 

 
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SZ: Appropriate imaging should be performed to evaluate for possible hemorrhage or thrombosis, and 
other diagnostic procedures should be performed as clinically appropriate. Prophylactic anticonvulsant 
treatment with a therapeutic dose of institutional standard agents (e.g., lorazepam, phenytoin, 
levetiracetam) should be administered if seizures develop, and continued throughout the blinatumomab 
infusion. Anti-convulsant therapy should be considered starting at least 24 - 48 hours prior to any 
subsequent blinatumomab infusions, and continuing for the remainder of those treatment cycles. 
Diagnostic measures to exclude potential infectious causes should be conducted once the patient has 
stabilized (i.e., a lumbar puncture to evaluate for bacterial, viral or fungal sources should be performed). 
Any identified pathology should be treated as clinically appropriate. 
 
CNS: A daily finger-nose-finger or writing sample test is recommended according to age-appropriate 
activities for patients. In adults treated with blinatumomab, it has been found that a daily handwriting 
sample can often predict future nervous system toxicity before the clinical toxicity develops. 
Dexamethasone should be used for clinically significant neurologic toxicity. In case of a change in 
finger-nose-finger or handwriting test it is recommended to start dexamethasone on the schedule above 
to prevent possible deterioration of nervous system toxicity. Patients who experience nervous system 
toxicity in the first cycle typically do not experience it again in subsequent cycles, although it is 
possible. 
 
TOCI: In patients with CRS who respond to tocilizumab, fever and hypotension often resolve within 
6 hours, and pressors and other supportive care measures can be weaned quickly thereafter. In some 
cases, however, symptoms may not completely resolve, and continued aggressive support may be 
necessary for several days. If the patient’s condition does not improve or stabilize within 24 hours of 
the tocilizumab dose, administration of a second dose of tocilizumab and/or a second 
immunosuppressive agent, such as dexamethasone, should be considered. Tocilizumab is generally not 
used in the management of CNS symptoms without significant hemodynamic instability or other life-
threatening symptomatology. 
TOCI Suggested Dosing: 
• 
<30 kg: 12 mg/kg 
• 
≥30 kg: 8 mg/kg 
 
 
5.3 
Cyclophosphamide 
Gross Hematuria: Omit in the presence of macroscopic hematuria.   
 
Microscopic hematuria:  Begin pre-hydration as in the treatment section of the protocol.  
Increasing the rate and duration of post-hydration should be considered (eg., 200 mL/m2/hr 
x 12-24 hours). Give IV mesna at a total dose that is 100% of the cyclophosphamide dose 
divided to 5 doses.  Give the first mesna dose 15 minutes before or at the same time as the 
cyclophosphamide dose and repeat at Hours 3, 6, 9 and 12 after the start of 
cyclophosphamide. This total daily dose of mesna can also be administered as IV 
continuous infusion. The continuous infusion should be started 15 - 30 minutes before or 
at the same time as cyclophosphamide and finished no sooner than 12 hours after the start 
of cyclophosphamide infusion. If the child develops gross hematuria, continue mesna 
infusion for 24 hours from the start of the cyclophosphamide infusion. 
 
Renal Dysfunction: If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, 
reduce dose of cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the 
creatinine clearance should be repeated with good hydration. 

 
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5.4 
Cytarabine (ARAC) 
Cytarabine Syndrome: Do not withhold cytarabine for fever if it is likely to have been 
caused by the cytarabine. Obtain blood cultures if a central line is present.  
 
For rash or conjunctivitis, withhold for Grade 3 - 4 toxicity until resolved. Make up missed 
doses and consider concurrent treatment with hydrocortisone or dexamethasone, and/or 
with dexamethasone ophthalmic drops for conjunctivitis.  
 
Myelosuppression: Do not interrupt high dose (3,000 mg/m2/dose) cytarabine, once started, 
for uncomplicated myelosuppression; do hold for proven or presumed serious infection and 
do not make up missed doses during Block 3. 
 
Once Continuation 1 and 2 have started, do not interrupt for uncomplicated 
myelosuppression; do hold for proven or presumed serious infection. 
 
Stipulations for High Dose Cytarabine: Adequate renal function (defined as creatinine 
within normal range) is required for the administration of high dose (3,000 mg/m2/dose) 
cytarabine. Creatinine clearance (CrCl) should be measured for patients with elevated 
creatinine or suspected renal insufficiency. For CrCl < 60 mL/min/1.73 m2, hold pending 
recovery and omit if CrCl < 30 mL/min/1.73 m2 or if recovery requires > 3 weeks. 
 
Neurotoxicity:  Discontinue cytarabine immediately for > Grade 2 CNS toxicity, (e.g., 
ataxia, nystagmus, dysarthria, dysmetria, seizures and/or encephalopathy). 
 
5.5 
Anthracycline-Mitoxantrone 
Consider Dexrazoxane prior to each dose for patients with: 
• 
Anticipated cumulative anthracycline dose >150 mg/m2.  
• 
Past or anticipated radiotherapy including the myocardium (including whole-abdomen 
or left flank irradiation).  
• 
Recommended dose of dexrazoxane is 10 x the DAUNOrubicin/DOXOrubicin dose or 
30 x the mitoXANtrone dose, given over 5-15 minutes immediately before the 
chemotherapeutic agent.  
 
Monitoring Cardiac Echocardiogram:  
At baseline and then recommended after cumulative dose of 175, 300, 375, and 450 mg/m2. 
 
Dose modification for cardiac toxicity:  
If left ventricular ejection fraction (EF) < 50% (as determined by the Biplane Simpson 
method), or if EF inevaluable shortening fraction (SF) < 24%, hold the anthracycline or 
anthracenedione and repeat the echocardiogram in one week.  If EF remains < 50% (or if 
EF inevaluable, SF < 24%), discontinue the anthracycline or anthracenedione and deliver 
alternate therapy as per the protocol or provider decision.  Resuming cardiotoxic therapy 
depends on the cause of the cardiac dysfunction and the results of further cardiac 
evaluation.   
 
Myelosuppression (beyond Induction):   
If patient has severe infection or severe mucositis, consider modifying or omitting 

 
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anthracycline. 
 
Hyperbilirubinemia:  
Direct Bilirubin 
Dose Adjustment 
< 3.0 mg/dl 
Full dose 
3.1 – 5.0 mg/dl 
Administer 50% of calculated dose 
5.1 – 6.0 mg/dl 
Administer 25% of calculated dose 
> 6.0 mg/dl 
Withhold dose and administer next scheduled dose if toxicity has resolved. Do 
not make up missed doses. 
 
Extravasation:  
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to 
institutional 
guidelines. 
Also, 
see 
https://cogmembers.org/_files/disc/pharmacy/
ExtravasationReference.pdf  for COG reference. 
 
5.6 
Etoposide  
Allergic Reaction: Premedicate with diphenhydramine (1-2 mg/kg slow IV push, 
maximum dose is 50 mg). If symptoms persist, add hydrocortisone 100-300 mg/m2. 
Continue to use premedication before etoposide in future. Also consider substituting an 
equimolar amount of etoposide phosphate, in the face of significant allergy and/or 
hypotension. Etoposide phosphate is a water soluble prodrug that does not contain 
polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that may induce 
allergic reactions and hypotension. Etoposide phosphate is rapidly converted to etoposide 
in vivo and provides total drug exposure, as represented by AUC (0-infinity), that is 
statistically indistinguishable from that measured for etoposide at equimolar doses. 
 
Hypotension: If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, 
reduce infusion rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to 
recover or falls further. Stop infusion if BP does not recover, continue NS. If the patient 
has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours 
prior to any subsequent infusion. 
 
Renal Insufficiency: If renal function decreases, adjust etoposide as follows: CrCl 10-50 
mL/min/1.73 m2, decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 
50%. 
 
Hyperbilirubinemia: If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct 
bilirubin is > 5 mg/dL, hold etoposide. 
 
 
5.7 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
Systemic toxicity: The dosage for IT methotrexate will not be reduced for systemic toxicity 
(myelosuppression, mucositis, etc.). Instead, leucovorin may be used at a dose of 
5 mg/m2/dose every 6 hours x 2 doses, beginning 24 hours after the IT therapy may be 
administered in an attempt to reduce the risk of worsening already existent 
myelosuppression (ANC < 500/µL) or mucositis. Do not administer leucovorin solely to 
prevent myelosuppression.  

 
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Dose modifications following an episode of acute neurotoxicity: 
Neurotoxicity has extremely protean manifestations, ranging from transient events, 
seizures or episodes of acute hemiparesis, to severe necrotizing encephalopathies.44-46  
 
The following guidelines are offered for consideration following an acute event, but it must 
be recognized that there are little data to support these approaches or any others. Many 
acute events, seizures or episodes of transient hemiparesis, are temporally related to the 
administration of intrathecal therapy, commonly 9 to 11 days after the IT administration.47 
 
Complete clinical evaluation including imaging of the brain is strongly recommended. 
For patients who return to their baseline pre-event neurological status, clinicians may: 
 
1. hold the next dose planned dose of IT therapy, or  
2. substitute IT cytarabine or IT cytarabine/hydrocortisone for 1 dose of IT 
methotrexate or 
3. proceed with IT methotrexate and include leucovorin rescue at a dose of 5 mg/m2 
IV/PO q 6 hrs x 2 doses beginning 24 hours after the LP. 
 
If the event does not recur, resumption of standard therapy should be considered for 
subsequent intrathecal therapy.  
 
For patients who do not return to baseline pre event neurological status or for those with  
recurrent events, or evidence of progressive encephalopathy, additional evaluations may 
be warranted and the treating physician may consider a more prolonged or definitive 
change in therapy upon discussion with the Study Chair.  
 
Leucovorin rescue of IT MTX without acute neurotoxicity 
Prevention of neurotoxicity by using leucovorin after IT MTX has not been studied in a 
randomized fashion. Neither the BFM, DFCI, nor COG have routinely introduced 
leucovorin rescue to prevent acute neurotoxicity, however SJCRH protocols use leucovorin 
rescue during remission induction and consolidation phases. The cumulative incidence of 
all neurotoxicities among non-DS patients enrolled on AALL0932 and AALL1131 indicate 
a less than 1% incidence of acute neurotoxicity during induction. For non-DS patients 
enrolled on AALL0932, the incidence during consolidation was 0.3%. For non-DS patients 
receiving consolidation therapy on AALL1131, the incidence was 3.3%.  
 
For the reasons above, it is permissible for patients receiving augmented consolidation such 
as that prescribed for NCI-SR-High (AALL1731) or NCI-HR (AALL1732) patients to 
receive leucovorin during consolidation therapy after the 4 doses of weekly IT MTX on 
the following schedule:  
1. Leucovorin, 5 mg/m2 IV/PO at hours 24 and 30 after IT MTX.  
 
It is not known if providing leucovorin rescue after IT MTX during consolidation as a 
measure to reduce acute neurotoxicity will reduce therapeutic efficacy in the context of 

 
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COG protocols.  
 
Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal 
chemotherapy via lumbar puncture:  
Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal 
therapy delivered by LP. Intraventricular chemotherapy should be given according to the 
same schedule, but at 50% of the corresponding age-based doses that would be given 
by LP. NOTE: Obstruction to CSF flow may be a contraindication to intrathecal and/or 
intraventricular therapy. 
 
Viral, bacterial, or fungal meningitis: Omit until resolved. 
 
5.8 
Intermediate-Dose Methotrexate (ID MTX) and Leucovorin Rescue  
[Please note that IDMTX refers to IV MTX 1000 mg/m2 given over 36 hrs] 
 
5.8.1 
ID MTX Infusion Guidelines and dose modifications for toxicity 
When IT therapy and ID MTX are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Hold trimethoprim/sulfamethoxazole (TMP-SMX), any nonsteroidal anti-
inflammatory medications, penicillins, proton pump inhibitors or aspirin-
containing medications on the day of ID MTX infusion and for at least 72 hours 
after the start of the ID MTX infusion and until the MTX level is less than 0.5 M 
for ID MTX. In the presence of delayed clearance continue to hold these medications 
until MTX level is less than 0.1 µM. 
 
Recommended Prehydration: to start at least 6 hours prior to commencement of 
intravenous methotrexate. Fluid: D5 ¼ NS with 30 - 50 mEq NaHCO3/L at 
125 mL/m2/hour. Ringers Lactate may be used as the initial fluid if a bicarbonate 
containing solution is unavailable. Adjust fluid volume and sodium bicarbonate to 
maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A bicarbonate 
bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH relatively 
quickly; a normal saline bolus may also be helpful in facilitating hydration.  
 
Hour 0: MTX 100 mg/m2 IV infused over 30 minutes. This is followed, 
immediately, by MTX 900 mg/m2 given by continuous IV infusion over 
35.5 hours. Be certain that the ID MTX infusion is completed in the 36 hour period. 
Note, even if the infusion is not complete at this time point, it must be stopped. 
 
Recommended Posthydration: Continue hydration using D 5 ¼ NS with 
30 – 50 mEq NaHCO3/L at 125 mL/m2/hour (3 L/m2/day) throughout IDMTX 
infusion until the last dose of leucovorin has been given. In patients with delayed 
MTX clearance, continue hydration until the plasma MTX concentration is below 
0.1 μM. 
 
Leucovorin rescue: 15 mg/m2 PO/IV at 48 and 54 hrs after the start of the MTX 
infusion. If 48 hr methotrexate level is ≤ 0.5 μM, then only two doses of leucovorin 
are administered (at 48 and 54 hours). If MTX level at 48 hours is > 0.5 μM, then 

 
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continue hydration and leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours 
until MTX levels are < 0.1 μM. 
 
Hour 48: Check plasma methotrexate level at 48 hours after start of the 
methotrexate infusion. If the level is ≤ 0.5 μM, then do not give more than two 
doses of leucovorin (48 and 54 hours). If MTX level at 48 hours is > 0.5 μM, then 
continue hydration and leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours 
until MTX levels are < 0.1 μM. 
 
For MTX levels that exceed these expected values modify the rescue regimen 
as noted below and increase hydration to 200 mL/m2/hr. Monitor urine pH to 
assure a value ≥ 7.0 and monitor urine output to determine if volume is ≥ 80% of 
the fluid intake, measured every 4 hours. If serum creatinine rises significantly, at 
any time point (> 100% in 24 hours), assure appropriate urine pH and urine volume 
as above and consider glucarpidase If urine output fails to continue at 80% of the 
fluid intake, consider furosemide or acetazolamide. Regardless of urine output, 
also consider glucarpidase (carboxypeptidase G2) (see below).  
 
48 hr MTX 
level 
Leucovorin Rescue 
≤ 0.5 M 
Continue 15 mg/m2 IV/PO q 6hrs for 2 doses. 
0.5 – 1 M 
Increase to 15 mg/m2 q 6 hrs until MTX level < 0.1 M (draw q 6-
24 hrs). 
1 – 5 M 
Increase to 15 mg/m2 q 3 hrs until MTX level < 0.1 M (draw q 6-
24 hrs). 
5 – 10 M 
Increase to 100 mg/m2 q 6hrs until MTX level < 0.1 M (draw q 6-
24 hrs). 
> 10 M 
Increase to 1000 mg/m2 q 6hrs until MTX level < 0.1 M (draw q 6-
24 hrs). 
Consider glucarpidase. 
 
Nephrotoxicity: Postpone course if pre-treatment (MTX) serum creatinine is 
> 1.5 x baseline or GFR creatinine clearance < 65 mL/minute/1.73m2. If there is a 
rising creatinine (> 100% in 24 hours) or the 48 hour methotrexate level is > 10 μ/L 
consider using glucarpidase. If renal function does not recover, omit MTX. Do not 
give ID MTX to a patient with this degree or renal impairment, assuming that 
prolonged excretion can be managed with glucarpidase. 
 
NOTE: For patients who have markedly delayed MTX clearance secondary to 
renal 
dysfunction, 
consider 
using 
glucarpidase 
(carboxypeptidase 
G2, 
Voraxaze).48,49 To obtain supplies of glucarpidase in the US contact the Voraxaze 
24-hour Customer Service line at 855-786-7292. Additional information can be 
found 
at 
https://www.voraxaze.com/Order-Voraxaze 
regarding 
product 
availability through ASD Healthcare, Cardinal, and McKesson. Canadian sites 
should contact McKesson at (877) 384-7425 for further information. Sites in 
Australia and New Zealand should contact Hospira at 1300 – 046 – 774 (local) or 
medicalinformationAUS@hospira.com. Patients requiring glucarpidase rescue 
will remain on study. 
 
Stop leucovorin 2 hours before administering glucarpidase as it is a competitive 
substrate and may compete with MTX for glucarpidase binding sites. 

 
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Dose of glucarpidase: 50 units/kg administered by intravenous bolus over 
5 minutes. Reconstitute each vial with 1 mL sodium chloride 0.9% (do not further 
dilute). Each vial contains 1,000 units/mL (after reconstitution) and round dose up 
to vial size. No further dose is required. 
 
Maintaining alkalinization of urine with sodium bicarbonate is essential to 
maintain urinary pH > 7. 
 
It is essential that patients are NOT co-prescribed the following medicines which 
reduce MTX excretion: NSAIDS, aspirin, ciprofloxacin, co-trimoxazole, 
penicillins, probenecid, omeprazole (or other proton pump inhibitors). 
 
Two hours after administration of glucarpidase, leucovorin should be administered 
at a dose of 250 mg/m2 every 6 hours by IV bolus (maximum rate: 160 mg/min) 
for up to 48 hours and then decreased based on plasma MTX concentrations to 
15 mg/m2 intravenously or orally every 6 hours until the plasma MTX 
concentration is < 0.2 μM. 
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn 
within 72 hours, PRIOR to a course of intravenous MTX. Blood samples for ALT 
should not be drawn following the start of MTX infusions as MTX causes 
significant short term elevation in ALT levels. 
 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 
consecutive cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then 
resume at full doses at point of interruption. 
Do not skip doses. 
> 20 X ULN 
Hold therapy until ALT < 10 X ULN, then 
resume at full doses at point of interruption.  
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, 
PT, albumin, total protein, and hepatitis A, B, 
C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy 
given. Notify Study Chair. 
* Please see COG Supportive Care Guidelines in Appendix I for trimethoprim-sulfamethoxazole 
(TMP/SMX) substitutions. 
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
Mucositis: For Grade 3 - 4 mucositis, withhold IV MTX until resolved. Increase 
leucovorin rescue following the next course from 2 to 4 doses on a q6 hr schedule. If 
subsequent course is not associated with Grade 3 - 4 mucositis, attempt to decrease 
the number of leucovorin doses to 2. If mucositis recurs despite the extended 
leucovorin, decrease the dose of MTX by 25%, increase hydration to 200 mL/m2/hr 
and continue increased leucovorin as above. Should subsequent courses be well 

 
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tolerated, use a stepwise approach to resuming a standard approach to drug delivery. 
Consider culturing lesions for herpes simplex if mucositis persists or recurs. 
 
See Section 5.13 for dose modifications when MTX is used post HSCT. 
 
5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
During Continuation: 
ANC < 500/L and/or platelets < 50,000/L:  
Discontinue dose until ANC is  750/L and platelets are  75,000/L. Restart 
mercaptopurine and/or MTX at 50% of the original dose on the same day the counts 
recover. Increase to 75% and then 100% of the original dose at 2-week intervals provided 
ANC remains  750/L and platelets remain  75,000/L. Consider a marrow evaluation 
in the face of persistent or prolonged neutropenia.  
 
Prolonged cytopenia is defined as ANC < 750/µL and/or platelets < 75,000/µL after 
withholding therapy for > 2 weeks. Perform a bone marrow examination after 2 weeks of 
withholding chemotherapy, if no recovery is apparent. If monocyte count is increasing or 
viral myelosuppression is clinically suspected, the bone marrow examination may be 
postponed for 1 - 2 weeks and omitted if ANC and platelets fully recover by the 4th week 
after therapy is withheld. 
 
If patient develops severe or unexpected myelosuppression, i.e., doesn’t tolerate at least 
half dose MP, see section below on thiopurine pharmacology testing. 
 
During Maintenance:  
Myelosuppression: If absolute neutrophil count (ANC) falls below 500/µL or if platelet 
count falls below 50,000/µL during Maintenance, mercaptopurine and methotrexate should 
be held until recovery above these levels. 
 
1. For the first drop below 500/µL ANC or platelet count < 50,000/µL, resume 
mercaptopurine and methotrexate at the same dose the patient was taking prior to the 
episode of myelosuppression when ANC ≥ 500 /µL and platelet count ≥ 50,000/µL. 
2. If ANC falls below 500/µL or if platelet count falls below 50,000/µL for a second (or 
greater) time, hold mercaptopurine and methotrexate until ANC is ≥ 750/µL and 
platelets are ≥ 75,000/µL. Consider discontinuing trimethoprim/sulfamethoxazole 
(TMP/SMX) in favor of an alternative approach to Pneumocystis prophylaxis. 
a. When ANC ≥ 750/µL and platelet count ≥ 75,000/µL, restart mercaptopurine 
and methotrexate at 50% of the dose prescribed at the time that the medications 
were stopped. 
b. Increase doses of mercaptopurine and methotrexate to 75% and then 100% of 
dose prescribed prior to stopping the medications at 2-4 week intervals 
provided ANC remains > 750 /µL and platelets remain > 75,000/µL. May 
increase both mercaptopurine and methotrexate simultaneously.  
c. Once at 100% of the dose prescribed prior to stopping, see below for 
instructions regarding further dose escalation. 

 
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Continue to follow ANC q 2-4 weeks with target ranges ANC 500 – 1,500/µL and platelet 
count ≥ 50,000/µL 
 
If patient develops severe or unexpected myelosuppression, i.e., doesn’t tolerate at least 
half dose mercaptopurine, in the absence of TMP/SMZ or other myelosuppressive agents, 
strongly consider evaluation of TPMT and/or NUDT15 status if not already done)  
 
Prolonged cytopenia is defined as ANC < 500/µL and/or platelets < 50,000/µL after 
withholding therapy for > 2 - 4 weeks. Consider a marrow evaluation in the face of 
persistent or prolonged neutropenia if no recovery is apparent. If monocyte count is 
increasing or viral myelosuppression is clinically suspected, the bone marrow examination 
may be postponed for 1-2 weeks and omitted if ANC and platelets fully recover by the 4th 
week after therapy is withheld. 
 
Inadequate Myelosuppression: For persistent ANC ≥ 1,500/µL, no dose escalations are 
recommended during the first cycle of Maintenance. 
• 
For ANC ≥ 1,500/µL on 3 CBC(s) done over 6 weeks or 2 successive monthly 
CBC(s), alternately increase doses of methotrexate or mercaptopurine by 25%. 
Always wait at least 4 weeks before making another dose adjustment. 
• 
If both methotrexate and mercaptopurine are increased once without a fall in ANC, 
consider noncompliance as a possibility. Noncompliance can be assessed by 
obtaining a sample for thiopurine metabolites. Although there are no specific 
values to use to indicate non-adherence, low concentrations of TGN and 
methylated derivatives in a sample taken after at least three weeks after continuous 
dosing may indicate non-adherence. Also consider observing the administration of 
an oral dose of methotrexate and checking plasma methotrexate concentration 2-4 
hours later; this value should be ≥ 0.2 µM.  
• 
If ANC remains high after intervention for possible noncompliance. 
o For patients who are heterozygous or homozygous deficient for 
TPMT/NUDT15 and have high ANCs as described above, increase 
methotrexate alone by 25% and repeat evaluation. Unless noncompliance 
is suspected, increase methotrexate preferentially over mercaptopurine 
Consider carefully increasing mercaptopurine doses as well, if high ANCs 
persist. Increase the mercaptopurine dose in 25% increments until ANC is 
in target. Always wait at least 4 weeks before making another dose 
adjustment or re-measuring TGN. If ANC remains high, alternate 
mercaptopurine dose increases with methotrexate dose increases. 
o If the methylated derivatives are significantly elevated, in concert with 
abdominal symptoms or Grade 4 SGPT/ALT, SGOT/AST and or direct 
bilirubin > 2 mg/dl, and ANC indicates that the 6-MP should be increased, 
consider adding allopurinol at a dose of 50 mg/m2 with a dose of 6-MP 
that has been decreased by 50-75%.50 
Mucositis Grade 3 - 4: 
MTX should be reduced to 50% if Grade 3 toxicity develops; withhold in the presence of 
Grade 4 toxicity until there is a resolution, then resume at 50% of original dose with gradual 

 
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dose escalation. If mucositis persists or recurs, consider culturing for herpes simplex. 
 
Liver Dysfunction: 
• 
For Grade 3 toxicity, increase in hepatic transaminases (SGPT/ALT or SGOT/AST to 
greater than >5.0 - 20.0 x ULN), obtain total direct bilirubin. Monitor SGPT/ALT or 
SGOT/AST and total direct bilirubin weekly during Consolidation as long as 
transaminases remain over 5x ULN.  
• 
Continue full dose therapy unless either of the following occurs: 
• 
Direct bilirubin > 2 mg/dL 
• 
Grade 4 SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) 
elevation on 2 determinations at least 1 week apart. 
• 
If either of these occurs, hold mercaptopurine and monitor labs as above, weekly. 
Restart at full dose therapy when the transaminase elevation is < Grade 3 (are less than 
5x ULN), as long as direct bilirubin is < 2 mg/dL 
• 
Exclude infectious hepatitis for persistent (> 1 month) Grade 3 elevations in 
SGPT/ALT 
or 
SGOT/AST(above 
5x 
ULN). 
Consider 
discontinuing 
trimethoprim/sulfamethoxazole (TMP/SMX) in favor of an alternative approach to 
Pneumocystis prophylaxis 
 
For dose modifications when MTX is given for GVHD prophylaxis see Section 5.13.3. 
 
Thiopurine Pharmacology Testing and Dosage Adjustments:  
Mercaptopurine and thioguanine are methylated directly by thiopurine methyltransferase 
(TPMT) to an inactive metabolite. TPMT activity varies tremendously among patients, 
because of a common inherited genetic defect in TPMT. One in 300 patients is completely 
deficient (homozygous defective) and 10% of the population are moderately deficient in 
TPMT activity because they have inherited one variant (non-functional) TPMT allele (i.e., 
heterozygotes). 10,51-53 Patients with low TPMT form higher concentrations of the 6-
thioguanine nucleotides (6-TGN) and are more susceptible to acute thiopurine toxicity 
(primarily myelosuppression, involving neutropenia, thrombocytopenia, and anemia). 
Patients with the complete deficiency of TPMT tolerate less than 10% of protocol doses of 
6 MP (10 to 30 mg/m2/day 3 days per week). About 35% of heterozygotes require a lower 
dose of 6-MP to avoid dose-limiting myelosuppression. 54  
 
There are now CLIA certified tests for TPMT genotype and phenotype, and for thiopurine 
metabolites (6-methyl mercaptopurine [6-MMP] and 6-TGN) measurements. Only 3 SNPs 
constitute well over 90% of the inactivating mutations in the gene, based on studies in 
numerous racial and ethnic groups worldwide. 51,55-58 Thus, the genotyping test has a low 
false negative rate, and may be preferable to TPMT phenotype testing in cases where a 
history of red cell transfusions would potentially confound assessments of RBC TPMT 
activity. When the genotyping result is coupled with a phenotyping test for TPMT or with 
thiopurine metabolite concentrations in erythrocytes, the reliability of the tests will be even 
greater. Moreover, metabolite levels can provide an index of patient compliance with 
thiopurine therapy. 
 
Recommendations for Thiopurine Monitoring and Dosage Adjustments:  
When myelosuppression has led to significant delays in therapy (> 2 weeks) or is 
disproportionate to the therapy, thiopurine testing should be performed: 

 
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- 
For patients who have received full dose thiopurine therapy during the 2 weeks 
immediately preceding the test, RBC thiopurine metabolites will likely predict TPMT 
status and actual thiopurine exposure. 
- 
In the absence of RBC transfusions for 3 months prior, TPMT activity will accurately 
reflect TPMT status 
- 
TPMT genotyping will be informative in all patients, if at least 1 mutant allele is 
identified. If not, and myelosuppression continues, send samples for TPMT activity 
and/or metabolites since TPMT genotyping will miss 5% - 10% of mutants. NOTE: 
Genotyping can be done despite recent transfusions. 
 
Suggested Dose Adjustments in Patients With Unacceptable Myelosuppression: 
- 
If the patient is homozygous deficient for TPMT, the thiopurine dose should be 
reduced to 10 - 20 mg/m2/day 3 days per week. If the patient is heterozygous for 
TPMT and has experienced significant myelosuppression, the thiopurine dose should 
be reduced by 30% - 50%. Do not increase the dose in response to a high ANC for 4 
weeks to allow for achievement of steady state. All other myelosuppressive 
medications should be delivered at full dose, and the thiopurine dose should be titrated 
based on blood counts. Further thiopurine pharmacologic measures are not often 
necessary.  
- 
If the patient is homozygous wild-type (high activity) for TPMT, then discontinue 
TMP/SMX and use pentamidine or dapsone. For modifications of the oral MP and 
MTX see the beginning of this section. 
5.10 
Steroids (Dexamethasone) 
Hypertension: Dose should not be reduced. Sodium restriction and anti-hypertensives 
should be employed in an effort to control hypertension.  
 
Hyperglycemia: Dose should not be reduced for hyperglycemia.  
 
Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase. 
Discontinue steroids, except for stress doses, in the presence of Grade 3 or 4 pancreatitis. In 
the case of asymptomatic Grade 2 pancreatitis (enzyme elevation or radiographic findings 
only), steroids should be held until symptoms and signs subside, and amylase/lipase levels 
return to normal and then consider resuming steroids.  
 
Osteonecrosis (ON): Do not modify corticosteroid therapy for osteonecrosis (also referred to 
as avascular necrosis) prior to Maintenance therapy. Consider omitting Maintenance steroid 
for osteonecrosis Grade 1 (clinically asymptomatic, radiographic finding only). Omit 
Maintenance steroid for osteonecrosis Grade 2 or greater, and notify study chair. Consider 
resuming Maintenance steroid after 6 months if joint symptoms have resolved and if MRI 
findings have significantly improved or normalized. 
 
Varicella: Steroids should be held during active infection except during Induction. Do not hold 
during incubation period following exposure. 
 
Inability to use oral doses: 
For dexamethasone, substitute the IV preparation mg for mg.  
 
Severe infection: Do not hold or discontinue steroids during Induction without serious 
consideration, as this is a critical period in the treatment of ALL. Later in therapy, one may 

 
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consider holding steroid until patient achieves cardiovascular stability, except for “stress 
doses.” 
 
5.11 
PO 6-Thioguanine (TG) 
Continuation: 
Infection: Oral TG will be held for suspected or proven serious infection. 
 
For severe and/or unexpected myelosuppression, evaluate for TPMT activity as described 
in Section 5.9. 
 
5.12 
Vincristine 
PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See text box 
below) 
 
Severe neuropathic pain (Grade 3 or greater):  
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated. NOTE: neuropathic pain 
can be not only severe but difficult to treat. However, because vincristine is an important 
component of curative therapy and the majority of neuropathies are ultimately reversible, 
vincristine therapy may be given at full dose at investigator discretion. Severe peripheral 
neuropathies, with or without a positive family history might suggest the need for a 
molecular diagnostic evaluation to rule out Charcot Marie Tooth Disease (CMT), Type 1A 
or Hereditary neuropathy with liability to pressure palsies. Drugs such as gabapentin may 
be of value. 
 
Vocal Cord paralysis:  
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated. See above for comment on 
CMT.  
 
Foot Drop, paresis:  
Should be Grade 3 to consider holding or decreasing dose. These toxicities are largely 
reversible but over months to years. Accordingly, holding doses of vincristine and/or 
lowering the dose may not result in rapid resolution of symptoms and may compromise 
cure. See above for comment on CMT. Physical therapy may be beneficial to maintain 
range of motion and provide AFO’s and other forms of support. Drugs such as gabapentin 
may be of value. 
 
Jaw pain: Treat with analgesics; do not modify vincristine dose. 
 
Hyperbilirubinemia59,60:  
 
Direct Bili 
Dose reduction 
< 3.1 mg/dL 
Full dose (maximum dose: 2 mg), 
3.1- 5.0 mg/dL 
50% of calculated dose (maximum dose: 1 mg), 
5.1-6.0 mg/dL 
75% of calculated dose (maximum dose: 0.5 mg), 
> 6.0 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has 
resolved. 
Do not make up missed doses. 

 
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Constipation or ileus (≥ Grade 3) or typhlitis: Hold dose(s); institute aggressive regimen to 
treat constipation if present. When symptoms abate resume at 50% of calculated dose 
(maximum dose: 1 mg) and escalate to full dose as tolerated. 
 
Extravasation: 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to 
institutional 
guidelines. 
Also 
see 
https://cogmembers.org/_files/disc/pharmacy/
ExtravasationReference.pdf for COG reference.  
 
 
 
5.13 
Stem Cell Transplant Regimen Agents  
5.13.1 Tacrolimus 
Tacrolimus commonly causes mild/moderate hypertension and alopecia and less 
commonly kidney or liver dysfunction, transplant associated microangiopathy 
(TAM), and neurological changes associated with significant hypertension. When 
trough levels are kept in the therapeutic range and patients receive adequate 
hydration and magnesium replacement, most of these side effects can be 
minimized. Hypertension should be managed with single or combination 
antihypertensive therapy. Tacrolimus should be held for severe toxicities thought 
Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
 
Peripheral Motor Neuropathy: 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal 
deep tendon reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using eating 
utensils) or unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity 
function. 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without 
causing loss of function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using 
eating utensils) or gait, without abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function (gait, 
fine motor skills as outlined above), or quality of life (loss of sleep, ability to perform normal activities 
severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 

 
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to be related to its administration (significant neurological changes/malignant 
hypertension, TAM, kidney failure, etc.). Other immune suppressive medications 
may be substituted if tacrolimus is not tolerated (MMF, cyclosporine, etc.). 
 
5.13.2 Cyclosporine 
Cyclosporine commonly causes mild/moderate hypertension and less commonly 
kidney or liver dysfunction, TAM, and neurological changes associated with 
significant hypertension. When trough levels are kept in the therapeutic range and 
patients receive adequate hydration and magnesium replacement, most of these 
side effects can be minimized. Hypertension should be managed with single or 
combination antihypertensive therapy. Cyclosporine should be held for severe 
toxicities thought to be related to its administration (significant neurological 
changes/malignant hypertension, TAM, kidney failure, etc.). Other immune 
suppressive medications may be substituted if cyclosporine is not tolerated 
 
5.13.3 Methotrexate 
The most common acute side-effects of methotrexate include delay of count 
recovery, worsened mucositis, and kidney and liver damage (can contribute to 
VOD). Toxicity is directly related to the length of exposure to the drug. While 
methotrexate is generally excreted rapidly, delayed excretion of methotrexate 
occurs with decreased renal function and in circumstances where patients have 
third-space fluid collections (pulmonary effusions, ascites, joint effusions, etc.). 
The attending transplant physician should assess each patient prior to delivery of 
each dose and decide whether full dose methotrexate should be administered. 
Guidelines for modification of methotrexate dosing are listed in the tables below. 
 
Table 5.13.3.1: Methotrexate Dose Modification for Renal Impairment 
 
Mild 
Moderate 
Severe 
Life-Threatening 
Serum creatinine 
> 1.5 - 2x baseline 
> 2 - 2.5x 
baseline 
> 2.5 - 3x 
baseline 
> 3x baseline or 
dialysis 
% Methotrexate 
Dose reduction 
(Day +1, 3, 6, 11) 
0 - 50% 
50 - 100% 
100%  
(no drug) 
100% 
(no drug) 
 
 

 
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Table 5.13.3.2: Methotrexate Dose Modification for Significant Mucositis  
Stomatitis, 
mucositis 
 
Painless ulcers, 
erythema, mild 
soreness or 
mild dysphagia 
 
Painful 
erythema, 
edema, 
ulcers or 
moderate 
dysphagia, 
but can eat 
without 
narcotics 
Cannot eat 
solids or 
requires 
narcotics to 
eat, requires 
parenteral 
or enteral 
support. 
Complete 
obstruction or 
perforation 
 
% Methotrexate 
Dose reduction 
(Day +1, 3, 6, 11) 
0% 
0% 
0 - 50% 
50 - 100% 
 
For significant third spacing (ascites, effusions, significant edema or weight gain 
> 5 - 10% above baseline) consider dose reductions of 50% and leucovorin rescue. 
 
5.13.4 Guidelines for Leucovorin Rescue  
Dose: Patients at risk for methotrexate toxicity should receive leucovorin at a dose 
of 5 - 10 mg/m2 IV Q6H x 4 doses beginning 24 hours after administration of 
methotrexate. While most patients will need only 4 doses of leucovorin, if 
methotrexate levels are elevated due to renal dysfunction or other problems, 
leucovorin doses should be continued until serum methotrexate concentration is 
< 1x10-7M. If serum methotrexate concentration is > 5x10-6M, increase dose to 
100 mg/m2/dose IV Q3H until the serum methotrexate level is < 1x10-8M. 
 
5.13.5 Mycophenolate Mofetil (MMF) 
MMF can cause decreased counts, nausea, vomiting, diarrhea, hypertension, 
dizziness, insomnia, hyperglycemia, electrolyte imbalances, rash, leg cramps, and 
bone pain. For significant diarrhea or low counts (neutropenia, etc.), a decrease of 
MMF by approximately 20% is usually sufficient to decrease the toxicity. Further 
dose modifications for significant toxicity likely caused by MMF are allowed. 
 
5.13.6 Adjustment of TBI/chemotherapy During the Preparative Regimen. 
The full dose of preparative regimen TBI and chemotherapy agents will be 
administered unless patients have a life threatening reaction thought likely to occur 
again with continued administration and an appropriate substitution cannot be 
made (i.e. etopophos for etoposide). 
 
5.13.7 Dose Adjustment of Chemotherapy for Patients Whose Weight Exceeds > 125% 
Ideal Body Weight (IBW) 
Chemotherapy given during the preparative regimen (thiotepa, cyclophosphamide, 
and etoposide) will be dosed based on actual weight for patients ≤ 125% IBW. 
Those > 125% IBW will be dosed based upon adjusted ideal body weight as 
follows: 
 
Adjusted ideal body weight = IBW + 0.25 (Actual weight – IBW). 
 

 
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The following formulas for pediatric and adult IBW calculations are 
recommended, but IBW may be calculated according to institutional standard 
operating procedures (SOPs). 
 
Recommended Ideal Body Weight Calculation for Children Age 1- 17 years 
IBW = Height (cm)2 x 1.65 
 
 
1000 
 
Recommended Ideal Body Weight Calculation for Adults (Height > 5 feet/60 
inches) 
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg 
 
IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg  
 
 
 

 
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6.0 
DRUG INFORMATION 
6.1 
BLINATUMOMAB 
(11/18/2019) 
(Blincynto®, AMG103, MT103, recombinant bispecific antibody derivative, NSC# 765986) 
 
Source and Pharmacology 
Blinatumomab is a fusion protein composed of two single-chain antibodies (scFv), murine anti-CD19 
scFv and murine anti-CD3 scFv. Through CD3 binding, blinatumomab recruits and engages T cells for 
redirected lysis of CD19-positive B cells, including those expressed with B-cell malignancies. T cells are 
bound by its anti-CD3 moiety, whereas B cells are bound by the anti-CD19 moiety. The subsequent serial 
lysis of multiple malignant cells by a single blinatumomab-activated T cell closely resembles a natural 
cytotoxic T cell reaction. Treatment with blinatumomab is associated with a rapid depletion of peripheral 
B cells, accompanied by T cell activation and a transient increase in cytokines.  
 
Blinatumomab consists of a single chain of 504 amino acids with a molecular weight of approximately 54 
kDa. The pharmacokinetics of blinatumomab was assessed over a dose range from 5 to 90 mcg/m2/day 
(approximately equivalent to 9-162 mcg/day). Following continuous intravenous infusion, the steady state 
serum concentration (Css) was achieved within a day and remained stable over time.  The estimated mean 
(SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L. The estimated mean (SD) 
systemic clearance was 2.92 (2.83) L/hour and the estimated mean (SD) half-life was 2.11(1.42) 
hours.  Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses. Like 
other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids 
via catabolic pathways. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of adult 
relapsed/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively. 
 
At this time there are no known drug interactions with blinatumomab. 
 
 
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Blinatumomab (AMG 103, NSC 765986) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 1276 patients. Below is the CAEPR for Blinatumomab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.5, September 4, 20191 

 
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116 
 Adverse Events with Possible  
 Relationship to Blinatumomab (AMG 103) 
 (CTCAE 5.0 Term) 
[n= 1276] 
 
 Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
 
Blood and lymphatic system 
disorders - Other (coagulopathy)2 
 
 Blood and lymphatic system disorders - 
Other (coagulopathy)2 (Gr 2) 
 
 
Blood and lymphatic system 
disorders - Other (hematophagic 
histiocytosis) 
  
 
 
Blood and lymphatic system 
disorders - Other (lymphadenitis) 
  
 
 
Blood and lymphatic system 
disorders - Other 
(lymphadenopathy) 
  
 
 
Blood and lymphatic system 
disorders - Other (pancytopenia) 
  
 
Disseminated intravascular 
coagulation2,3 
 
 Disseminated intravascular coagulation2,3 
(Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastric hemorrhage 
  
 
 
Gastrointestinal disorders - Other 
(pneumoperitoneum) 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Oral hemorrhage 
  
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills3 
 
 Chills3 (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue3 
 
 
 Fatigue3 (Gr 2) 
Fever3 
 
 
 Fever3 (Gr 2) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatic function abnormal)4 
 
 Hepatobiliary disorders - Other (hepatic 
function abnormal)4 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
Cytokine release syndrome3 
 
 Cytokine release syndrome3 (Gr 3) 
 
Immune system disorders - Other 
(immunodeficiency 
[immunoglobulin decreased])5 
 
 Immune system disorders - Other 
(immunodeficiency [immunoglobulin 
decreased])5 (Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to Blinatumomab (AMG 103) 
 (CTCAE 5.0 Term) 
[n= 1276] 
 
 Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
  
INFECTIONS AND INFESTATIONS 
  
Infection6 
 
 
 Infection6 (Gr 4) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
 
 
Injury, poisoning and procedural 
complications - Other 
(overdose)7 
  
INVESTIGATIONS 
  
 
 
Activated partial thromboplastin 
time prolonged2 
  
 
Alanine aminotransferase 
increased4 
 
 Alanine aminotransferase increased4 (Gr 
3) 
 
Alkaline phosphatase increased4 
 
 Alkaline phosphatase increased4  
(Gr 2) 
 
Aspartate aminotransferase 
increased4 
 
 Aspartate aminotransferase increased4 
(Gr 4) 
 
Blood bilirubin increased4 
 
 Blood bilirubin increased4 (Gr 2) 
 
Blood lactate dehydrogenase 
increased 
 
  
 
 
Creatinine increased8 
  
 
GGT increased4 
 
 GGT increased4 (Gr 2) 
 
 
Investigations - Other (blood 
fibrinogen increased)2 
  
 
Investigations - Other (C-reactive 
protein increased) 
 
 Investigations - Other (C-reactive protein 
increased) (Gr 2) 
 
Investigations - Other (fibrin D 
dimer increased)2 
 
  
Lymphocyte count decreased 
 
 
 Lymphocyte count decreased (Gr 4) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased2 
 
 
 Platelet count decreased2 (Gr 2) 
 
Weight gain 
 
 Weight gain (Gr 2) 
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hyperuricemia 
 
  
 
Hypoalbuminemia 
 
  
 
Hypocalcemia 
 
  
Hypokalemia 
 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
 
 
Tumor lysis syndrome9 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
  
 
Generalized muscle weakness 
 
  
 
Myalgia 
 
  

 
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 Adverse Events with Possible  
 Relationship to Blinatumomab (AMG 103) 
 (CTCAE 5.0 Term) 
[n= 1276] 
 
 Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Ataxia10 
 
  
 
Cognitive disturbance10 
 
  
 
Dizziness10 
 
 Dizziness10 (Gr 2) 
 
 
Dysarthria10 
  
 
Dysphasia10 
 
  
 
Encephalopathy10 
 
  
 
 
Facial nerve disorder10 
  
Headache10 
 
 
 Headache10 (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Leukoencephalopathy 
  
 
Memory impairment10 
 
  
 
Nervous system disorders - Other 
(apraxia) 
 
  
 
Nervous system disorders - Other 
(cerebellar syndrome)10 
 
  
 
 
Nervous system disorders - 
Other10  
  
 
Paresthesia10 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
Seizure10 
 
  
 
Somnolence10 
 
  
 
 
Transient ischemic attacks10 
  
 
Tremor10 
 
 Tremor10 (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
 
Agitation10 
  
 
Anxiety10 
 
  
 
Confusion10 
 
  
 
 
Hallucinations10 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
 
Personality change10 
  
 
 
Psychosis10 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
Epistaxis 
 
  
 
 
Hypoxia 
  
 
Oropharyngeal pain 
 
  
 
 
Pneumonitis 
  
 
Voice alteration10 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Hyperhidrosis 
 
  
 
Pruritus 
 
  
 
Skin and subcutaneous tissue 
disorders - Other (rash)11 
 
 Skin and subcutaneous tissue disorders - 
Other (rash)11 (Gr 2) 
VASCULAR DISORDERS 
  

 
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 Adverse Events with Possible  
 Relationship to Blinatumomab (AMG 103) 
 (CTCAE 5.0 Term) 
[n= 1276] 
 
 Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
  
 
 
Capillary leak syndrome3 
  
 
Flushing3 
 
  
 
Hypertension3 
 
 Hypertension3 (Gr 2) 
 
Hypotension3 
 
 Hypotension3 (Gr 2) 
 
Thromboembolic event2 
 
 Thromboembolic event2 (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.   Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Blinatumomab (AMG 103) is known to cause a variety of adverse events associated with coagulopathy 
which may include: Activated partial thromboplastin time prolonged, Disseminated intravascular 
coagulation, Fibrinogen decreased, INR increased, Investigations - Other (blood fibrinogen increased), 
Investigations - Other (fibrin D dimer increased), Investigations - Other (activated partial thromboplastin 
time shortened), Investigations - Other (antithrombin III decreased), Investigations - Other (coagulation 
factor XII level decreased), Investigations - Other (coagulation factor XIII level increased), Investigations - 
Other (haptoglobin decreased), Investigations - Other (protein S decreased), Platelet count decreased, and 
Thromboembolic events. 
 
3Symptoms of cytokine release syndrome (CRS) and/or allergic reaction may include chills, fever, fatigue, 
flushing, bronchospasm, and hypotension.  In some cases, disseminated intravascular coagulation (DIC), 
capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome 
(HLH/MAS) have been reported in the setting of CRS. 
 
4Symptoms of hepatic dysfunction may include Alanine aminotransferase increased, Alkaline phosphatase 
increased, Aspartate aminotransferase increased, Blood bilirubin increased, and GGT increased under the 
INVESTIGATIONS SOC. 
 
5Immunodeficiency 
(immunoglobulin 
decreased) 
includes 
immunoglobulins 
decreased, 
blood 
immunoglobulin G decreased, blood immunoglobulin M decreased, and blood immunoglobulin A 
decreased. 
 
6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
7Overdoses have been observed. Overdoses resulted in adverse reactions, which were consistent with the 
reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the 
event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive 
care. Consider re-initiation of blinatumomab at the correct therapeutic dose when all toxicities have resolved 
and no earlier than 12 hours after interruption of the infusion. 
 
8Acute kidney injury (acute renal failure) is associated with increased creatinine levels. 
 
9Tumor lysis syndrome is defined as a massive overload of potassium, phosphate, uric acid, plus 
hypocalcemia, potentially causing lethal cardiac arrhythmias and/or renal failure. 
 
10Blinatumomab (AMG103) is known to cause a variety of nervous system disorders which may include: 
Ataxia, Cognitive disturbance, Concentration impairment, Depressed level of consciousness, Dizziness, 
Dysphagia, Dysarthria, Dysesthesia, Dysphasia, Encephalopathy, Facial nerve disorder, Headache, 

 
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Lethargy, Memory impairment, Paresthesia, Peripheral sensory neuropathy, Seizure, Somnolence, Syncope, 
Transient ischemic attacks, Tremor, Voice alteration, Nervous system disorders - Other (allodynia), Nervous 
Systems disorders - Other (cerebellar syndrome), Nervous system disorders - Other (dysgraphia), Nervous 
system disorders - Other (epilepsy), Nervous system disorders - Other (facial palsy), Nervous system 
disorders - Other (hemiparesis), Nervous system disorders - Other (hypertonia), Nervous system disorders 
- Other (hypotonia), Nervous system disorders - Other (pleocytosis), and Nervous system disorders - Other 
(polyneuropathy).  Additionally, symptoms of some nervous system disorders are adverse events under the 
PSYCHIATRIC DISORDERS SOC and may include: Agitation, Anxiety, Confusion, Hallucinations, 
Personality change, and Psychosis. 
 
11Rash includes rash, rash maculo-papular, erythema, local erythema, erythematous rash, generalized rash, 
exanthema, allergic dermatitis, and palmar-plantar erythrodysesthesia syndrome. 
 
Adverse events reported on blinatumomab (AMG 103) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that blinatumomab (AMG 103) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Heart failure; Left ventricular systolic 
dysfunction; Myocardial infarction; Pericardial effusion; Sinus bradycardia; Supraventricular tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and genetic 
disorders - Other (aplasia) 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision; Optic nerve disorder; Papilledema; Periorbital edema; Photophobia 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Dyspepsia; Dysphagia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait 
disturbance; General disorders and administration site conditions - Other (thrombosis in device); 
Hypothermia; Malaise; Multi-organ failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Vascular access 
complication 
INVESTIGATIONS - Cardiac troponin I increased; Electrocardiogram QT corrected interval prolonged; 
INR increased; Investigations - Other (hypoproteinemia); Investigations - Other (lipase decreased); Lipase 
increased; Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperkalemia; Hyperphosphatemia; Hyponatremia; Metabolism and nutrition disorders - Other (fluid 
overload) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Muscle cramp; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Amnesia; Facial muscle weakness; Muscle weakness left-sided; 
Nervous system disorders - Other (difficulty following commands); Neuralgia 
PSYCHIATRIC DISORDERS - Delirium; Depression; Psychiatric disorders - Other (altered mental 
status); Psychiatric disorders - Other (sleep disorder); Restlessness 
RENAL AND URINARY DISORDERS - Acute kidney injury7; Hematuria; Proteinuria; Urinary 
incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Bronchospasm3; Pleural effusion; Productive cough; Pulmonary edema; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Purpura; Skin and subcutaneous tissue 
disorders - Other (skin irritation) 
VASCULAR DISORDERS - Hematoma 
 

 
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Note: Blinatumomab (AMG 103) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
Pregnancy and lactation  
Pregnancy Category Unknown: The effect of blinatumomab on fertility has not been evaluated. 
Blinatumomab is not recommended in pregnant women and in women of childbearing potential not using 
contraception. It is not known whether blinatumomab or its metabolites are excreted in human milk. Women 
are not allowed to breastfeed while receiving blinatumomab and for at least 48 hours after the last dose.   
 
Formulation and Stability 
Blinatumomab is available as a 38.5 mcg preservative-free, white to off-white lyophilized powder for 
injection in 4 mL single-use vial. The agent is formulated with 3.68 mg citric acid monohydrate, 105 mg 
trehalose dihydrate, and 25.55 mg lysine hydrochloride, and 0.7 mg polysorbate 80, pH 7. The stopper of the 
vial is latex free. 
 
IV solution stabilizer for blinatumomab (NSC 773150) is not for reconstitution of blinatumomab; it is a 
component of the final intravenous product. The stabilizer is available as a 10 mL single-use vial of a 
preservative-free, clear, colorless-to-slightly yellow liquid solution. Each solution consists of 25 mM citric acid 
monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% (w/v) polysorbate 80, pH 7. The stopper of the vial is 
latex free. 
 
Store intact vials of blinatumomab and the IV solution stabilizer of blinatumomab refrigerated at 2° – 8°C (36° 
– 46°F). Protect from light. Shelf life stability studies of the intact vials of blinatumomab and stabilizer solution 
are on-going.  
 
The stability of the prepared IV solution in preservative-free 0.9% NaCl is 8 days when stored refrigerated 
at 2° – 8°C (36° – 46°F). For storage prior to administration, the prepared infusion solution must be kept at 
2° C to 8° C (36°F to 46°F). The total storage and administration time must not exceed 8 days. Once at 
room temperature, discard the IV bag after 96 hours (4 days). 
 
The stability of the prepared IV solution in Bacteriostatic 0.9% NaCl is 14 days when stored refrigerated 
at 2° – 8°C (36° – 46°F). For storage prior to administration, the prepared infusion solution must be kept at 
2° C to 8° C (36°F to 46°F). The total storage and administration time must not exceed 14 days. Once at 
room temperature, discard the IV bag after 168 hours (7 days). The 7-day infusion with Bacteriostatic 
0.9% NaCl preserved with benzyl alcohol is not allowed in patients weighing less than 22 Kg. 
 
Preparation  
Only trained staff may prepare the blinatumomab IV solution. Blinatumomab must be prepared in an ISO Class 
5 containment device, ideally in an ISO Class 7 room as described in USP <797>, but ISO Class 7 is not 
required. Use aseptic technique and prepare blinatumomab IV solution under a qualified biological safety 
cabinet. 
 
The label on the IV bag must include the following: 
• 
Patient name and number 
• 
Name of the drug 
• 
Dose (mcg/day and volume/day) 
• 
Infusion rate 
• 
Expiration date and time  
• 
CAUTION: NEW DRUG – Limited by United States law to investigational use. 

 
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• 
Additional information as required by state, local, and country pharmacy regulations. 
 
Blinatumomab must be dispensed in an acceptable IV bag. Acceptable bags include those made 
of polyolefin/polyethylene, ethylene vinyl acetate (EVA), or PVC non-DEHP.   
 
The final IV solution must be prepared in the following sequential order (do not deviate from this order; 
refer to the table below for volume details):  
 
1. Reconstitute blinatumomab lyophilized powder 
 
Blinatumomab 38.5 mcg/vial 
Add 3 mL of Sterile Water for Injection (SWFI) to the vial to 
yield 3.08 mL of blinatumomab at a final concentration of 
12.5 mcg/mL. 
a. Rotate the vial to dissolve all powder.  Do not shake. 
b. The stability of the reconstituted vial is 4 hours at room temperature (22°C – 27°C) 
or 24 hours refrigerated at 2° – 8°C. 
2. Add the appropriate amount of 0.9% NaCl into the IV bag  
3. Add the IV solution stabilizer for blinatumomab to the IV bag  
a. Gently mix the contents of the bag to avoid foaming.  
b. Discard remaining IV solution stabilizer vial. 
4. Add the calculated dose (mL) of blinatumomab into the solution in the IV bag  
a. Rotate the IV bag to mix the solution thoroughly.  Do not shake. Avoid foaming 
the IV bag. 
b. Visually inspect for floating particles or discoloration of the IV solution.  If floaters 
or discoloration is present, do not use the prepared solution.  
c. The total volume of blinatumomab IV solution will account for the volume of the IV 
infusion set for the inpatient or outpatient setting. 
 
Note: Overfill volume depends on the volume of the IV set used at each institution. See 
Volume Calculation Table below for details. 
 
 
VOLUME CALCULATION TABLE 
 
Volume to be prepared 
Volume to be infused 
(rate) 
24-hour IV bag 
(includes 30 mL 
overfill) 
1. Add ____ mL NaCl (calculated volume of 
0.9% NaCl)1 into approved IV bag* 
2. Add 3 mL IV solution stabilizer for 
blinatumomab2 
3. Add ____ mL blinatumomab (calculated 
dose volume per 150 mL bag)3  
150 mL total volume4 
120 mL 
(5 mL/hr) 

 
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10.9% NaCl (mL) = total volume to be prepared (150 mL) – stabilizer solution volume (3 mL) 
– blinatumomab calculated dose volume (mL) per 150 mL bag 
 
2Stabilizer solution (3 mL) = 0.02 x total volume to be prepared (150 mL) 
 
3Blinatumomab calculated dose volume per 150 mL bag (mL) = 24 hour dose (mcg) ÷ 24 hour 
infusion volume (120 mL) x total volume to be prepared (150 mL) ÷ blinatumomab 
concentration (12.5 mcg/mL) 
 
4Total volume (150 mL) = Volume to be infused (120 mL) + IV infusion set volume (30 mL) 
 
Volume to be prepared 
Volume to be infused 
(rate) 
ALTERNATE 
24-hour IV bag 
(includes 30 mL 
overfill) 
1. Add ____ mL NaCl (calculated volume of 
0.9% NaCl)1 into approved IV bag* 
2. Add 5.4 mL IV solution stabilizer for 
blinatumomab2 
3. Add ____ mL blinatumomab (calculated 
dose volume per 270 mL bag)3  
270 mL total volume4 
240 mL 
(10 mL/hr) 
Note rate difference 
10.9% NaCl (mL) = total volume to be prepared (270 mL)  – stabilizer solution volume (5.4 
mL) – blinatumomab calculated dose volume (mL) per 270 mL bag 
 
2Stabilizer solution (5.4 mL) = 0.02 x total volume to be prepared (270 mL) 
 
3Blinatumomab calculated dose volume per 270 mL bag (mL) = 24 hour dose (mcg) ÷ 24 hour 
infusion volume (240 mL) x total volume to be prepared (270 mL) ÷ blinatumomab 
concentration (12.5 mcg/mL) 
 
4Total volume (270 mL) = Volume to be infused (240 mL) + IV infusion set volume (30 mL) 
 
Volume to be prepared 
Volume to be infused 
(rate) 
48-hour IV bag 
(includes 30 mL 
overfill) 
4. Add ____ mL NaCl (calculated volume of 
0.9% NaCl)1 into approved IV bag* 
5. Add 5.4 mL IV solution stabilizer for 
blinatumomab2 
6. Add ____ mL blinatumomab (calculated 
dose volume per 270 mL bag)3  
270 mL total volume4 
240 mL 
(5 mL/hr) 

 
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124 
10.9% NaCl (mL) = total volume to be prepared (270 mL)  – stabilizer solution volume (5.4 
mL) – blinatumomab calculated dose volume (mL) per 270 mL bag 
 
2Stabilizer solution (5.4 mL) = 0.02 x total volume to be prepared (270 mL) 
 
3Blinatumomab calculated dose volume per 270 mL bag (mL) = 48 hour dose (mcg) ÷ 48 hour 
infusion volume (240 mL) x total volume to be prepared (270 mL) ÷ blinatumomab 
concentration (12.5 mcg/mL) 
 
4Total volume (270 mL) = Volume to be infused (240 mL) + IV infusion set volume (30 mL) 
 
Volume to be prepared 
Volume to be infused 
(rate) 
72-hour IV bag 
(includes 30 mL 
overfill) 
1. Add ____ mL NaCl (calculated volume of 
0.9% NaCl)1 into approved IV bag* 
2. Add 7.8 mL IV solution stabilizer for 
blinatumomab2 
3. Add ____ mL blinatumomab (calculated 
dose volume per 390 mL bag)3  
390 mL total volume4 
360 mL 
(5 mL/hr) 
10.9% NaCl (mL) = total volume to be prepared (390 mL)  – stabilizer solution volume (7.8 
mL) – blinatumomab calculated dose volume (mL) per 390 mL bag 
2Stabilizer solution (7.8 mL) = 0.02 x total volume to be prepared (390 mL) 
3Blinatumomab calculated dose volume per 390 mL bag (mL) = 72 hour dose (mcg) ÷ 72 hour 
infusion volume (360 mL) x total volume to be prepared (390 mL) ÷ blinatumomab 
concentration (12.5 mcg/mL) 
4Total volume (390 mL) = Volume to be infused (360 mL) + IV infusion set volume (30 mL)  
 
 
Volume to be prepared 
Volume to be infused 
(rate) 
96-hour IV bag 
(includes 30 mL 
overfill) 
1. Add ____ mL NaCl (calculated volume of 
0.9% NaCl)1 into approved IV bag* 
2. Add 10.2 mL IV solution stabilizer for 
blinatumomab2 
3. Add ____ mL blinatumomab (calculated 
dose volume per 510 mL bag)3  
510 mL total volume4 
480 mL 
(5 mL/hr) 
10.9% NaCl (mL) = total volume to be prepared (510 mL)  – stabilizer solution volume 
(10.2 mL) – blinatumomab calculated dose volume (mL) per 510 mL bag 
 
2Stabilizer solution (10.2 mL) = 0.02 x total volume to be prepared (510 mL) 
 
3Blinatumomab calculated dose volume per 510 mL bag (mL) = 96 hour dose (mcg) ÷ 96 hour 
infusion volume (480 mL) x total volume to be prepared (510 mL) ÷ blinatumomab 
concentration (12.5 mcg/mL) 
 
4Total volume (510 mL) = Volume to be infused (480 mL) + IV infusion set volume (30 mL)  
* Approved bags include those made of polyolefin/polyethylene, ethylene vinyl acetate (EVA), or 
PVC non-DEHP. 

 
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VOLUME CALCULATION TABLE: 168 hour (7 day) bags (for patients > 22 Kg) 
 
Volume to be prepared 
Volume to be infused 
(rate) 
168-hour IV bag 
(includes 10 mL 
overfill) 
1. Add 90 mL Bacteriostatic Sodium 
Chloride preserved with 0.9% benzyl 
alcohol into compatible empty IV bag.1 
2. Add 2.2 mL IV Solution Stabilizer into 
90 mL Bacteriostatic Sodium Chloride 
IV bag2 
3. 
Add the calculated dose volume of 
blinatumomab into solution.3 
4. Q.S. with preservative-free 0.9% NaCl 
to final volume of 110 mL.4 
100.8 mL 
(0.6 mL/hr) 
 
1Approved bags include those made of polyolefin/polyethylene, ethylene vinyl acetate (EVA), 
or PVC non-DEHP. 
 
2Stabilizer solution (2.2 mL) = 0.02 x total volume to be prepared (110 mL) 
 
3Blinatumomab calculated dose volume per 110 mL bag (mL) =  168-hour dose (mcg) ÷ 
volume to be infused (100.8 mL) x total volume to be prepared (110 mL) ÷ 12.5 mcg/mL of 
blinatumomab 
 
4Calculated volume of preservative-free 0.9% NaCl (mL):                                                               
[Total volume to be prepared (110 mL)] – [Bacteriostatic Sodium Chloride volume (90 mL)] - 
[IV stabilizer solution volume (2.2 mL)] – [blinatumomab calculated dose volume (mL)] = 
_____mL preservative-free NS 
 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Premedication with dexamethasone is required prior to the first dose of blinatumomab in the first cycle, prior 
to a step dose and when restarting an infusion after an interruption of 4 or more hours in the first cycle. 
 
IV infusion and infusion set details: 
Blinatumomab must be administered as an infusion through an acceptable central line at rates  described in the 
tables above to deliver the intended daily dose. Only non-DEHP PVC , polyolefin, or EVA tubing/lines 
with a 0.2 µm inline filter are acceptable for bags prepared for 24 to 96 hour infusions (i.e., prepared 
with preservative-free normal saline).  
 
For 168 hour (7-day) infusions prepared with bacteriostatic sodium chloride, use non-DEHP PVC, 
polyolefin, or EVA tubing/lines; an in-line filter is NOT required during the administration of 
blinatumomab 7-day IV bag. This is to alleviate the IV pressure or backflow into the IV line during the 
IV infusion of 7-day bag.  
 
Avoid flushing the line during the Blinatumomab infusion to avoid bolus dosing. There are some times when 
there will be unavoidable flushing for central line care. It is also unavoidable to flush the line at completion of 
the Blinatumomab 28 day cycle. For outpatient administration, use FDA approved pumps. Only the exact 
volume should be administered; any remaining overfill should be discarded appropriately.  

 
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Infusion pump requirements: 
Use a programmable pump that is approved by the appropriate regulatory authority for the country in which 
the subject is undergoing treatment. The pump alarm must be visual and auditory. The pump must be 
lockable. Elastomeric pumps are NOT allowed. CADD pumps are allowed; however, the cassettes used in 
CADD pumps are not compatible with blinatumomab and thus, not allowed.  
 
Should blinatumomab need to be administered through a pharmacy satellite or home health care service 
center, refer to the outpatient administration guidelines in Appendix VII-A . 
 
Record all infusion interruptions. Blinatumomab continuous infusion administration should not be 
interrupted, if possible. In case of infusion interruption due to any technical or logistical reasons (e.g. routine 
PORT needle changes, procedural sedation), the interruption should be as short as possible and the infusion 
restarted as soon as possible.  
 
For interruptions lasting longer than four hours, the re-initiation of the infusion must take place in the hospital 
under supervision of the investigator for at least 12 hours after re-initiation of the infusion to evaluate for 
possible side effects. Monitor patients for potential adverse events as described in the protocol and the 
Investigator Brochure. 
 
Monitor patients for cytokine release syndrome, tumor lysis syndrome, and infusion reaction. Refer to protocol 
for specific recommendation. Monitor patients for psychiatric events such as confusion, disorientation, and 
cognitive attention disturbances. Patients should not drive or operate dangerous machinery while receiving 
blinatumomab. 
 
Supplier  
Blinatumomab and the solution stabilizer for blinatumomab is supplied by Amgen, Inc and distributed by 
the Division of Cancer Treatment and Diagnosis (DCTD), NCI. Do not use commercial supply. 
 
Obtaining the Agent 
Agent Ordering:  
NCI supplied agent may be requested by the eligible participating investigator (or their authorized designee) 
at each participating institution. The CTEP assigned protocol number must be used for ordering all CTEP 
supplied investigational agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), 
NIH Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP supplied investigational agents for the study should be 
ordered under the name of one lead participating investigator at that institution. This study does not need a 
starter supply. Confirmation of patient enrollment to an arm with blinatumomab is required for initial drug 
shipment.  
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, and a “current” password, and active person registration status.  
For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
 
Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 

 
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the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. Questions about IB access may be directed to the PMB IB 
coordinator via email. 
 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/ 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
PMB email: PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
 

 
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6.2 
ASPARAGINASE Erwinia chrysanthemi 
(05-07-19) 
(Erwinia chrysanthemi, Erwinase®, ErwinazeTM, Crisantaspase) NSC #106977   
 
Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by 
a reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells associated with acute 
lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic lymphosarcoma are 
asparagine-dependent but lack asparagine synthetase activity. The administration of L-asparaginase 
produces an anti-neoplastic effect by catalyzing asparagine into aspartic acid and ammonia. As a 
result, these cells lack the ability to produce the asparagine necessary for protein metabolism and 
survival. Deamination of glutamine may also play a role in the antineoplastic activity of 
asparaginase. 
 
Asparaginase Erwinia chrysanthemi (Erwinaze®) is asparaginase derived from cultures of Erwinia 
chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical subunits has a 
molecular weight of approximately 35 kDa. Asparaginase Erwinia chrysanthemi is 
immunologically distinct from E. coli L-asparaginase and may allow continued asparaginase 
therapy when a hypersensitivity reaction occurs to Escherichia coli-derived asparaginase. The 
package labeling states that there is insufficient information to characterize the incidence of 
antibodies to asparaginase Erwinia chrysanthemi. Several factors are involved in immunogenicity 
assay results and the assessment of antibodies, including assay methodology, assay sensitivity and 
specificity, sample handling, timing of sample collection, concomitant medications, and the 
underlying disease state. The following data have been reported on each of the three preparations 
of asparaginase: 
 
Clinical Pharmacology 
of Asparaginase 
Formulation 
Elimination half-life (IM) 
% Anti-Asparaginase 
Antibody positive 
patients 
Native Escherichia Coli 
26-30 hours 
45-75 
Pegylated-asparaginase 
5.5-7 days 
5-18 
Erwinia Asparaginase 
16 hours (7-13 hrs package insert) 
30-50 
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations: The 
Past, the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 (4): 367-393. 
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per mL. 
Clinical trials with asparaginase Erwinia chrysanthemi demonstrated that 100% of patients 
achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13, respectively) following 
the third total dose when given on a Monday, Wednesday, Friday schedule using the IM route of 
administration. In a multicenter study characterizing the pharmacokinetic profile of 25,000 
International Units/m2 Erwinaze® given intravenously over one hour on the same dosing schedule 
of Monday, Wednesday, Friday for 2 consecutive weeks, 83% (20/24) and 43% (9/21) of evaluable 
patients achieved an asparaginase activity level of ≥ 0.1 International Units/mL at 48 post-dose 5 
and 72 hours post-dose 6, respectively.61 No formal drug interaction studies have been performed 
with asparaginase Erwinia chrysanthemi.  
 
 
 
 
 

 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Allergic reactions, 
anaphylaxis, urticaria 
Local injection site reactions, 
fever 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Pancreatitis, glucose 
intolerance, 
thrombosis, hemorrhage, 
transient ischemic attack, 
disseminated intravascular 
coagulation, 
hyperbilirubinemia, alanine 
aminotransferase increased, 
aspartate aminotransferase 
increased, hyperglycemia, 
hyperammonemia, vomiting, 
nausea, abdominal pain, 
headache, diarrhea, seizure  
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of L-asparaginase have been noted in 
animals. Adequate, well-controlled studies of asparaginase Erwinia 
chrysanthemi have NOT been conducted. It is not known whether asparaginase 
Erwinia chrysanthemi will cause fetal harm or affect the ability to reproduce. It 
is not known if asparaginase Erwinia chrysanthemi is excreted into breast milk. 
The use of asparaginase Erwinia chrysanthemi should be avoided in pregnant or 
lactating patients. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for 
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000 International 
Units of asparaginase Erwinia chrysanthemi and the following inactive ingredients: glucose 
monohydrate (5.0 mg), sodium chloride (0.5 mg). Store intact vials between 2°C and 8°C (36° to 
46ºF). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Erwinia asparaginase can be administered by intramuscular injection or by intravenous infusion. 
Use appropriate precautions for preparation of a hazardous agent. Visually inspect the powder in 
vial for foreign particles or discoloration prior to reconstitution.  
 
For intramuscular administration, the contents of each vial should be reconstituted by slowly adding 
1 mL or 2 mL of sterile, preservative-free NS to the inner vial wall. The final concentration is 10,000 
International Units per mL when using 1 mL for reconstitution or 5,000 International Units per mL 
when using 2 mL for reconstitution. Gently mix or swirl the contents to dissolve the contents of the 
vial. Do not shake or invert the vial. The resulting solution should be clear and colorless. Discard 
if any particulate matter or protein aggregates are visible. Withdraw the appropriate dosing 
volume into a polypropylene syringe within 15 minutes of reconstitution. Polycarbonate luer-
lok syringes from B-D (1 mL) are also acceptable (personal communication, EUSA Pharma). 
Discard any unused drug; do not save or use any unused drug remaining in the vial. No more than 
2 mL should be given at any one injection site. Doses larger than 2 mL should be divided and given 
in separate administration sites. 

 
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For intravenous use, slowly inject the appropriate volume of reconstituted solution into a Normal 
Saline 100 mL infusion bag; do not shake or squeeze the bag. Infuse Erwinia asparaginase over 
1 hour. Do not infuse other intravenous drugs through the same intravenous line while infusing 
Erwinia asparaginase. Please see http://www.erwinazesupply.com to check which batches may 
require the use a 0.2-micron, low protein binding, in-line filter for IV administration. 
 
Administer the dose within a 4 hour time period from reconstitution. If the dose is not used 
within this time period, discard the dose. Do not freeze or refrigerate the reconstituted solution. 
 
The product used in Australia has an 8 hour expiry (from Porton Biopharma, Salisbury, UK). 
 
Have available during and after the infusion: antihistamine, epinephrine, oxygen, and IV 
corticosteroids. Observe patient for ONE hour after administration for signs of hypersensitivity 
reactions. 
 
Drug Ordering: 
In the United States, asparaginase Erwinia chrysanthemi (Erwinaze) is McKesson Plasma and 
Biologics. Verify your institution has a contract with McKesson Plasma and Biologics before 
ordering. If not, contact McKesson at 877-625-2566 for assistance setting up an account. 
 
 
Orders may be placed online or via phone, fax, or email. Orders placed by 7:30 pm EST will ship 
the next day. 
Orders may be placed online via http://Connect.McKesson.com 
Orders may be submitted via fax to 888-752-7626 
Orders may be submitted via email or MPBOrders@McKesson.com 
Email all other information requests to MPB@McKesson.com 
Regular order hours: M-F 9:00 am – 7:30 pm EST; 
Emergency order after hours services (24/7/365): 877-625-2566 
 
CANADIAN SITES 
Asparaginase Erwinia chrysanthemi is commercially available in Canada. Canadian sites may 
purchase the Canadian commercial supply from Jazz Pharmaceuticals via CGF Pharmatech, 
Montreal, Quebec, (order desk phone: 1-514-343-0344 or 1-866-343-0344, fax: 1-514-343-0340). 
CGF requests that a site fax a Purchase Order number. There is no special fax order form. 
Shipments are sent Monday to Wednesday only and usually arrive at the site within 48-72 hours. 
 
6.3 
CYCLOPHOSPHAMIDE INJECTION  
(03/13/13) 
(Cytoxan) NSC #26271 
 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is inactive 
until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active 
compounds. The initial product is 4-hydroxycyclophosphamide (4-HC), which is in equilibrium with 
aldophosphamide, which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent 
in vitro than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those 
produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the 
urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges 
from 4.1 to 16 hours after IV administration.  

 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Anorexia, nausea & 
vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, 
nasal stuffiness with 
rapid administration, 
arrhythmias (rapid 
infusion), skin rash, 
anaphylaxis, SIADH 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with 
high dose (acute – CHF 
hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail 
changes, impaired wound 
healing, infection 
secondary to immune 
suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: 
ovarian failure1 (L), 
interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(ALL, ANLL, AML), 
bladder carcinoma (long 
term use > 2 years), 
bladder fibrosis  
Unknown 
Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in 
combination with other antineoplastic agents) have been noted in humans. 
Toxicities include: chromosomal abnormalities, multiple anomalies, pancytopenia, 
and low birth weight. Cyclophosphamide is excreted into breast milk. 
Cyclophosphamide is contraindicated during breastfeeding because of reported 
cases of neutropenia in breast fed infants and the potential for serious adverse 
effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The 
product will withstand brief exposures to temperatures up to 30ºC (86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Cyclophosphamide for Injection:  
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then reconstitute 
to 20 mg/mL with NS ONLY to avoid a hypotonic solution. If the drug will be further diluted prior 

 
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to administration, then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben 
preserved only) to a concentration of 20 mg/mL.  Following reconstitution further dilute in dextrose or 
saline containing solutions for IV use.  
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.4 
CYCLOSPORINE A  
(11/16/17) 
(Cyclosporine, CYA, Sandimmune®, Neoral®, Gengraf®) NSC #290193 
 
Source and Pharmacology:  
Cyclosporine (CSA) is a lipophilic fungal peptide consisting of 11 amino acids. CSA is a potent 
immunosuppressive agent which prolongs survival of allogeneic transplants involving skin, heart, 
kidney, pancreas, bone marrow, small intestine, and lung. Current evidence suggests that cyclosporine 
selectively inhibits the transcription of IL-2, the action of which stimulates the proliferation of 
activated T-lymphocytes. CSA has been shown in vitro to be a potent inhibitor of P-glycoprotein, 
which has been postulated to be a factor in multi-drug resistance to various antineoplastic agents. The 
terminal half-life of CSA is approximately 19 hours (range 10 to 27 hours). Ninety-nine percent of 
CSA is metabolized. Elimination is primarily biliary with approximately 6% excreted in the urine. In 
the circulation, CSA is mainly bound to high, low, or very low density lipoproteins and to 
chylomicrons. Only a small fraction circulates unbound. The volume of distribution varies from 
3.5 L/kg to 13 L/kg with higher concentrations of drug found in the liver, lymphocytes, kidney, heart, 
lung, pancreas, fat, neural, and muscle cells. CSA clearance rates have been shown to be higher in 
pediatric patients and for patients < 25 years old. The absorption of cyclosporine from the 
gastrointestinal tract is incomplete and variable exhibiting large intra- and inter-patient variability. 
Drugs that stimulate or inhibit hepatic P450 enzymes will alter clearance of CSA and close attention 
to potential drug interactions is crucial. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 
children out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Hypertension (L), 
immunosuppression (L) 
Headache (L), nausea 
and vomiting, diarrhea 
Anaphylaxis, 
angioedema, seizure (L), 
arrhythmia, chest pain, 
fever, facial flushing 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Tremor (L), renal 
dysfunction (acute with 
decrease in GFR, 
impaired urinary 
concentrating ability, and 
sodium retention) 
Hypomagnesemia (L), 
hyperlipidemia (L) 
Confusion (L), 
somnolence (L), 
insomnia, depression (L), 
anxiety, dizziness, rash, 
urticaria, acne, 
hyperkalemia, 
encephalopathy, 
hemolytic-uremic 
syndrome, cardiac failure, 
MI, leukopenia (L), 
anemia, 
thrombocytopenia, 
increased creatinine, 
infections, 
hyperbilirubinemia (L), 
hepatic insufficiency  

 
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Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
Hirsutism (L) 
Gingival hyperplasia (L) Tinnitus, vestibular 
disorder, cholelithiasis, 
cataracts (L), 
gynecomastia, chronic 
renal dysfunction 
Late: 
Any time after 
completion of 
treatment 
 
 
Lymphoproliferative 
disorders, skin 
malignancies 
Unknown 
Frequency and 
Timing:   
Fetal toxic effects of cyclosporine have been noted in animals. Of the reported 
outcomes of 116 pregnancies in women receiving cyclosporine during 
pregnancy, 90% of whom were transplant patients, and most of whom received 
cyclosporine throughout the entire gestational period, the only consistent 
patterns of abnormality were premature birth (gestational period of 28 to 36 
weeks) and low birth weight for gestational age. Cyclosporine is excreted in 
human milk; nursing should be avoided. 
(L) Toxicity may also occur later. 
 
 
Formulation and Stability:  
IV formulation: 
Cyclosporine (non-modifiedSandIMMUNE®) is available as a (50 mg/mL) 5 mL ampule use 
containing 650 mg polyoxyethylated castor oil (cremophor) and 32.9% alcohol. Store at 
temperatures below 30°C (86°F) and protected from light. 
 
Oral formulations: 
1. Non-modified:  
Cyclosporine (SandIMMUNE®) 25 mg and 100 mg capsule, 100 mg/mL oral solution. 
Inactive ingredients include: Sandimmune® Capsule = dehydrated alcohol, sorbitol, glycerol, 
corn oil, gelatin, polyoxyethylated glycolysed glycerides. Sandimmune® Solution = olive oil, 
dehydrated alcohol, polyoxyethylated glycolysed glycerides. 
 
2. Modified:  
Cyclosporine (modified, Neoral®, Gengraf®) is available as a 25 mg capsule, 100 mg capsule, 
and 100 mg/mL oral solution. Inactive ingredients include: Neoral® capsule and solution = 
dehydrated alcohol, corn oil, polyoxyl 40 hydrogenated castor oil, α tocopherol, gelatin, and 
propylene glycol. Gengraf® Capsule and solution = dehydrated alcohol, gelatin, polyethylene 
glycol, polyoxyl 35 castor oil, polysorbate 80, propylene glycol, and sorbitan monooleate.  
 
Store capsules in the original unit-dose container at controlled room temperature, 15°-30°C (59°-
86°F). Store oral solutions in the original container at controlled room temperature, 68°-77°F (20°-
25°C). Do not store in the refrigerator. Once opened, the contents must be used within two months. 
At temperatures below 68°F (20°C) the solution may gel; light flocculation or the formation of a 
light sediment may also occur. There is no impact on product performance or dosing using the 
syringe provided. Allow to warm to room temperature, 77°F (25°C), to reverse these changes.  
 
NOTE:  Sandimmune®, Neoral®, and Gengraf® ARE NOT BIOEQUIVALENT. Liquid 
formulations of each trade name are equivalent to capsules of that same trade name. Conversion from 
one trade name product to another is generally done at a 1:1 ratio, but requires close monitoring. 
Conversions from IV to PO are usually done at a 1:3 ratio, but should be monitored closely. Adjusting 
emulsion products to the same trough concentration as other oral products results in greater total 
exposure to the drug. 

 
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Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Injection: 
Dilute 1 mL (50 mg) of cyclosporine injection IV concentrate (non-modified, SandIMMUNE®) in 
20 mL-100 mL NS or D5W (0.5-2.5 mg/mL). Diluted infusion solutions are stable for 24 hours at 
room temperature under fluorescent light.  
 
Cyclosporine injection was physically and chemically stable for at least 14 days when diluted in 
NS or D5W to a concentration of 0.2 and 2.5 mg/mL and stored at 25°C in polypropylene–
polyolefin bags (Li M, et al. Am J Health-Syst Pharm. 2011; 68:1646- 50). 
 
Cyclosporine injection was stable for at least two weeks when diluted in NS or D5W to a 
2.5 mg/mL concentration and stored at 25°C in EVA containers. Cyclosporine injection is stable 
for up to 1 week when diluted in NS or D5W to a 0.2 mg/mL concentration and stored in EVA 
containers at 25°C (Li M, et al. Am J Health-Syst Pharm 2013; 70:1970-1972). 
 
The Cremophor® EL (polyoxyethylated castor oil) contained in the concentrate for intravenous 
infusion can cause phthalate stripping from PVC. It is strongly recommended that glass bottles 
and non-PVC tubing be used to minimize patient exposure to DEHP.  
 
Monitor closely for an acute allergic reaction for the first 30 minutes and at frequent intervals 
thereafter. Note: cyclosporine absorbs into plastics and can give falsely high serum or blood 
concentrations if blood samples are collected from the same line through which cyclosporine was 
administered. 
 
Oral:  
Administer at a consistent time of day and at consistent intervals with regard to meals.  Do not use 
plastic or styrofoam cups. If diluted with juice or milk, use a glass container and rinse with additional 
diluent, and then consume to ensure that complete dose has been taken. Do not use water or cleaning 
agents on the dosing syringe. To improve palatability, mix Sandimmune® with milk, chocolate milk 
or orange juice; mix Neoral® or Gengraf® with orange juice or apple juice but NOT milk. After mixed, 
have patient consume immediately. DO NOT MIX GRAPEFRUIT JUICE with any cyclosporine-
containing product.  Grapefruit juice consumption should be avoided during therapy with 
cyclosporine. 
 
Supplier: Commercially available. See package insert for further information. 
 
6.5 
CYTARABINE - ALL ROUTES 
(07/13/15) 
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878 
 
Source and Pharmacology: 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but significant, 
incorporation of cytarabine into both DNA and RNA has also been reported. It exhibits cell Phase 
specificity, primarily killing cells undergoing DNA synthesis (S-Phase) and under certain 
conditions blocking the progression of cells from the G1 Phase to the S-Phase. Cytarabine is 
metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate 
(Ara-CTP), an effective inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). It appears that 
the balance of kinase and deaminase levels may be an important factor in determining sensitivity 

 
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or resistance of the cell to cytarabine. It has an initial distributive Phase t½ of about 10 minutes, 
with a secondary elimination Phase t½ of about 1 to 3 hours. Peak levels after intramuscular or 
subcutaneous administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized and eliminated 
more slowly with a t½ of about 2 hours. 
 
Toxicity: (Intravenous, SubQ, IM) 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, anorexia   
 
With High Dose: 
conjunctivitis  
Flu-like symptoms with 
fever, rash  
 
Ara-C syndrome (fever, 
myalgia, bone pain, 
occasionally chest pain, 
maculopapular rash, 
malaise, conjunctivitis), 
anaphylaxis, swelling, 
pain and redness at the 
site of the medication 
injection (SubQ or IM 
injection) 
 
With High Dose: 
cardiomyopathies 
(vasculitis, and 
pericarditis), cerebral and 
cerebellar dysfunction 
including: 
encephalopathy, aseptic 
meningitis, ataxia, 
dysphasia, nystagmus, a 
decreased level of 
consciousness, 
personality changes, 
somnolence, seizures  
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Myelosuppression (anemia, 
thrombocytopenia, 
leukopenia, megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia 
Diarrhea, hypokalemia, 
hypocalcemia, 
hyperuricemia 
 
With High Dose: capillary 
pulmonary leak syndrome 
(RDS, pulmonary edema) 
Hepatotoxicity, sinusoidal 
obstruction syndrome 
(SOS, formerly VOD), 
urinary retention, renal 
dysfunction, pain and 
erythema of the palms 
and soles 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
 
Asymptomatic 
nonoliguric 
rhabdomyolysis 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It 
is unknown whether the drug is excreted in breast milk. 
 
Toxicity:  (Intrathecal) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
 
Arachnoiditis 
Rash, somnolence, 
meningismus, 
convulsions, paresis 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, 
ataxia 

 
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Delayed: 
Any time later 
during therapy, 
excluding the above 
condition 
 
 
Necrotizing 
leukoencephalopathy, 
paraplegia, blindness (in 
combination with XRT 
& systemic therapy) 
 
Formulation:  
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a sterile 
powder for reconstitution. It is also available at a 20 mg/mL concentration with benzyl alcohol (25 
mL per vial) or as a preservative free solution (5 mL, 50 mL per vial), and at a 100 mg/mL 
concentration with benzyl alcohol (20 mL vial) or as preservative free solution (20 mL vial). 
Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); 
excursions permitted to 15°-30°C (59°-86°F). Cytarabine solutions should be protected from light.  
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the protocol. 
 
IV Infusion: 
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection. Solution 
containing bacteriostatic agent should not be used for the preparation of doses > 200 mg/m2. May be 
further diluted with dextrose or sodium chloride containing solutions. May give by IV push 
injection, by IV infusion, or by continuous infusion.  
 
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a concentration of 20-
100 mg/mL. 
 
High Dose (≥ 1000 mg/m²/dose): Administer steroid eye drops (dexamethasone or prednisolone), 
2 drops each eye q6h beginning immediately before the first dose and continuing 24 hours after the 
last dose. If patient does not tolerate steroid eye drops, administer artificial tears on a q2-4 hour 
schedule. 
 
Stability:  When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 hours 
at room temperature. Solutions reconstituted without a preservative should be used immediately. 
Discard if solution appears hazy. Diluted solutions in D5W or NS are stable for 8 days at room 
temperature; however, the diluted cytarabine should be used within 24 hours for sterility concerns.  
 
Subcutaneous or IM: Dilute with Bacteriostatic Water for Injection or NS to a concentration not to 
exceed 100 mg/mL. Rotate injection sites for subcutaneous/IM administration.  
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.6 
DEXAMETHASONE 
(05/07/19) 
(Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521  
 
Source and Pharmacology:   
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects. 
Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to approximately 5 mg 
of prednisone. Glucocorticoids produce widespread and diverse physiologic effects on carbohydrate, 
protein, and lipid metabolism, electrolyte and water balance, functions of the cardiovascular system, 
kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce the concentration of 
thymus-dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 

 
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selectively bind to the cortisol receptors on human lymphoid cells which are found in larger numbers 
on leukemic lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors 
and inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose transport 
or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. Elimination half-lives 
for the following age groups have been reported to be: infants and children under 2 years of age: 2.3 
to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults (age not specified): 3 to 6 hours. The 
biologic half-life is 36-72 hours. It is primarily metabolized in the liver and excreted by the kidneys. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-
adrenal axis suppression, 
acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial, fungal, parasitic, 
viral), edema 
Pancreatitis (L), 
increased intraocular 
pressure (L), 
hypertension, psychosis, 
vertigo, headache 
Delayed: 
Any time later 
during therapy 
Cushing’s syndrome 
(moon facies, truncal 
obesity) 
Striae and thinning of the 
skin, easy bruising, muscle 
weakness, osteopenia  
Spontaneous fractures 
(L), growth suppression, 
peptic ulcer and GI 
bleeding, pseudotumor 
cerebri (increased 
intracranial pressure 
with papilledema, 
headache), aseptic 
necrosis of the femoral 
and humeral heads (L), 
urolithiasis1 (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (which may be 
reversible on 
discontinuation of 
dexamethasone in 
children) 
 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54% 
metabolized by enzymes in the placenta. In animal studies, large doses of 
cortisol administered early in pregnancy produced cleft palate, stillborn fetuses, 
and decreased fetal size. Chronic maternal ingestion during the first trimester 
has shown a 1% incidence of cleft palate in humans. There are no reports of 
dexamethasone excretion into breast milk in humans; however, it is expected 
due to its low molecular weight that it would partition into breast milk. 
1 Mainly reported in pediatric patients with ALL. Howard SC et al. Urolithiasis in pediatric patients with 
acute lymphoblastic leukemia. Leukemia 2003; 17: 541-6. 
(L) Toxicity may also occur later. 
 
 
 
 
 

 
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Formulation and Stability: 
Oral: 
Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid formulations are 
available in 0.5 mg/5 mL and 1 mg/1 mL concentrations. Inactive ingredients vary depending on 
manufacturer but tablet formulations may include: calcium or magnesium stearate, corn starch, 
lactose, and various dyes. Liquid formulations may include: 5%-30% alcohol, benzoic acid, sorbitol, 
sodium saccharin, glycerin, purified water, and various dyes.  
 
Australia – only 0.5 mg and 4 mg tablets available. 
 
Injection: 
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL, 5 mL, and 
30 mL vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Vials are available in multi-dose vials as 
well as unit of use vials and syringes. Inactive ingredients vary depending on manufacturer but 
include creatinine, sodium citrate, sodium hydroxide to adjust pH, Water for Injection, sodium 
sulfite, bisulfite and metabisulfite, methyl and propyl paraben, benzyl alcohol, and EDTA. 
 
Australia – 1 mg/mL solution for injection available. 
 
Guidelines for Administration: See Treatment and Dose Modifications section of the protocol. 
 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV use, it 
may be further diluted in dextrose or saline containing solutions. Avoid using benzyl alcohol-
containing dexamethasone solutions in neonates. Diluted solutions that contain no preservatives 
should be used within 24 hours, but maintain stability for at least 14 days in PVC bags at room 
temperature protected from light. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further information. 
 
6.7 
ETOPOSIDE – INJECTION 
(11/15/2016) 
(Toposar®, Etopophos®,VP-16) NSC #141540 
 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and 
DNA which results in single and double strand DNA breaks. Its main effect appears to be in the S 
and G2 Phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 
11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is 
excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 
10 mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². 
Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary 
excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion 
appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is 
recovered in the bile as etoposide. Metabolism accounts for most of the non renal clearance of 
etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a 
high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily 
serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related 

 
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to toxicity. Preliminary data suggests that systemic exposure for unbound etoposide correlates 
better than total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted 
to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide 
phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
Nausea, vomiting 
Anorexia 
Transient hypotension 
during infusion; 
anaphylaxis (chills, fever, 
tachycardia, dyspnea, 
bronchospasm, 
hypotension) 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Myelosuppression 
(anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, 
mucositis, hepatotoxicity, 
chest pain, 
thrombophlebitis, 
congestive heart failure, 
Stevens-Johnson 
Syndrome, exfoliative 
dermatitis 
Delayed: 
Any time later 
during therapy 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory 
cycles, hypomenorrhea, 
onycholysis of nails 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
 
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals 
at 1/20th of the human dose. It is unknown whether the drug is excreted in breast 
milk. 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 
mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL 
contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 
80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace 
contains nitrogen. Unopened vials of etoposide are stable until expiration date on package at 
controlled room temperature (20˚-25˚C or 68˚-77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 
32.7 mg sodium citrate USP, and 300 mg dextran 40.  Etoposide phosphate must be stored under 
refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide phosphate are stable until the 
expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 

 
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Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are stable 
at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours 
at room temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly 
unpredictable at concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to the 
risk of precipitate formation. However, the use of an in-line filter is not mandatory since etoposide 
precipitation is unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by 
rapid intravenous injection. Slow rate of administration if hypotension occurs.  
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred with 
etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close as possible, 
preferably within 4 hours, to the time of administration or alternatively as per institutional policy; 
glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be used to 
minimize exposure to DEHP. 
 
Etoposide Phosphate: 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, 
Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for 
Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide 
equivalent (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), respectively. Use diluents without 
benzyl alcohol for neonates and infants < 2 years of age or patients with hypersensitivity to 
benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic 
containers under refrigeration for 7 days. When reconstituted with a diluent containing a 
bacteriostat, store at controlled room temperature for up to 48 hours. Following reconstitution with 
SWFI, D5W, or NS store at controlled room temperature for up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as low as 
0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under refrigeration or 
at controlled room temperature for 24 hours. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
CANADIAN SITES 
Etoposide for Injection is available as a 20mg/mL solution. 
 
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may purchase 
and import the USA commercial supply from Bristol Laboratories via an International Distributor 
(Pharma Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-8022, email: pharexp@aol.com) 
under the authority of the protocol’s No Objection Letter (NOL). Drug Accountability Log (DAL) 
must record Lot #’s and expiry dates of shipments received and doses dispensed.  Sites may use 
their own DAL as long as it complies with all elements of ICH GCP and Division 5 of the Food 
and Drugs Act. Each site is responsible for the procurement (import +/- purchase) of Etoposide 
Phosphate (Etopophos). Sites may import and manage a single clinical trial supply for multiple 
protocols as long as each protocol has an NOL and the protocol the patient is registered on is 
recorded on the DAL. 
 
 

 
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6.8 
FILGRASTIM, TBO-FILGRATIM, FILGRATIM-SNDZ 
(05/13/2019) 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, Zarxio®, 
Grastofil®) NSC #614629 
 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant 
DNA technology. Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons 
manufactured by recombinant DNA technology utilizing E coli bacteria into which has been 
inserted the human granulocyte colony stimulating factor gene. It differs from the natural protein in 
that the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a lineage specific 
colony-stimulating factor which regulates the production of neutrophils within the bone marrow 
and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional 
activation (including enhanced phagocytic ability, priming of the cellular metabolism associated 
with respiratory burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). Filgrastim exhibits nonlinear pharmacokinetics with clearance 
dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared by the kidney. The 
elimination half-life is similar for subcutaneous and intravenous administration, approximately 
3.5 hours. The time to peak concentration when administered subcutaneously is 2-8 hours 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more 
common with IV 
administration than 
subq):skin (rash, urticaria, 
facial edema), respiratory 
(wheezing, dyspnea) and 
cardiovascular (hypotension, 
tachycardia), low grade fever  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic 
rupture, rash or exacerbation 
of pre-existing skin rashes, 
sickle cell crises in patients 
with SCD, excessive 
leukocytosis, Sweet’s 
syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined to 
patients with severe chronic 
neutropenia and long term 
administration) 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. 
Conflicting data exist in animal studies and filgrastim is known to pass the 
placental barrier. It is unknown whether the drug is excreted in breast milk. 
 
 
 

 
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Formulation and Stability:  
Neupogen® supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. Neupogen® vials 
are preservative free single use vials.  Discard unused portions of open vials.  
 
Neupogen®, Granix® and Zarxio® are also available as single use prefilled syringes containing 
300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous administration. Store 
refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not shake. Prior to injection, filgrastim and 
filgrastim-sndz may be allowed to reach room temperature for a maximum of 24 hours (infusion 
must be completed within 24 hours of preparation). TBO-filgrastim may be removed from 2°C 8°C 
(36°F 46°F) storage for a single period of up to 5 days between 23°C to 27°C (73°F to 81°F). Avoid 
freezing and temperatures > 30ºC.  
 
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations > 15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to concentrations 
between 5 mcg/mL and 15 mcg/mL. At concentrations below 15 mcg/mL, human serum albumin 
should be added to make a final albumin concentration of 0.2% (2 mg/mL) in order to minimize 
the adsorption of filgrastim to plastic infusion containers and equipment for all 3 products 
(communication on file from Teva Pharmaceuticals USA). Filgrastim or filgrastim-sndz dilutions 
of 5 mcg/mL or less are not recommended. Tbp-filgratim dilutions below 2 mcg/mL are not 
recommended. Diluted filgrastim biosimilar products should be stored at 2º-8ºC (36º-46ºF) and 
used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
 
Guidelines for Administration:  
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
 
Filgrastim or biosimilar products should not be administered within 24 hours of (before AND 
after) chemotherapy. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information  
 
CANADIAN SITES: 
Grastofil® brand of filgrastim biosimilar is available in Canada. See package insert for further 
information. 
6.9 
FLUDARABINE 
(01/10/18) 
(Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) NSC# 312887 
 
 
Source and Pharmacology:  
Fludarabine phosphate is a synthetic purine nucleoside. It differs from the physiologic nucleosides, 
adenosine, in that the sugar moiety is arabinose instead of ribose, and by the addition of a fluorine 
atom to the purine base adenine. Fludarabine is also a fluorinated nucleotide analog the antiviral 
agent vidarabine, (ara-A). The addition of fluorine results in increased aqueous solubility and 
resistance to enzymatic degradation by adenosine deaminase. Fludarabine (2-fluoro-ara-A) is 
commercially available as the monophosphate salt (2-fluoro-ara-AMP). The monophosphorylation 
increases the drug's aqueous solubility while maintaining pharmacologic activity. The chemical 
name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono β-D-arabino-
furanosyl) (2-fluoro-ara-AMP) and the molecular weight is 365.2.  

 
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Fludarabine is a purine antagonist antimetabolite. In vivo, fludarabine phosphate is rapidly 
dephosphorylated to 2-fluoro-ara-A and then it is phosphorylated intracellularly by deoxycytidine 
kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting 
DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA 
synthesis. The mechanism of action of this antimetabolite is not completely characterized and may 
be multi-faceted. 
 
Phase I studies in humans have demonstrated that within several minutes after intravenous infusion, 
fludarabine phosphate is converted to the active metabolite, 2-fluoro-ara-A and becomes 
undetectable. Therefore, pharmacokinetics studies have focused on 2-fluoro-ara-A. Fludarabine 
phosphate 25 mg/m2 
infused intravenously over 30 minutes to adult cancer patients, showed a 
moderate accumulation of 2-fluoro-ara-A. During a 5-day treatment schedule, 2-fluoro-ara-A 
plasma trough levels increased by a factor of about 2.  
Fludarabine is widely distributed. The volume of distribution at steady state (Vss) reported after 
daily administration of 25mg/m2 for 5 days to adults averaged at 96-98 L/m2. Tissue distribution 
studies in animals indicate that the highest concentrations of the drug are in liver, kidney, and 
spleen. Although the extent to which fludarabine and/or its metabolites distribute into the CNS in 
humans has not been determined to date, severe neurologic toxicity (e.g., blindness, coma) has been 
reported in patients receiving the drug, particularly in high dosages. There is evidence from animal 
studies that fludarabine distributes into the CNS and that a toxic metabolite (2-fluoroadenine, 
possibly formed by bacteria in the GI tract), can be absorbed systematically via enterohepatic 
circulation and distributed into CSF. According to in vitro data, about 19-29% of fludarabine is 
bound to plasma proteins.  
Following IV administration, fludarabine phosphate is dephosphorylated rapidly to fludarabine. 
Plasma concentrations of fludarabine decline in a linear, dose-independent manner. The elimination 
profile of fludarabine also has been reported to be either biphasic or triphasic; however, reported 
terminal elimination half-lives have been similar. In adult cancer patients receiving fludarabine 25 
mg/m2 as a 30-minute IV infusion daily for 5 days, a terminal half-life of about 20 hours was 
reported. In a limited number of pediatric patients, the plasma concentration profile of fludarabine 
exhibited both monoexponential and biexponential decay, with a mean t1/2 of 10.5 hours in patients 
with monoexponential elimination and a t1/2 of 1.2-1.4 and 12.4-19 hours, respectively, in patients 
with biexponential elimination.  
Renal clearance accounts for about 40% of the total body clearance of fludarabine. Renal 
elimination appears to become more important at high dosages of the drug. The dose of fludarabine 
needs to be adjusted in patients with moderate renal impairment. 
The use of fludarabine in combination with pentostatin is not recommended due to the risk of severe 
pulmonary toxicity. 
 
Toxicity: 
 
Common 
Happens to 21-
100 subjects out 
of every 100 
Occasional 
Happens to 5-20 subjects 
out of every 100 
Rare 
Happens to < 5 subjects out of every 
100 
Immediate: 
Fever, fatigue, 
weakness, pain, 
nausea, vomiting, 
Edema including 
peripheral edema, chills, 
rash, diarrhea, rhinitis, 
Anaphylaxis, tumor lysis syndrome, 
dehydration*  

 
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Common 
Happens to 21-
100 subjects out 
of every 100 
Occasional 
Happens to 5-20 subjects 
out of every 100 
Rare 
Happens to < 5 subjects out of every 
100 
Within 1-2 
days of 
receiving drug 
anorexia, cough, 
dyspnea 
diaphoresis, malaise, 
abdominal pain, 
headache, back pain, 
myalgia, stomatitis, flu-
like syndrome 
 
 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Myelosuppressio
n (anemia, 
neutropenia, 
thrombocytopeni
a), infection 
(urinary tract 
infection, herpes 
simplex infection, 
pneumonia, upper 
respiratory) 
Weight loss, 
gastrointestinal bleeding, 
hemoptysis, paresthesia, 
allergic pneumonitis, 
bronchitis, pharyngitis, 
visual disturbance, 
hearing loss, 
hyperglycemia  
Sinusitis, dysuria, opportunistic 
infections and reactivation of latent 
viral infections like Epstein-Barr virus 
(EBV), herpes zoster and John 
Cunningham (JC) virus (progressive 
multifocal leukoencephalopathy 
[PML])L, EBV associated 
lymphoproliferative disorder, 
panycytopenia (can be prolonged), 
pulmonary hypersensitivitya (dyspnea, 
cough, hypoxia, interstitial pulmonary 
infiltrate), pulmonary toxicity (acute 
respiratory distress syndrome 
[ARDS], pulmonary fibrosis, 
pulmonary hemorrhage, respiratory 
distress, respiratory failure), 
pericardial effusion, skin toxicity 
(erythema multiforme, Stevens-
Johnson syndrome, toxic epidermal 
necrolysis, pemphigus), liver failure, 
renal failure, hemorrhage, transfusion-
associated graft-versus-host disease 
has occurred following transfusion of 
nonirradiated blood products, 
phlebitis*, sleep disorder*, cerebellar 
syndrome*, depression*, mentation 
impaired*, alopecia*, pruritus*, 
seborrhea*, esophagitis*, 
constipation*, mucositis*, dysphagia*, 
hesitancy*, cholelithiasis*, abnormal 
liver function tests *, osteoporosis*, 
arthralgia*, abnormal renal function 
test*, proteinuria*, epistaxis*, 
hemorrhagic cystitis*, eosinophilia*  
Delayed: 
Any time later 
during therapy, 
excluding the 
above 
conditions 
 
 
Neurotoxicity (increased with high 
doses): seizures, agitation, confusion, 
weakness, visual disturbances, optic 
neuritis, optic neuropathy, 
photophobia, blindness, paralysis, 
coma, death, peripheral neuropathya); 
autoimmune phenomena: 
thrombocytopenia/thrombocytopenic 
purpura (ITP), Evans syndrome, 
hemolytic anemia, acquired 
hemophilia 

 
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Common 
Happens to 21-
100 subjects out 
of every 100 
Occasional 
Happens to 5-20 subjects 
out of every 100 
Rare 
Happens to < 5 subjects out of every 
100 
Late: 
Any time after 
completion of 
treatment 
 
 
Myelodysplastic syndrome/acute 
myeloid leukemia (mainly associated 
with prior or concomitant or 
subsequent treatment with other 
anticancer treatments), skin cancer 
(new onset or exacerbation) 
Unknown 
Frequency 
and Timing: 
Pregnancy Category D  
Based on its mechanism of action, fludarabine phosphate can cause fetal harm when 
administered to a pregnant woman. Fludarabine phosphate was embryolethal and 
teratogenic in both rats and rabbits. 
(L) Toxicity may also occur later. 
* Reported in ≤ 3% of subjects.  Since these are not considered life threatening they are not included in the 
consent. 
a These effects were not reported in children. 
 
 
Formulation and Stability: 
Fludarabine phosphate injection is available as sterile lyophilized powder and in solution. Each 
single-dose vial of powder contains 50 mg of the active ingredient fludarabine phosphate, 50 mg 
of mannitol, and sodium hydroxide to adjust the pH to 7.7. After reconstitution, the pH range for 
the final product is 7.2-8.2. The single-dose solution vial contains 25 mg/mL, 2 mL of fludarabine 
phosphate. It may contain mannitol and is preservative-free.  
Fludarabine phosphate vials should be stored refrigerated at 2-8ºC (36-46ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Fludarabine phosphate powder should be reconstituted with 2 mL of Sterile Water for Injection. 
The solid cake should fully dissolve in 15 seconds or less. The resulting concentration is 25 mg/mL. 
When reconstituted to a final concentration of 25 mg/mL, the drug is stable for at least 16 days at 
room temperature and normal light conditions. The manufacturer recommends that the solution be 
used within 8 hours after reconstitution. 
 
Prior to administration, fludarabine 25 mg/mL solution or the reconstituted 25 mg/mL solution 
should be further diluted in 100 mL or 125 mL of D5W or NS. Concentrations of 0.25 to 1 mg/mL 
have been used in clinical trials. When diluted to a final concentration of 1 mg/mL, fludarabine is 
stable for at least 16 days at room temperature and normal light conditions. The manufacturer 
recommends that the diluted solution be used within 8 hours after preparation. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration. 
 
Supplier:  Commercially available from various manufacturers. See package insert for further 
information. 
 
 

 
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6.10 
INTRATHECAL TRIPLES 
(05/08/12) 
(Methotrexate/Hydrocortisone/Cytarabine, IT-3)  
 
Source and Pharmacology:  
The intrathecal route of administration of a drug produces more consistent CSF drug concentrations 
at relatively smaller doses because of the volume difference between the CSF and blood 
compartments (140 mL vs. 3500 mL in an adult). (The CSF volume of children after the first 3 years 
is equivalent to that of an adult). Drug half-lives are longer as well because clearance is related to 
flow rather than metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination 
curve from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT injection of cytarabine 
the elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 hours respectively, which 
is 8-fold longer than the clearance from plasma. The elimination of hydrocortisone is similarly 
prolonged. 
 
Intrathecal Triple Therapy (Methotrexate/ Hydrocortisone/Cytarabine) Toxicity:  
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus and 
pleocytosis)  
Rash, anaphylaxis (L), paresis, 
bleeding into subarachnoid or 
subdural space (risk > with 
platelet counts < 20,000), 
confusion, fatigue, 
disorientation, seizures 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Myelosuppression, 
somnolence, ataxia, cranial 
nerve palsy, transient and 
rarely permanent paraplegia 
(L), speech disorders 
Delayed: 
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive 
disturbances (L), learning 
disabilities (L) 
Demyelinating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after 
the completion 
of treatment 
 
 
Progressive CNS 
deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial 
irradiation. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg preservative free sterile 
powder for injection vial. Cytarabine 100 mg preservative free sterile powder for injection. 
Hydrocortisone sodium succinate 100 mg vial sterile powder for injection.   
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
For intrathecal administration, dilute each agent with 5-10 mL preservative free NS, lactated ringers 
or Elliot’s B solution or as per institutional standard of practice. The volume of CSF removed should 
be equal to at least half the volume delivered. 

 
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*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med 1962 Dec 
20; 267:1273-8 
 
Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with 
the patient remaining prone after the procedure may facilitate drug distribution. These procedures have 
not been validated in clinical trials. They are allowed but not mandated for patients on COG studies. 
 
Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative and should be 
administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.11 
LEUCOVORIN CALCIUM 
(05/07/19) 
(LCV, Wellcovorin®, citrovorum factor, folinic acid, Calcium folinate) NSC #003590  
 
Source and Pharmacology:   
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid 
(THF). The biologically active compound of the mixture is the (-)- l-isomer, known as Citrovorum 
factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate 
reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. 
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid 
antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, 
leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer 
therapy, such as 5-fluorouracil. Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid (an 
active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition of this 
enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at approximately 
1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life of total reduced folates 
was approximately 6.2 hours.  Following oral administration, leucovorin is rapidly absorbed and 
expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer (the 
biologically active form) but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin 
is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 
75% for 50 mg, and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the CSF folate 
levels. 
 
 
 
Patient Age 
(years) 
Doses 
(MTX/Hydrocortisone/Ara-C) 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
0 – 0.99 
7.5 mg / 7.5 mg / 15 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
1 – 1.99 
8 mg / 8 mg / 16 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
2 – 2.99 
10 mg / 10 mg / 20 mg 
5-10 mL 
8 mL 
80 + 20 mL  
(younger children) 
3 – 8.99 
12 mg / 12 mg / 24 mg 
5-10 mL 
10 mL 
100 + 20 mL  
(older children) 
9 or greater 
15 mg / 15 mg / 30 mg 
5-10 mL 
13 mL 
130 + 30 mL  
(adults) 

 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Anaphylaxis, urticaria, 
seizure 
Unknown 
Frequency and 
timing: 
Fetal toxicities and teratogenic effects of leucovorin in humans are unknown. 
It is unknown whether the drug is excreted in breast milk. 
 
 
Formulation and Stability:  
Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile powder for 
injection. The 10 mg/mL preservative free liquid is available in 50 mL vials containing sodium 
chloride 400 mg/vial. Store preservative free liquid in the refrigerator at 2°-8°C (36°-46°F) 
protected from light. The powder for injection is available in 50 mg, 100 mg, 200 mg, and 350 mg 
vials. Store at room temperature 15°-25°C (59°-77°F) protected from light. Reconstitute the sterile 
powder with sterile water for injection or bacteriostatic water for injection to a concentration of 
10 mg/mL leucovorin calcium. Do not use diluents containing benzyl alcohol for doses 
> 10 mg/m² or in infants < 2 years of age or patients with allergy to benzyl alcohol. When 
Bacteriostatic Water is used, the reconstituted solution is good for 7 days. If reconstituted with SWFI, 
use solution immediately as it contains no preservative. One milligram of leucovorin calcium 
contains 0.004 mEq of leucovorin and 0.004 mEq of calcium. 
 
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: corn starch, 
dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose, microcrystalline 
cellulose, and sodium starch glycolate. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.  
 
Injection: 
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin 
should be injected intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV 
leucovorin and sodium bicarbonate are incompatible. 
 
Oral: 
Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and may be 
taken without regard to meals. Doses > 25 mg should be given IV due to the saturation of 
absorption. 
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain 
methotrexate unless there are special circumstances. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 

 
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6.12 
MERCAPTOPURINE 
(11/27/17) 
(6-MP, Purinethol®, PurixanTM, 6-mercaptopurine) NSC #000755 
 
Source and Pharmacology:  
Mercaptopurine is an analogue of the purine bases adenine and hypoxanthine. The main intracellular 
pathway for MP activation is catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl 
transferase (HGPRT) which catalyzes the conversion of MP to several active nucleotide 
metabolites including thioinosinic acid, a ribonucleotide which can interfere with various metabolic 
reactions necessary for nucleic acid (RNA and DNA) biosynthesis. It can also cause 
pseudofeedback inhibition of the first step in de novo purine biosynthesis or convert to another 
ribonucleotide which can cause feedback inhibition. Mercaptopurine can be incorporated into DNA 
in the form of TG nucleotides as well and thus produce toxicity. The absorption of an oral dose of 
MP is incomplete and variable, with only about 16%-50% of an administered dose reaching the 
systemic circulation secondary to a first pass metabolism in the liver. Food intake and co-
administration with cotrimoxazole (TMP/SMX) significantly reduces absorption of MP. After IV 
administration, MP has a plasma half-life of 21 minutes in children and 47 minutes in adults. 
Approximately 19% is bound to protein. Mercaptopurine is well distributed into most body 
compartments except the CSF. (With high dose IV MP the CSF to plasma ratio is 0.15.) MP is 
metabolized by xanthine oxidase in the liver to 6-Thiouric acid an inactive metabolite. In patients 
receiving both MP and allopurinol (a xanthine oxidase inhibitor) the dose of MP must be reduced by 
50-75%. Since TPMT, 6-thiopurine methyltransferase, is also one of the enzymes involved in the 
metabolism of MP, those individuals who have an inherited deficiency of the enzyme may be 
unusually sensitive to the myelosuppressive effects of MP and prone to develop rapid bone marrow 
suppression following the initiation of treatment. Mercaptopurine is excreted in urine as metabolites 
and some unchanged drug; about half an oral dose has been recovered in 24 hours. A small 
proportion is excreted over several weeks. 
 
 
Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of 
patients) 
Neutrophil count decreased, white blood cell decreased, anorexia, fatigue  
Occasional 
(4 - 20% of 
patients) 
Diarrhea, nausea, vomiting, malaise, oligospermia, infection, fever, platelet count 
decreased, anemia, mucositis, stomach pain, ulcerative bowel lesion, skin rash, alanine 
aminotransferase increased, aspartate aminotransferase increased 
Rare 
(≤3% of 
patients) 
Urticaria, skin hyperpigmentation, alopecia, hyperuricemia, hepatic failure, hepatic 
necrosis, blood bilirubin increased, pulmonary fibrosis, secondary malignant neoplasm, 
renal toxicity, uricosuria, pancreatitis 
Pregnancy and 
Lactation 
Pregnancy Category D 
Mercaptopurine can cause fetal harm, including an increased incidence of abortion and 
stillbirth. Advise women to avoid becoming pregnant while receiving mercaptopurine. 
Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, 
rabbit, and hamster). It is not known whether mercaptopurine is excreted in human milk; 
breastfeeding should be avoided. 
 
Formulation and Stability:  
Mercaptopurine is available as a 50 mg tablet containing mercaptopurine and the inactive 
ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. Store at 15°-25°C 
(59°-77°F) in a dry place. In the United States, mercaptopurine is also available as an oral 

 
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suspension in a concentration of 20 mg/mL (2000 mg/100 mL per bottle). The oral suspension is a 
pink to brown viscous liquid supplied in amber glass multiple-dose bottles with a child resistant 
closure. It should be stored at 15°-25°C (59°-77°F) in a dry place.  
 
NOTE: the concentration of the commercially available suspension (20 mg/mL) and the 
compounded suspension (50 mg/mL) are NOT the same; doses should be prescribed in the 
milligrams required, not mL.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Mercaptopurine should be taken consistently at the same time every day.  
 
If allopurinol is also given, the oral dose of mercaptopurine should be reduced by 67-75%. Patients 
with severe myelosuppression should have their thiopurine S-methyltransferase (TPMT) status 
and/or their thiopurine metabolite concentrations evaluated, so that the dose of mercaptopurine can 
be reduced in patients with a TPMT defect. Patients with the rare homozygous deficient TPMT 
phenotype may tolerate only 1/10th to 1/20th the average mercaptopurine dose. TPMT testing and 
thiopurine metabolite measurements are commercially available. 
 
Suspension: 
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be compounded. 
The suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a mortar and adding 8.5 
mL sterile water for irrigation. The mixture is triturated to form a smooth paste. Next, 16.5 mL simple 
syrup (pH=7) are added with continuous mixing and finally cherry syrup (pH=7.1) is added to a total 
volume of 50 mL. The suspension is stable in amber glass bottles at room temperature (19ºC -23ºC) 
for up to 5 weeks. The suspension should be shaken well before each use. Procedures for proper 
handling and disposal of cytotoxic drugs should be used when preparing the suspension. (Aliabadi 
HM, Romanick M, Desai S et al. Effect of buffer and antioxidant on stability of mercaptopurine 
suspension. Am J Heath-Syst Pharm. 65:441-7, 2008.) 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. PLEASE NOTE there is a difference in the concentration of the commercially 
available (20 mg/mL) and extemporaneously compounded (50 mg/mL) oral suspensions. 
  
 
6.13 
METHOTREXATE-ALL ROUTES 
(05/07/19) 
(MTX, amethopterin, Trexall®, Xatmep®) NSC #000740 
 
Source and Pharmacology:  
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic 
acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one 
carbon fragments necessary for the synthesis of purines and the conversion of deoxyuridylate to 
thymidylate in the synthesis of DNA and cell reproduction. The polyglutamated metabolites of MTX 
also contribute to the cytotoxic effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity 
is highly dependent on the absolute drug concentration and the duration of drug exposure. MTX is 
actively transported across cell membranes. At serum methotrexate concentrations exceeding 
0.1 µmol/mL, passive diffusion becomes a major means of intracellular transport of MTX. The drug 
is widely distributed throughout the body with the highest concentration in the kidney, liver, spleen, 
gallbladder and skin. Plasma concentrations following high dose IV MTX decline in a biphasic 
manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of 8-15 hours. About 50% is 
bound to protein. After oral administration, approximately 60% of a 30 mg/m2 dose is rapidly 

 
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absorbed from the GI tract, with peak blood levels at 1 hour. At doses > 30 mg/m² absorption 
decreases significantly. Even at low doses absorption may be very erratic, varying between 23% and 
95%. The elimination of MTX from the CSF after an intrathecal dose is characterized by a biphasic 
curve with half-lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the lumbar 
concentration of MTX is ~100 times higher than in plasma. (Ventricular concentration is ~ 10% of 
lumbar concentration). MTX is excreted primarily by the kidneys via glomerular filtration and active 
secretion into the proximal tubules. Renal clearance usually equals or exceeds creatinine clearance. 
Small amounts are excreted in the feces. There is significant entero-hepatic circulation of MTX. The 
distribution of MTX into third-space fluid collections, such as pleural effusions and ascitic fluid, can 
substantially alter MTX pharmacokinetics. The slow release of accumulated MTX from these third 
spaces over time prolongs the terminal half-life of the drug, leading to potentially increased clinical 
toxicity.  
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Transaminase elevations Nausea, vomiting, 
anorexia 
Anaphylaxis, chills, fever, 
dizziness, malaise,  
drowsiness, blurred vision, 
acral erythema, urticaria, 
pruritus, toxic epidermal 
necrolysis, Stevens-Johnson 
Syndrome, tumor lysis 
syndrome, seizures1, 
photosensitivity 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Myelosuppression, 
stomatitis, gingivitis, 
photosensitivity, fatigue 
Alopecia, folliculitis, acne, 
renal toxicity (ATN, increased 
creatinine/BUN, hematuria), 
enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 
(headache, drowsiness, 
aphasia, paresis, blurred 
vision, transient blindness, 
dysarthria, hemiparesis, 
decreased reflexes) diarrhea, 
conjunctivitis 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
Learning disability1 (L) 
Pneumonitis, pulmonary 
fibrosis (L), hepatic fibrosis 
(L), osteonecrosis (L), 
leukoencephalopathy1 (L), 
pericarditis, pericardial 
effusions, hyperpigmentation 
of the nails 
Late: 
Any time after the 
completion of therapy 
 
 
Progressive CNS 
deterioration1 
Unknown Frequency 
and Timing:   
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of 
methotrexate have been noted in humans. The toxicities include: congenital defects, 
chromosomal abnormalities, severe newborn myelosuppression, low birth weight, 
abortion, and fetal death.  Methotrexate is excreted into breast milk in low 
concentrations. 
1 May be enhanced by HDMTX and/or cranial irradiation. 
 (L) Toxicity may also occur later. 
 

 
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Intrathecal Therapy (Methotrexate Single Agent) 
 
Toxicity: 
 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea, headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus,  nuchal 
rigidity, and pleocytosis)   
Anaphylaxis, vomiting, 
seizures(L), malaise, 
confusion, back pain, 
rash, bleeding into 
subarachnoid or subdural 
space (risk > with platelet 
counts < 20,000), 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve 
palsy, subacute 
myelopathy 
(paraparesis/paraplegia), 
speech disorders, pain in 
the legs, bladder 
dysfunction 
Delayed: 
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive disturbances 
(L)1, 
learning disability (L)1 
 
 
Leukoencephalopathy1 (L) 
Late: 
Any time after 
the completion 
of treatment 
 
 
Progressive CNS 
deterioration1 
1 May be enhanced by HDMTX and/or cranial irradiation. 
 (L) Toxicity may also occur later. 
 
Formulation & Stability:  
Methotrexate tablets are available as 2.5 mg, 5 mg, 7.5 mg, 10 mg and 15 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: anhydrous 
lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline 
cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium carbonate 
monohydrate, talc and titanium dioxide and various dyes. Store at controlled room temperature 
15°-30°C (59°-86°F) and protect from light.  
 
Australia/NZ – only 2.5 mg and 10 mg tablets available. 
 
Methotrexate is also available as a clear yellow to orange oral solution (Xatmep®) that contains 
2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL) in a 120 
mL bottle. Inactive ingredients include purified water, sodium citrate, citric acid, methylparaben 
sodium, propylparaben sodium, and sucralose. It may also contain sodium hydroxide or 
hydrochloric acid for pH adjustment. It is packaged in a high-density polyethylene (HDPE) bottle 
with a child-resistant cap and tamper-evident seal. Store oral solution under refrigeration (2°C to 
8°C/36°F to 46°F) prior to dispensing. Avoid freezing and excessive heat. After dispensing, patients 
may store methotrexate oral solution at room temperature (20°C to 25°C/68°F to 77°F) for up to 
60 days; excursions permitted to 15°C to 30°C (59°F to 86°F). 

 
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Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg vials. The 
powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. Methotrexate for 
Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL preservative free vials 
and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL solutions contain 
approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, respectively. The preserved 
vials contain 0.9% benzyl alcohol as a preservative.  
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions permitted to 
15º-30ºC (59º- 86 Fº). Protect from light  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
Leucovorin rescue may be necessary with certain doses of methotrexate. 
 
Oral administration:  Food or milk delays absorption and reduces peak concentration. 
Methotrexate for oral use should preferentially be given on an empty stomach, 1 hour before or 
2 hours after food or milk and at the same time each day. Methotrexate injection diluted in water 
can be used for oral administration, if an oral formulation is not readily available (Marshall PS, 
Gertner E. Oral administration of an easily prepared solution of injectable methotrexate diluted in 
water: a comparison of serum concentrations vs methotrexate tablets and clinical utility. J 
Rheumatol 23:455-8, 1996). 
 
For IM/IV use:  Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free 
SWFI, D5W or NS to a 50 mg/mL concentration. The powder for injection may be further diluted 
in NS or dextrose containing solutions to a concentration of ≤ 25mg/mL for IV use. 
 
The 25 mg/mL solution may be given directly for IM administration or further diluted in Saline or 
Dextrose containing solutions for IV use. Do not use the preserved solution for high dose 
methotrexate administration due to risk of benzyl alcohol toxicity. Methotrexate dilutions are 
chemically stable for at least 7 days at room temperature but contain no preservative and should be 
used within 24 hours. Diluted solutions especially those containing bicarbonate exposed to direct 
sunlight for periods exceeding 4 hours should be protected from light. 
 
High dose methotrexate requires alkalinization of the urine, adequate hydration and leucovorin 
rescue. Avoid sulfamethoxazole/trimethoprim, probenecid, penicillins, cephalosporins, aspirin, 
proton pump inhibitors, and NSAIDS as renal excretion of MTX is inhibited by these agents. 
 
For Intrathecal use: Use preservative free 25 mg/mL solution. 
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s, or Elliot’s 
B solution as per institutional standard of practice. The volume of CSF removed should be equal to 
at least half the volume delivered. 
 
Note: When IT therapy and ID MTX are scheduled for the same day, deliver the IT therapy within 
6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX 
bolus). 
 
For IT administration, use the preservative free formulation. The volume to be given IT should be 
in the range of 5-10 mL. The volume of CSF removed should be equal to at least half the volume 
delivered (see drug monograph). 

 
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* Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 
1962 Dec 20; 267:1273-8 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with 
the patient remaining prone after the procedure may facilitate drug distribution. These procedures have 
not been validated in clinical trials. They are allowed but not mandated for patients on COG studies. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains no 
preservative and should be administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.14 
MITOXANTRONE 
(11/27/17) 
(Novantrone®, CL 232315, DAD, DHAD, Mitozantrone) NSC #301739 
 
Source and Pharmacology: 
Mitoxantrone is a substituted alkylaminoanthraquinone and is a potent inhibitor of DNA and RNA 
synthesis in vitro and binds strongly to DNA. Mitoxantrone most likely acts through intercalation 
between base pairs of the DNA double helix causing crosslinks and strand breaks. In addition, it is 
a topoisomerase II inhibitor, an enzyme responsible for uncoiling and repairing damaged DNA. It 
has a cytocidal effect on both proliferating and non-proliferating cultured human cells, suggesting 
lack of cell cycle Phase specificity. The drug disappears rapidly from plasma (drug found only in the 
3-minute sample) and < 1% appears in the urine in 24 hours. The mean alpha half-life of 
mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma 
(terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours). Primary 
excretion is biliary with 25% appearing in the feces; renal excretion accounting for only 11% of the 
total dose. Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic 
dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients 
with normal hepatic function receiving the same dose. Mitoxantrone is approximately 95% protein 
bound. 
 
Toxicity: 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to 
< 5 children out of 
every 100 
Patient Age (years) 
Methotrexate 
dose 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
1–1.99 
8 mg 
5–10 mL 
5 mL 
50 +  10 mL 
(babies) 
2–2.99 
10 mg 
5-10 mL 
8 mL 
80 + 20 mL 
(younger children) 
3–8.99 
12 mg 
5-10 mL 
10 mL 
100 + 20 mL 
(older children) 
9 or greater 
15 mg 
5-10 mL 
13 mL 
130 + 30 mL 
(adults) 

 
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Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
diarrhea, fever, 
anorexia, green blue 
discoloration of the 
urine and/or sclera 
Abdominal pain, back 
pain, headache, 
phlebitis, constipation 
Anaphylaxis, 
angioedema, cardiac 
arrhythmias1 
(bradycardia), seizures, 
extravasation reactions 
rare but if occur can 
lead to: (erythema, 
swelling, pain, burning 
and/or blue 
discoloration of the 
skin and rarely tissue 
necrosis), tumor lysis 
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Myelosuppression (L), 
mucositis /stomatitis, 
immunosuppression, 
alopecia, fatigue  
Transient elevation of 
LFTs, pruritus with 
desquamation of the 
skin due to progressive 
dryness 
Rash, conjunctivitis, 
(GI) hemorrhage, 
interstitial pneumonitis 
Delayed: 
Any time later during 
therapy 
Amenorrhea, menstrual 
disorders, temporary 
reduction in sperm 
count 
Cardiotoxicity 
(decreased LVEF)2 (L) 
CHF, hepatotoxicity 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of mitoxantrone have been noted 
in animals. Toxicities include: low birth weight and prematurity. 
Mitoxantrone is excreted in human milk and significant concentrations 
(18 ng/mL) have been reported for 28 days after the last administration. 
1 Rarely clinically significant. 
2 Risk increases with chest radiation and prior anthracycline dosage 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
The concentrate is a sterile, non-pyrogenic, non-preserved, dark blue aqueous solution containing 
mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride 
(0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients 
with 0.14 mEq of sodium per mL. Mitoxantrone is provided as 20 mg (10 mL), 25 mg (12.5 mL) 
and 30 mg (15 mL) vials. Store intact vials at 15°-25°C (59°-77°F). Undiluted mitoxantrone 
injection should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under 
refrigeration. Refrigeration of the concentrate may result in a precipitate, which redissolves on 
warming to room temperature. DO NOT FREEZE.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Mitoxantrone must be diluted prior to injection. DO NOT GIVE IV PUSH. The dose of 
mitoxantrone should be diluted in at least 50 mL or to a concentration ≤ 0.5 mg/mL with either NS 
or D5W. The dilution is stable at room temperature for 48 hours with no loss of potency. Admixture 
with heparin may result in precipitation. Mitoxantrone is an irritant: Care should be taken to avoid 
extravasation; the use of a central line is suggested.  
 
Supplier: Commercially available. See package insert for more detailed information. 
 

 
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Special precautions: Incompatible with heparin; precipitate may form. 
 
6.15 
MYCOPHENOLATE MOFETIL 
(12/06/18) 
(CellCept®, MMF, RS-61443) NSC# 724229 
 
Source and Pharmacology:  
Mycophenolate (MMF) is the morpholinoethyl ester of mycophenolic acid (MPA), an antibiotic 
with immunosuppressant properties isolated from Penicillium spp. The chemical name for oral 
mycophenolate mofetil is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-
3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7 and a 
molecular weight of 433.50. Mycophenolate mofetil is a white to off-white crystalline powder 
which is slightly soluble in water (43 μg/mL at pH 7.4); the solubility increases in acidic medium 
(4.27 mg/mL at pH 31 3.6). The intravenous product is the hydrochloride salt of mycophenolate 
mofetil. The chemical name for the hydrochloride salt of mycophenolate mofetil is 
2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-
4-methyl-4-hexenoate hydrochloride. It has an empirical formula of C23H31NO7 HCl and a 
molecular weight of 469.96. 
 
MMF has been used in a variety of solid organ and hematopoietic stem cell transplant settings for 
the prevention of acute rejection. MMF is a prodrug which, after oral administration, is rapidly and 
primarily hydrolyzed by the liver, to the biologically active metabolite mycophenolic acid. MPA is 
metabolized principally by glucuronyl transferase to form the pharmacologically inactive phenolic 
glucuronide of MPA (MPAG). In vivo, MPAG is converted to MPA via enterohepatic recirculation. 
Mycophenolic acid inhibits nucleic acid synthesis and produces a potent, noncompetitive, and 
reversible inhibition of inosine monophosphate dehydrogenase (IMPDH), blocking the de novo 
synthesis of guanosine nucleotides without being incorporated into DNA. Both T and B 
lymphocytes rely on this de novo pathway for purine synthesis. As a result, the proliferative 
responses of T and B lymphocytes to both mitogenic and allospecific stimulation are inhibited. 
Other rapidly dividing cell lines are capable of recycling purine nucleotides via the "salvage" 
pathway, which is not blocked by mycophenolic acid. 
 
In vitro and in vivo studies have demonstrated the ability of mycophenolic acid to block 
proliferative responses of T and B lymphocytes, inhibit antibody formation and the generation of 
cytotoxic T-cells, and suppress antibody formation by B lymphocytes. Mycophenolic acid prevents 
the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular 
adhesion of these cells to endothelial cells, and may inhibit recruitment of leukocytes into sites of 
inflammation and graft rejection. Antirejection effects have been attributed to decreased 
recruitment of activated lymphocytes to the graft site. 
 
The mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous 
mycophenolate mofetil (based on MPA AUC) was 94% in a small sample of healthy, adult 
volunteers. In this group the mean (±SD) apparent volume of distribution of MPA was 
approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, 
respectively. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. MPAG 
is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable 
renal transplant patients; however, at higher MPAG concentrations (e.g., patients with renal 
impairment), the binding of MPA may be reduced as a result of competition between MPAG and 
MPA for protein binding. A negligible amount of the agent (< 1% of dose) is excreted as MPA in 
the urine. Most of the administered dose (~87%) is excreted in the urine as MPAG. Bile acid 

 
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sequestrants (e.g., cholestyramine) reduce the AUC of MPA by interfering with the enterohepatic 
circulation of the drug. 
 
Mycophenolate mofetil can cause fetal harm when administered to a pregnant woman. Use of MMF 
during pregnancy is associated with an increased risk of first trimester pregnancy loss and an 
increased risk of congenital malformations, especially external ear and other facial abnormalities 
including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. 
According to the package labeling, the National Transplantation Pregnancy Registry (NTPR) 
presents data on 33 MMF-exposed pregnancies in 24 transplant patients. Of these, there were 15 
spontaneous abortions and 18 live-born infants. Four of the 18 infants had structural malformations 
(22%). In postmarketing data (collected 1995-2007) of 77 women exposed to systemic MMF 
during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 
malformed offspring had ear abnormalities. Because these postmarketing data are reported 
voluntarily, it is not always possible to reliably estimate the frequency of particular adverse 
outcomes. These malformations seen in offspring were similar to findings in animal reproductive 
toxicology studies. In animal reproductive toxicology studies, there were increased rates of fetal 
resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received 
MMF doses equivalent to 0.02 to 0.9 times the recommended human dose for renal and cardiac 
transplant patients, based on body surface area conversions. In rat offspring, malformations 
included anophthalmia, agnathia, and hydrocephaly. In rabbit offspring, malformations included 
ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia. If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus. 
 
Women of childbearing potential should have a negative serum or urine pregnancy test with a 
sensitivity of at least 25 mIU/mL within 1 week prior to beginning therapy (manufacturer’s 
recommendation). MMF should not be initiated until a negative pregnancy test report is obtained. 
Women of childbearing potential taking MMF must receive contraceptive counseling and use 
effective contraception. It is recommended by the manufacturer that the patient begin using two 
chosen methods of contraception 4 weeks prior to starting MMF, unless abstinence is the chosen 
method. She should continue contraceptive use during therapy and for 6 weeks after stopping 
MMF. Patients should be aware that MMF reduces blood levels of the hormones in the oral 
contraceptive pill and could theoretically reduce its effectiveness. 
 
An approved medication guide (https://www.mycophenolaterems.com/REMSMaterials.aspx) 
must be dispensed with each refill of mycophenolate mofetil. 
 
The table below lists the toxicity profile of mycophenolate mofetil: 
 
Incidence 
Toxicities 
Common 
(> 20% of patients) 
Hypertension, edema (face, limbs, trunk), rash maculo-papular, 
cholesterol high, hyperglycemia, hyperkalemia, hypocalcemia, 
hypokalemia, hypomagnesemia, abdominal pain, constipation, 
diarrhea, nausea, vomiting, anorexia, dyspepsia, anemia, white blood 
cell decreased, platelet count decreased, back pain, anxiety, 
generalized muscle weakness, dizziness, headache, insomnia, tremor, 
creatinine increased, dyspnea, cough, fever, pleural effusion, alanine 
aminotransferase increased, alkaline phosphatase increased, aspartate 
aminotransferase increased, blood bilirubin increased, GGT 
increased, pain, paresthesia, infection1 

 
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Occasional 
(4-20% of patients) 
Sepsis, urinary tract pain, urinary frequency, phlebitis (IV only), 
thrombosis (IV only)  
Rare 
(<3% of patients) 
Phlebitis, Neoplasms benign, malignant and unspecified (including 
cysts and polyps) - Other, [Malignant epithelial neoplasm of skin, 
non-melanoma; lymphoproliferative disease or lymphoma], gastric 
ulcer, gastrointestinal hemorrhage, gastric perforation, mucositis oral, 
thromboembolic event, infective endocarditis, renal calculi, 
pulmonary fibrosis, pneumonitis, neutrophil count decreased, 
leukoencephalopathy, colitis, pancreatitis, pure red cell aplasia 
Pregnancy & 
Lactation 
Pregnancy Category D  
Mycophenolate is associated with an increased risk of congenital 
malformations and spontaneous abortions when used during 
pregnancy. Adverse events have been reported in animal studies at 
doses less than the equivalent recommended human dose. Data from 
the National Transplantation Pregnancy Registry (NTPR) have 
observed an increase in structural malformations (including ear 
malformations) in infants born to mothers taking mycophenolate 
during pregnancy. Spontaneous abortions have also been noted. 
Females of childbearing potential should have a negative pregnancy 
test within 1 week prior to beginning therapy. Two reliable forms of 
contraception should be used beginning 4 weeks prior to, during, and 
for 6 weeks after therapy. The effectiveness of hormonal 
contraceptive agents may be affected by mycophenolate. 
 
It is unknown if mycophenolate is excreted in human milk. Due to 
potentially serious adverse reactions, the decision to discontinue the 
drug or discontinue breast-feeding should be considered. Breast-
feeding is not recommended during therapy or for 6 weeks after 
treatment is complete. 
1Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Formulation and Stability: 
Mycophenolate mofetil is available in the following preparations: 
• 
Capsule: 250 mg 
• 
Tablet: 500 mg 
• 
Powder for suspension, oral: 200 mg/mL (following reconstitution) 
• 
Powder for reconstitution, injection: 500 mg per vial 
 
A delayed release tablet (mycophenolic acid, Myfortic) is also commercially available.  This 
preparation is not interchangeable with mycophenolate mofetil (Cellcept®, MMF) due to 
differences in absorption. This tablet is not discussed in this monograph and should not be used by 
patients treated on this protocol.  
 
Inactive ingredients in the 250 mg capsules include the following: croscarmellose sodium, 
magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells contain black 
iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium 
dioxide, and yellow iron oxide. 
 
Inactive ingredients in the 500 mg tablets include black iron oxide, croscarmellose sodium, FD&C 
blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium 

 
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stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), red iron oxide, talc, 
and titanium dioxide; may also contain ammonium hydroxide, ethyl alcohol, methyl alcohol, n-
butyl alcohol, propylene glycol, and shellac. 
 
Inactive ingredients in the powder for oral suspension include aspartame, citric acid anhydrous, 
colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate dihydrate, sorbitol, 
soybean lecithin, and xanthan gum. 
 
The injectable product is available as a sterile, white to off-white, lyophilized powder in vials 
containing mycophenolate mofetil hydrochloride for administration by intravenous infusion only. 
Each vial contains the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt. 
Inactive ingredients include polysorbate 80 (25 mg), citric acid (5 mg), and sodium hydroxide to 
adjust the pH. Reconstitution and dilution with D5W yields a final solution of mycophenolate 
mofetil that is slightly yellow in color. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Preparation: 
To prepare the oral suspension, add 47 mL of water to the bottle and shake well for approximately 
1 minute. Add another 47 mL of water to the bottle and shake well for an additional minute. The 
final concentration is 200 mg/mL of mycophenolate mofetil. Avoid inhalation or direct contact 
with skin or mucous membranes of the dry powder or the constituted suspension. If such contact 
occurs, wash thoroughly with soap and water; rinse eyes with water. 
 
To prepare the intravenous injection, reconstitute the contents of each vial with 14 mL of D5W. 
Dilute the contents of a vial with D5W to a final concentration of 6 mg/mL. Each vial is vacuum-
sealed; if a lack of vacuum is noted during preparation, the vial should not be used. 
 
Stability: 
Oral formulations should be stored at 25°C (77°F); excursions are permitted to 15°C to 30°C (59°F 
to 86°F). Protect from moisture and light. Once reconstituted, the oral solution may be stored at 
room temperature or under refrigeration. Do not freeze. The mixed suspension is stable for 60 days. 
 
Store intact vials and diluted solutions at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F 
to 86°F). Do not freeze. Begin infusion within 4 hours of reconstitution. 
 
Administration: 
Oral formulations of MMF should be administered on an empty stomach to avoid variability in 
MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 French, 
1.7 mm interior diameter). Do not mix the oral suspension with other medications. Some products 
may contain phenylalanine; refer to the package labeling for additional details. 
 
The intravenous solution should be given over at least 2 hours. Do not administer by rapid or bolus 
injection. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further information. 
 
 

 
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6.16 
PEGASPARGASE 
(06/05/17) 
(PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase, 
Oncaspar®) NSC #624239 
 
Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase is modified by 
covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 
5000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-
asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is 
derived from Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a 
reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is 
notably lacking in malignancies of lymphoid origin. Asparaginase depletes L-asparagine from 
leukemic cells (especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic 
acid and ammonia. In predominately L-asparaginase naive adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of 
pegaspargase were determined. Apparent volume of distribution was equal to estimated plasma 
volume. L-asparaginase was measurable for at least 15 days following the initial treatment with 
Pegaspargase. The approximate t½ in adult patients is 5.73 days. The enzyme could not be detected 
in the urine. The half-life is independent of the dose administered, disease status, renal or hepatic 
function, age, or gender. In a study of newly diagnosed pediatric patients with ALL who received 
either a single intramuscular injection of pegaspargase (2500 IU/m2), E. coli L-asparaginase 
(25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-lives for the three forms of 
L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The 
plasma half-life of pegaspargase is shortened in patients who are previously hypersensitive to native 
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is cleared by the 
reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal fluid levels 
are < 1% of plasma levels.  
 
 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-
2 days of 
receiving 
drug 
Allergic reactions (total 
likelihood of local, and or 
systemic reaction 
especially if previous 
hypersensitivity reaction to 
native asparaginase), pain 
at injection site, weakness, 
fatigue, diarrhea  
Allergic reactions 
(total likelihood of 
local, and or systemic 
reaction if no previous 
hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, 
hyper/hypotension, 
tachycardia, periorbital 
edema, chills, fever, 
dizziness, dyspnea, 
bronchospasm, lip edema, 
arthralgia, myalgia, urticaria, 
mild nausea/vomiting, 
abdominal pain, flatulence, 
somnolence, lethargy, 
headache, seizures (L), 
hyperuricemia  
Prompt: 
Within 2-
3 weeks, 
prior to the 
next course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT 
and bleeding times 
(secondary to decreased 
Hyperglycemia, 
abnormal liver 
function tests, 
pancreatitis (L), 
Hemorrhage (L), DIC, 
thrombosis, anorexia, weight 
loss, CNS ischemic attacks, 
edema, azotemia and 
decreased renal function, 

 
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Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
synthesis of fibrinogen, 
AT-III & other clotting 
factors) (L) 
increased serum 
lipase/amylase 
mild leukopenia, 
granulocytopenia, 
thrombocytopenia, 
pancytopenia, hemolytic 
anemia, infections (sepsis 
with/without septic shock, 
subacute bacterial 
endocarditis [SBE], URI), 
CNS changes including 
irritability, depression, 
confusion, EEG changes, 
hallucinations, coma and 
stupor, paresthesias, 
hypertriglyceridemia, 
hyperlipidemia, Parkinson-
like syndrome with tremor 
and increase in muscular 
tone, hyperbilirubinemia, 
chest pain  
Delayed: 
Any time 
later during 
therapy 
 
 
Renal failure, urinary 
frequency, hemorrhagic 
cystitis, elevated creatinine 
and BUN, fatty liver deposits, 
hepatomegaly, liver failure 
Unknown 
Frequency 
and 
Timing:  
Animal reproduction studies have not been conducted with pegaspargase. It is not 
known whether pegaspargase can cause fetal harm when administered to a pregnant 
woman or can affect reproduction capacity. However, fetal toxicities and teratogenic 
effects of asparaginase have been noted in animals. It is unknown whether the drug is 
excreted in breast milk. 
(L)Toxicity may also occur later. 
 
Formulation and Stability: 
Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic sodium 
phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%, sodium chloride, 
USP 8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific activity of pegaspargase is 
at least 85 IU per milligram protein. Available in 5 mL vials as Sterile Solution for Injection in 
ready to use single-use vials, preservative free. Keep refrigerated at 2°-8°C (36°-46°F). Do not use 
if stored at room temperature for more than 48 hours. DO NOT FREEZE. Do not use product if it 
is known to have been frozen. Freezing destroys activity, which cannot be detected visually.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
For IM administration: the volume at a single injection site should be limited to 2 mL. If the volume 
to be administered is greater than 2 mL, multiple injection sites should be used.  
 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to 2 hours 
through a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of NS or D5W is 
stable for 48 hours at room temperature. Pegaspargase diluted in 100 mL of NS is stable for up to 
72 hours refrigerated (4ºC [39°F]) (refrigerated stability data on file with Sigma-Tau).  Avoid 
excessive agitation. DO NOT SHAKE. Do not use if cloudy of if precipitate is present.  
 

 
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Have available during and after the infusion: antihistamine, epinephrine, oxygen, and IV 
corticosteroids. Observe patient for ONE hour after administration for signs of hypersensitivity 
reactions. 
 
Supplier: Comercially available. See package insert for further information.   
 
6.17 
TACROLIMUS 
(11/27/17) 
(FK-506, Prograf®) NSC #717865 
  
Source and Pharmacology:  
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. 
Tacrolimus is a potent immunosuppressive agent which prolongs the survival of the host and 
transplanted grafts in animal transplant models of liver, kidney, heart, bone marrow, small bowel 
and pancreas, lung and trachea, skin, cornea, and limb. Tacrolimus inhibits T-lymphocyte 
activation, although the exact mechanism of action is not known. Experimental evidence suggests 
that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, 
calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin 
inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of 
activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the 
formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition 
of T-lymphocyte activation (immunosuppression). Additionally, tacrolimus may inhibit cellular 
activities such as nitric oxide synthetase activation and apoptosis, and may potentiate the action of 
corticosteroids in these processes. Tacrolimus activity is primarily due to the parent drug. The 
plasma protein binding of tacrolimus is approximately 99% and is independent of concentration 
over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, 
and has a high level of association with erythrocytes. The t½ in adult patients ranges from 11-
19 hours. The pharmacokinetics of tacrolimus have been studied in pediatric liver transplant 
patients (0.7 to 13.2 years of age). Following the IV administration of a 0.037 mg/kg/day dose to 
12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 
11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral 
administration to 9 pediatric patients, the absolute bioavailability was 31 ± 21%. Whole blood 
trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed 
higher doses than adults to achieve similar tacrolimus trough concentrations. Tacrolimus is 
extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 
system (CYP3A) in the liver and to a lesser extent in the intestinal mucosa. The major metabolite 
identified in incubations with human liver microsomes is 13-demethyl tacrolimus. The main route 
of elimination is via the biliary tract and excretion in feces. The mean clearance in renal dysfunction 
and mild hepatic dysfunction is the same as normal volunteers. Severe hepatic dysfunction (Pugh 
score > 10) led to a substantially decreased clearance. A retrospective comparison of Black and 
Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses 
to attain similar trough concentrations; there were no gender-based differences. The absorption of 
tacrolimus from the gastrointestinal tract is incomplete and variable exhibiting large intra- and 
inter-patient variability. Administration with food significantly decreases the rate and extent of 
absorption Drugs that stimulate or inhibit hepatic p-450 enzymes will alter clearance of tacrolimus 
and close attention to potential drug interactions is crucial. 
 
 
 
 
 

 
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Toxicity: 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Headache (L), 
hypertension (L), nausea, 
vomiting, anorexia, 
immunosuppression (L), 
diarrhea, constipation, 
fever 
Chest pain 
Anaphylaxis with the 
injection, allergic reaction, 
hypotension, asthma, 
dyspnea, increased cough, 
flu like syndrome, pleural 
effusion, seizure (L), 
tachycardia, angina 
Prompt: 
Within 2-
3 weeks, prior to 
the next course 
Tremor (L), ), renal 
dysfunction (acute with 
decrease in GFR, 
impaired urinary 
concentrating ability, and 
sodium retention), 
elevated creatinine/BUN, 
anemia, insomnia, 
asthenia, pain 
(abdominal, back, pain), 
hyperglycemia, 
hypomagnesemia (L), 
hyper/hypokalemia (L), 
hypophosphatemia, 
paresthesia  
Alopecia, dizziness, 
elevated LFTs, UTI, 
peripheral edema, 
rash, pruritus, 
hyperlipidemia, 
hypercholesteremia 
Dyspepsia, dysphagia, 
gastritis, esophagitis, 
flatulence, CNS 
abnormalities (confusion 
(L), somnolence (L), 
depression (L), anxiety, 
anxiousness, abnormal 
dreams, emotional labiality, 
hallucinations, psychosis, 
hypertonia, incoordination, 
neuropathy, nervousness 
encephalopathy), 
coagulation disorder, 
leukopenia (L), 
thrombocytopenia, 
polycythemia, anemia, 
leukocytosis, infections 
(bacterial, fungal, viral –
sepsis, cellulites, fungal 
dermatitis, herpes simplex, 
sinusitis, pharyngitis, 
abscess, pneumonia, 
bronchitis, peritonitis), 
hyperbilirubinemia (L), 
thrombosis, phlebitis, 
arthralgia, myalgia, 
electrolyte abnormalities 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
 
Acne, exfoliative dermatitis, 
skin discoloration, 
photosensitivity reaction, 
skin ulcer, delayed wound 
healing, hirsutism 
(hypertrichosis) (L), gingival 
hyperplasia, abnormal 
vision, amblyopia, ear pain, 
otitis, tinnitus, GI 
hemorrhage, GI perforation, 
cholelithiasis, cholestatic 
jaundice, chronic renal 
dysfunction, renal failure, 
post-transplant diabetes 
mellitus (L), myocardial 
hypertrophy, elevated liver 

 
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Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to < 5 children out 
of every 100 
function tests, liver damage, 
ascites 
Late: 
Any time after 
completion of 
treatment 
 
 
Lymphoproliferative 
disorders, skin malignancies 
Unknown 
Frequency and 
Timing:  
Fetal toxic effects of tacrolimus have been noted in animals. Tacrolimus is 
transported across the placenta and its use during pregnancy has been associated 
with neonatal hyperkalemia and renal dysfunction. Tacrolimus is excreted in 
human milk, nursing should be avoided. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Injection: 
Tacrolimus is available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg 
anhydrous tacrolimus per 1 mL. Each mL also contains polyoxyl 60 hydrogenated castor oil (HCO-
60), 200 mg, and dehydrated alcohol, USP, 80% v/v. Store between 5°C and 25°C (41°F and 77°F). 
 
Oral: 
Tacrolimus is available for oral administration as capsules containing the equivalent of 0.5 mg, 
1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include lactose, hydroxypropyl 
methylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell 
contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and 
titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide. 
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Injection: 
Tacrolimus Injection must be diluted with NS or D5W before use to a concentration between 
0.004 mg/mL and 0.02 mg/mL. Diluted infusion solution should be stored in glass or polyethylene 
containers and should be discarded after 24 hours. The polyoxyethylated castor oil contained in the 
concentrate for intravenous infusion can cause phthalate stripping from PVC. It is strongly 
recommended that non-PVC tubing be used to minimize patient exposure to DEHP. Due to the 
chemical instability of tacrolimus in alkaline media, tacrolimus injection should not be mixed or 
co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir). 
 
Tacrolimus 0.001 mg/mL solution stored in polyolefin bags at room temperature (20–25°C) was 
stable for 24 hours when prepared in NS and for at least 48 hours when prepared in D5W. Solutions 
of 0.01 and 0.1 mg/mL prepared in either NS or D5W were stable for at least 48 hours at room 
temperature in polyolefin bags (Lee JH, et al. Am J Health-Syst Pharm. 2016;73:137-42). 
 
Monitor closely for an acute allergic reaction for the first 30 minutes and at frequent intervals 
thereafter.  
 
Oral:  
Administer at a consistent time of day and at consistent intervals with regard to meals. Tacrolimus 
may be given with food as long as it is given the same way each time; however; administration with 

 
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food significantly decreases the rate and extent of absorption.  Grapefruit or grapefruit juice should 
be avoided during the entire course of tacrolimus administration. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.18 
THIOGUANINE 
(12/05/2016) 
(6-thioguanine, thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141, Tabloid®, 
Lanvis®) NSC #752 
 
Source and Pharmacology:  
Thioguanine is a purine analogue of the nucleic acid guanine with the substitution of a thiol group in 
place of the hydroxyl group on guanine. The main intracellular pathway for 6-TG activation is 
catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) which 
catalyzes the conversion of 6-TG to the active nucleotide, 6-thioguanylic acid. The monophosphate 
nucleotide form of 6-TG inhibits de novo purine synthesis and purine interconversion reactions, 
whereas the nucleotide triphosphate metabolite is incorporated directly into nucleic acids. 
Incorporation of fraudulent nucleotides into DNA interferes with DNA replication and results in 
the formation of DNA strand breaks. The net consequence of its action is a sequential blockade of 
the synthesis and utilization of the purine nucleotides. The relative contribution of each of these 
actions to the mechanism of cytotoxicity of 6-TG is unclear. The absorption of an oral dose of 6-
TG is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% 
to 46%). 
 
6-TG undergoes deamination by the enzyme guanine deaminase resulting in 6-thioxanthene, which 
is then oxidized by xanthine oxidase to 6-thiouric acid. In contrast to mercaptopurine, 6-TG is not 
a direct substrate for xanthine oxidase. Because the inhibition of xanthine oxidase results in the 
accumulation of 6-thioxanthene, an inactive metabolite, adjustments in 6-TG dosage are not 
required for patients receiving allopurinol. Since TPMT, 6-thiopurine methyltransferase, is one of 
the enzymes involved in the deactivation of 6-TG, those individuals who have an inherited 
deficiency of the enzyme may be unusually sensitive to the myelosuppressive effects of 6-TG and 
prone to developing rapid bone marrow suppression following the initiation of treatment. 
 
Peak levels occur 2 to 4 hours after oral administration with a median half-life is about 90 minutes 
(range: 25-240 minutes). Very little unchanged drug is excreted renally. 
 
Toxicity: 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Anorexia, nausea, 
vomiting, diarrhea, 
malaise 
Urticaria, rash, hyperuricemia 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
 
Toxic hepatitis (L), increased 
SGOT (AST)/SGPT (ALT), 
ataxia, mucositis 
Delayed: 
Anytime later during 
therapy 
 
 
Hepatic fibrosis(L), sinusoidal 
obstruction syndrome (SOS, 
formerly VOD) (L), 
hyperbilirubinemia 

 
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Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of thioguanine have been noted in animals. 
It is unknown whether the drug is excreted in breast milk. 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Each greenish-yellow, scored tablet contains 40 mg thioguanine. Store at 15°-25°C (59°-77°F) in 
a dry place. 
 
For patients unable to swallow tablets, a 20 mg/mL oral suspension may be compounded. Crush 
fifteen (n=15) 40 mg tablets in a mortar and reduce to a fine powder. Add 10 mL methylcellulose 
1% in incremental proportions and mix to a uniform paste. Transfer to a graduated cylinder, rinse 
mortar with simple syrup, and add quantity of simple syrup sufficient to make 30 mL. Dispense in 
an amber glass bottle and label "shake well" and "refrigerate". If methylcellulose is not available, 
substitute 15 mL of Ora-Plus in place of the methylcellulose and qs with Ora-Sweet (in place of 
simple syrup) to a final volume of 30 mL. Both preparations are stable for 63 days at 19°C – 
23°C. (Aliabadi HM, Romanick M, Somayah V, et al. Stability of compounded thioguanine oral 
suspensions. Am J Health Syst Pharm 2011;68:1278.)   
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Thioguanine should be taken consistently at the same time every day.  
 
Substantial dosage reductions may be required in patients with an inherited deficiency of the 
enzyme thiopurine methyltransferase (TPMT) due to accumulation of active thioguanine 
metabolites resulting in a higher incidence of myelosuppression. 
 
Supplier: Commercially available. See package insert for more detailed information.  
 
6.19 
THIOTEPA 
(01/23/18) 
(Tepadina, Tespa, Thiophosphamide, Triethylenethiophosphoramide Tspa, WR-45312) NSC 
#6396 
 
Source and Pharmacology:  
Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically 
to nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release 
of ethylenimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principal 
bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage 
between the purine base and the sugar and liberates alkylated guanines. Thiotepa is desulfurated by 
cytochrome P-450 enzymes such as 2B1 and 2C11 which catalyze the conversion of thiotepa to 
tepa. Tepa is less toxic than thiotepa and has been demonstrated to produce alkali-labile sites in 
DNA, rather than cross-links. These findings indicate that tepa reacts differently from thiotepa and 
produces monofunctional alkylation of DNA. A second metabolite of thiotepa, a mercapturic acid 
conjugate, is formed via glutathione conjugation. Monochloro tepa is the third metabolite found in 
the urine.  
Following short intravenous infusion (less than 5 minutes), peak concentrations of thiotepa were 
measured within 5 minutes. At steady state, the volume of distribution was independent of dose 
and ranged from 0.3 to 1.6 liters per kilogram (L/kg).  

 
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Approximately 4.2% of the original dose is eliminated in the urine within 24 hours as tepa. The 
elimination half-life of thiotepa ranges from 2.3 to 2.4 hours. The half-life of tepa ranged from 3 to 
21.1 hours in one study. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
Nausea, vomiting, anorexia, 
fatigue, weakness 
Pain at the injection site, 
dizziness, headache, 
blurred vision, abdominal 
pain, contact dermatitis, 
rash 
Anaphylaxis, laryngeal 
edema, wheezing, hives  
Prompt: 
Within 2-
3 weeks, prior to 
next course 
Myelosuppression; at 
higher doses in 
conditioning regimens for 
BMT: mucositis, 
esophagitis 
At higher doses in 
conditioning regimens 
for BMT: 
encephalopathy 
(inappropriate behavior, 
confusion, somnolence), 
increased liver 
transaminases, increased 
bilirubin, 
hyperpigmentation of the 
skin (bronzing effect) 
Febrile reaction, 
conjunctivitis, dysuria, 
urinary retention 
Delayed: 
Anytime later 
during therapy, 
excluding the 
above 
conditions 
Gonadal 
dysfunction/infertility, 
azoospermia, amenorrhea  
 
Alopecia, secondary 
malignancy 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities: Carcinogenic and teratogenic effects of thiotepa 
have been noted in animal models at doses ≤ to those used in humans. It is not 
known if thiotepa is excreted into human breast milk. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of 
nonpyrogenic, sterile lyophilized powder. Store in a refrigerator at 2°-8°C (36°-46°F). PROTECT 
FROM LIGHT AT ALL TIMES. 
 
Note: FDA is allowing temporary importation of a European product (Tepadina). Verify product, 
storage, and preparation instructions prior to dispensation and administration. Refer to specific 
product labeling for details. 
 
Tepadina: Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light; 
do not freeze. Reconstituted solution (10 mg/mL) is stable for 8 hours when stored at 2°C to 8°C 
(36°F to 46°F). Solution further diluted for infusion is stable for 24 hours when stored at 2°C to 
8°C (36°F to 46°F), or for 4 hours when stored at 25°C (77°F). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Reconstitute Thiotepa for Injection with 1.5 mL of Sterile Water for Injection resulting in a drug 
concentration of approximately 10 mg/mL. (As per manufacturer’s information: Actual content per 
vial 15.6 mg; withdrawable amount 14.7 mg/1.4 mL; approximate reconstituted concentration: 

 
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10.4 mg/mL). When reconstituted with Sterile Water for Injection, solutions of thiotepa should be 
stored at refrigerated temperatures 2°-8°C (36°-46°F) protected from light and used within 8 hours. 
The reconstituted solution is hypotonic and should be further diluted with Sodium Chloride Injection 
(0.9% NaCl) prior to use. Thiotepa at a concentration of 1-5mg/mL in 0.9% NaCl is stable for 24 
hours at room temperature. At concentration of 0.5mg/mL it is stable for only one hour and stability 
decreases significantly at concentrations of less than 0.5mg/mL. Therefore, solutions diluted to 
0.5mg/mL should be used immediately 
 
In order to eliminate haze, filter solutions through a 0.22 micron filter [Polysulfone membrane 
(Gelman’s Sterile Aerodisc®, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore’s 
MILLEX®-GSFilter Unit)] prior to administration. Filtering does not alter solution potency. 
Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after filtration 
should not be used.  
 
Tepadina: Reconstitute each 15 mg vial with 1.5 mL SWFI, or each 100 mg vial with 10 mL SWFI, 
to a concentration of 10 mg/mL. Gently mix by repeated inversions. Solution may be clear or 
opalescent; do not use if particulate matter is present. Further dilute reconstituted solution for IV 
infusion in 500 mL NS (1,000 mL NS if dose >500 mg). If dose is <250 mg, dilute in an appropriate 
volume of NS to achieve a final concentration of 0.5 to 1 mg/mL. 
 
When thiotepa is given in bone marrow transplant doses, bath the patient and change linen 
frequently (≥ 2 baths/day) to avoid the contact dermatitis and discoloration of the skin that is seen 
with high dose. 
 
Supplier: Commercially available. See package insert for further information.  
 
6.20 
VINCRISTINE SULFATE 
(08/16/12) 
(Oncovin®, VCR, LCR) NSC #67574 
 
Source and Pharmacology:  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, disrupting 
microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. The initial, middle, 
and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of 
the terminal half-life in humans is from 19 to 155 hours. The liver is the major excretory organ in 
humans and animals; about 80% of an injected dose of vincristine sulfate appears in the feces and 
10% to 20% can be found in the urine. The p450 cytochrome involved with vincristine metabolism 
is CYP3A4. Within 15 to 30 minutes after injection, over 90% of the drug is distributed from the 
blood into tissue, where it remains tightly, but not irreversibly bound. It is excreted in the bile and 
feces. There is poor CSF penetration.  
 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Jaw pain, headache 
Extravasation (rare) but if 
occurs = local ulceration, 
shortness of breath, and 
bronchospasm 
Prompt: 
Alopecia, constipation 
Weakness, abdominal 
pain, mild brief 
Paralytic ileus, ptosis, 
diplopia, night blindness, 

 
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Within 2-
3 weeks, prior to 
the next course 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
hoarseness, vocal cord 
paralysis, SIADH, seizure, 
defective sweating 
Delayed: 
Any time later 
during therapy 
Loss of deep tendon 
reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
Difficulty walking or 
inability to walk; 
sinusoidal obstruction 
syndrome (SOS, formerly 
VOD) (in combination); 
blindness, optic atrophy; 
urinary tract disorders 
(including bladder atony, 
dysuria, polyuria, nocturia, 
and urinary retention); 
autonomic neuropathy 
with postural hypotension; 
8th cranial nerve damage 
with dizziness, nystagmus, 
vertigo and hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in 
combination with other antineoplastic agents) have been noted in humans. The 
toxicities include: chromosome abnormalities, malformation, pancytopenia, 
and low birth weight. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 mg 
(1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are added for pH control. The 
pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a sterile, preservative 
free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until 
time of use. 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the 
Safety and Quality Council (Australia) all support the use of minibag rather than syringe for the 
infusion of vincristine. The delivery of vincristine via either IV slow push or minibag is acceptable 
for COG protocols. Vincristine should NOT be delivered to the patient at the same time with any 
medications intended for central nervous system administration. Vincristine is fatal if given 
intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine 
sulfate must be administered via an intact, free-flowing intravenous needle or catheter. Care should 
be taken to ensure that the needle or catheter is securely within the vein to avoid extravasation 
during administration. The solution may be injected either directly into a vein or into the tubing of 
a running intravenous infusion. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the 
statement: “Do not remove covering until moment of injection. For intravenous use only - Fatal if 
given by other routes.” 
 

 
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Supplier: Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
All baseline studies must be performed prior to starting protocol therapy unless otherwise 
indicated. Obtain other studies prior to start of phase unless otherwise indicated.  
 
7.1a 
HR/IR Patients 
 
STUDIES TO BE OBTAINED 
Baseline 
Block 1  
Block 2 
Block 3 
Blinatumomab Blocks 
Hx/PE with VS/Wt (BSA) 
X 
 
start of 
phase 
start of 
phase 
start of phase* 
CBC/diff/plts 
X 
weekly 
weekly 
weekly 
weekly 
Bilirubin0, ALT, creatinine, BUN 
X 
weekly 
weekly 
weekly 
weekly 
Local Bone Marrow (BM) 
Evaluation 
X1 
end of 
phase 
end of 
phase 
end of 
phase 
end of phase 
Bone Marrow (BM) for central 
flow MRD2  
 
end of 
phase+ 
end of 
phase++ 
end of 
phase+++ 
end of Cycle 1++,  
end of Cycle 2+++ 
Bone Marrow (BM) for 
Immunophenotyping 
X2,7 
 
 
 
 
Bone Marrow (BM) for future 
research banking 
X8 
X8 
 
 
 
CSF cell count and cytospin 
X 
with 
each IT 
with each 
IT 
with each 
IT 
with each IT 
Peripheral Blood for 
Pharmacokinetics (PK) 
 
 
 
 
Cycle 1: Day 2 and Day 
146 
Peripheral Blood for 
Immunogenicity 
 
 
 
 
• Prior to (Hour 0) start 
of first blinatumomab 
infusion (Cycle 1) 
• End of Cycle 2$  
Peripheral Blood for future 
research banking 
X8 
X8 
X8 
 
X8 
Echocardiogram 
X 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
Testicular exam 
X 
end of 
phase 
end of 
phase 
 
 
Testicular biopsy 
X4 
X5 
 
 
 
0 Adequate liver function as defined by direct bilirubin is required for eligibility (see Section 3.2.5.2). 
1 BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse patients should 
include morphology, immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis must be performed at a COG 
approved cytogenetics lab and cases will be reviewed retrospectively by the COG Cytogenetics Committee. See Section 13.2 
for details. 
2 See Section 13.3 for details on shipping and handling  
3 Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active 
patients must use an acceptable method of birth control.  
4 Patients with suspected testicular involvement at relapse (either isolated or with concurrent BM/CNS relapse) 
must have biopsy performed at baseline. 
5 Patients with definite or equivocal residual testiculomegaly at end of Block 1 must have a biopsy to determine 
whether TRT is to be given during designated blocks of therapy (see Experimental Design Schema). 
6 See lab manual on protocol webpage for sample collection and shipping details 
7 Includes optional sample for CRLF2 expression for consenting patients (see Section 7.2 and Section 13.4). 

 
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8 Optional for future research (see Section 7.2 and Section 13.1). 
* See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
$ In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. 
+ Evaluation 1 
++ Evaluation 2 
+++ pre-HSCT evaluation 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care.  
 
7.1b 
LR Patients 
 
STUDIES TO BE 
OBTAINED 
Baseline 
Block 1  
Block 2 
Block 3, 
Blinatumomab 
blocks, Continuation  
Maintenance and 
post-therapy 
Hx/PE with VS/Wt 
(BSA) 
X 
 
start of 
phase 
start of phase* 
every 28 days 
during 
maintenance 
CBC/diff/plts 
X 
weekly 
weekly 
weekly 
every 28 days 
during 
maintenance 
Bilirubin0, ALT, 
creatinine, BUN 
X 
weekly 
weekly 
weekly 
every 28 days 
during 
maintenance 
Local Bone Marrow 
(BM) Evaluation 
X1 
end of 
phase 
end of 
phase 
 
 
Bone Marrow (BM) for 
central flow MRD2  
 
end of 
phase+ 
end of 
phase++ 
 
 
Bone Marrow (BM) for 
Immunophenotyping 
X2,7 
 
 
 
 
Bone Marrow (BM) for 
future research banking 
X9 
X9 
 
 
 
CSF cell count and 
cytospin 
X 
with 
each IT 
with 
each IT 
with each IT 
with each IT 
Absolute lymphocyte 
count with T and B 
subset quantification 
 
 
 
 
At end of each 12 
week maintenance 
cycle, and every 3 
months after 
completion of 
therapy for 1 year 
Peripheral Blood for 
Pharmacokinetics (PK) 
 
 
 
Blinatumomab Cycle 
1:Day 2 and Day 146 
 
Peripheral Blood for 
Immunogenicity 
 
 
 
• Prior to (Hour 0) start 
of first blinatumomab 
infusion (Cycle 1) 
• End of Cycle 2$  
Prior to start of 
Maintenance 
Cycle 1 therapy8 
Peripheral Blood for 
future research banking 
X9 
X9 
X9 
 
X9 
Echocardiogram 
X 
 
 
 
 
Pregnancy Test3 
X 
 
 
 
 
Testicular Biopsy 
X4 
X5 
 
 
 
0 Adequate liver function as defined by direct bilirubin is required for eligibility (see Section 3.2.5.2). 
1 BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse 
patients should include morphology, immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis 
must be performed at a COG approved cytogenetics lab and cases will be reviewed retrospectively by the COG 
Cytogenetics Committee. See Section 13.2 for details. 
2 See Section 13.3 for details on shipping and handling 
3 Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  

 
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4 Patients with suspected testicular involvement at relapse (either isolated or with concurrent BM/CNS 
relapse) must have biopsy performed at baseline. 
5 Patients with definite or equivocal residual testiculomegaly at end of Block 1 must have a biopsy to 
determine whether TRT is to be given during designated blocks of therapy (see Experimental Design Schema). 
6 See lab manual on protocol webpage for sample collection and shipping details 
7 Includes optional sample for CRLF2 expression for consenting patients (see Section 7.2 and Section 13.4). 
8 Arm D ONLY. Prior to start of Maintenance therapy for eligible patients (see Section 13.7 and lab manual 
for details) 
9 Optional for future research (see Section 7.2 and Section 13.1). 
* See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
$ In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. 
+ Evaluation 1 
++ Evaluation 2 
This table only includes evaluations necessary to answer the primary and secondary 
aims. Obtain other studies as indicated for good clinical care.  
 
 
7.1c 
HSCT 
Observation 
Prior to 
transplant 
(Tx) 
1-2 
weeks 
after 
ANC> 
500/µL 
3 mo 
Post-
Tx 
6 mo 
Post-
Tx 
9 mo 
Post-
Tx 
1 yr. 
Post-
Tx 
2 
yrs. 
Post-
Tx 
3 
yrs. 
Post-
Tx 
4 
yrs. 
Post-
Tx 
5 
yrs. 
Post-
Tx 
At 
subsequent 
relapse 
Bone 
Marrow 
(BM) for 
central 
MRD1 
X+++ 
X* 
X** 
 
 
 
 
 
 
 
 
CSF cell 
count and 
cytospin 
X 
 
 
 
 
 
 
 
 
 
X 
CBC, 
differential, 
platelets 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
BUN, 
Creatinine 
X 
 
 
 
 
 
 
 
 
 
 
LFT 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pulmonary 
function test 
X 
 
 
 
 
 
 
 
 
 
 
Performance 
score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
See Section 13.3 for details on shipping and handling; (see Section 7.2) 
+++ pre-HSCT evaluation 
* Day 30 (25-30) 
** Day100 (+/- 3 weeks) 
This table only includes evaluations necessary to answer the primary and secondary aims. 
Obtain other studies as indicated for good clinical care. 
 
7.1d 
Salvage Therapy (Blinatumomab-S) 
 
STUDIES TO BE 
OBTAINED 
Blinatumomab Blocks 
Hx/PE with VS/Wt 
(BSA) 
Start of phase* 
CBC/diff/plts 
weekly 

 
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Bilirubin, ALT, 
creatinine, BUN 
weekly 
Local Bone Marrow 
(BM) Evaluation 
end of phase 
Bone Marrow (BM) for 
central flow MRD2 
pre-HSCT 
CSF cell count and 
cytospin 
with each IT 
Peripheral Blood for 
Pharmacokinetics (PK) 
Cycle 1: Day 2 and Day 14** 
Peripheral Blood for 
Immunogenicity 
• Prior to (Hour 0) start of first blinatumomab infusion (Cycle 1) 
• End of Cycle 2$ 
* See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
** See lab manual on protocol webpage for sample collection and shipping details 
$ 
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. 
 
 
7.1e 
Recommended Observations: Blinatumomab Blocks 
The investigator is recommended to monitor the patient’s vital signs (body temperature, 
heart rate and blood pressure) approximately every 4 hours during the first 12 hours after 
the start of a cycle, and upon resumption after suspension for adverse event. On Day 2 and 
3 vital signs should be measured once daily. 
 
 
7.2 
Research Studies 
The following are correlative biology studies for which patient participation is optional. 
Please see Section 13.0 for details on volumes of specimen collection and shipping 
information. Note: Patient consent is required. 
Study  
(see section for details) 
Summary of Sample and Timing 
Banking for Future 
Research * 
(Section 13.1) 
Peripheral blood:  
• 
Baseline 
• 
End Block 1 
• 
End Block 2 (Arm A, C or D, End of Blinatumomab 
Cycle 1 (Arm B) 
• 
Relapse 
 
Bone marrow:  
• 
Baseline 
• 
End Block 1 
Relapse 
CRLF2 expression  
(Section 13.4) 
No separate specimen required – cell pellet from required 
baseline central flow bone marrow will be used 
 
Protein Cell Stress  
(Section 13.6) 
Peripheral blood: 
• 
Day 1 of Block 1  
o Before chemotherapy (Hour 0)  
o After Chemotherapy (Hour 6 and Hour 24) 
Blinatumomab 
Pharmacodynamics (PD) 
(Section 13.5) 
 
Bone marrow: 
• 
End Block 1 (All patients) 
• 
End Block 2 (LR patients on Arm D only) 
 

 
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Peripheral blood: 
• 
Prior to (Hour 0) start of first blinatumomab 
infusion 
• 
During (Hour 6, Hour 12, Day 2, Day 7, Day 14, 
Day 21) first blinatumomab infusion** 
* For cases with a limited amount of tissue available for analysis, please prioritize specimen for 
tissue banking. 
**In the event that the infusion is interrupted, the peripheral blood collection should likewise be 
delayed to account for the interruption. i.e. collect the timed sample after X days of infusion 
rather than X days from start of infusion.  
 
7.3 
At Relapse 
Patients who relapse and have consented to cell banking at time of enrollment should 
have samples of bone marrow sent to the Molecular Reference Laboratory for cell 
banking (see Section 13.1.) 
 
7.4 
Follow-up 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Treatment failure but not eligible to receive blinatumomab salvage  
b) Treatment failure that receives blinatumomab salvage but does not achieve CR after 
2 cycles of blinatumomab 
c) Adverse events requiring removal from protocol therapy 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Completion of planned therapy. 
f) Physician determines it is in patient’s best interest. 
g) Development of a second malignancy. 
h) Second relapse at any site. 
i) Repeat eligibility studies are outside the parameters required for eligibility (if applicable, 
see Section 3.2 ). 
j) Inevaluable  
k) Found to be ineligible for HSCT (See Section 4.9.1) 
l) Pre-Randomization (HR/IR or LR): Interval development of significant central 
nervous system pathology that would preclude treatment with blinatumomab (see 
Section 3.2.6.12 for definition). 
m) Amendment #10: Patient found to be HR/IR at the completion of Block 1. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless consent was withdrawn. 
 

 
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8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Design 
9.1.1 
Primary Endpoint 
A primary objective (HR/IR Randomization) of AALL1331 is to compare disease-
free survival (DFS) of HR and IR relapse patients randomized to Block 2 and 3 
chemotherapy (Control) vs. two blocks of blinatumomab (Experimental), followed 
by allogeneic HSCT. DFS is defined as time from start of randomization to event 
(treatment failure, relapse, second malignancy, death) or last follow-up for those 
who are event-free. DFS event date will be set at Day 1 if patients are deemed as 
TF after randomization. 
 
Another primary objective (LR Randomization) of AALL1331 is to compare DFS 
of LR relapse patients randomized to chemotherapy alone (Control: Block 3, 
Continuation 
1, 
Continuation 
2 
and 
Maintenance) 
vs. 
blinatumomab/chemotherapy (Experimental: blinatumomab, Continuation 1, 
blinatumomab, Continuation 2, blinatumomab, Maintenance). DFS is defined as 
time from start of randomization to first event (relapse, second malignant 
neoplasm, remission death) or last follow up for those who are event-free. 
 
The primary analyses of DFS will include all randomized patients provided that 
randomization is performed per protocol. The analyses will be based on the intent-
to-treat principle.  
 
9.1.2 
Secondary Endpoints 
A secondary objective (HR/IR Randomization) of AALL1331 is to compare 
overall survival (OS) of HR and IR relapse patients randomized to Block 2 and 3 
chemotherapy (Control) vs. two blocks of blinatumomab (Experimental), followed 
by allogeneic HSCT. OS is defined as time from start of randomization to death or 
last date of contact. 
 
Another secondary objective (LR Randomization) of AALL1331 is to compare OS 
of LR relapse patients randomized to chemotherapy alone (Control: Block 3, 
Continuation 
1, 
Continuation 
2 
and 
Maintenance) 
vs. 
blinatumomab/chemotherapy (Experimental: blinatumomab, Continuation 1, 
blinatumomab, Continuation 2, blinatumomab, Maintenance). OS is defined as 
time from start of randomization to death or last date of contact. 
 

 
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9.1.3 
Exploratory Endpoints 
The exploratory endpoints associated with HR/IR Randomization are to compare 
the rates of MRD positivity (>0.01%) at the end of Block 2 and 3 between 
randomized arms for HR and IR relapse patients. 
Other exploratory endpoints include estimating the CR rate, MRD negativity 
(< 0.01%) rate and proportion that proceed to HSCT after treatment with 
blinatumomab for treatment failure patients not previously receiving 
blinatumomab, assessing the feasibility and safety of rapid taper of immune 
suppression for subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-
HSCT with no aGVHD, and collecting biologic samples for the prospective 
correlative biology studies described in Section 7.0.  
Blinatumomab PK will be evaluated by summarizing blinatumomab steady state 
concentrations and systemic clearance obtained from non-compartmental analysis. 
In addition, a population PK approach using a non-linear mixed effect model will 
also be used to assess blinatumomab PK. Exposure-response analyses will be 
performed to explore associations among blinatumomab exposure, relevant 
clinical covariates and clinical measures of saftery and efficacy. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
9.2.1 
Stratification to be used in the randomization 
All patients are assigned to Stratum 1 at enrollment. All HR/IR relapse patients 
who do not meet the treatment failure criteria at the end of Block 1 will be eligible 
for HR/IR randomization and randomized equally between experimental 
(blinatumomab) and control (chemotherapy) arms. The randomization will occur 
upon recovery from Block 1 of therapy, and will be stratified by: 1) Risk Group 
(HR vs. IR); 2) For HR patients, site of relapse (marrow vs. IEM); 3) For 
HR – marrow patients, duration of first remission (< 18 months vs. 18-36 months 
from diagnosis); 3) For HR-marrow patients, MRD level end Block 1 (< 0.1% vs. 
≥ 0.1%) to ensure balanced randomization within these subsets (see table below). 
 
Stratum # 
Risk-Site 
CR1 mos 
MRD status 
2 
HR-Marrow 
< 18 
MRD < 0.1% 
3 
HR-Marrow 
< 18 
MRD ≥ 0.1% 
4 
HR-Marrow 
18-36 
MRD < 0.1% 
5 
HR-Marrow 
18-36 
MRD ≥ 0.1% 
6 
HR-IEM 
<18 
- 
7 
IR 
- 
- 
 
All late B-ALL marrow and late B-ALL IEM relapse patients with end Block 1 
MRD < 0.1% will eligible for LR randomization and randomized equally between 
experimental 
(blinatumomab) 
and 
control 
(chemotherapy) 
arms. 
The 
randomization will occur upon recovery from Block 1 of therapy, and will be 
stratified by: 1) site of relapse (marrow vs. IEM); and 2) MRD level at time of 
randomization (< 0.01% vs. ≥ 0.01%) to ensure balanced randomization within 
these subsets. 
 
 

 
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Stratum # 
Site 
CR1 mos 
MRD status 
8 
LR-Marrow 
≥ 36 
MRD < 0.01% 
9 
LR-Marrow 
≥ 36 
MRD ≥ 0.01% or MRD < 0.1% 
with sensitivity 1/1000 
10 
LR-IEM 
≥ 18 
MRD < 0.01% 
11 
LR-IEM 
≥ 18 
MRD ≥ 0.01% or MRD < 0.1% 
with sensitivity 1/1000 
 
9.2.2 
Sample size with power calculation (Activation Protocol) 
Sample size calculations driving this study are based on the two randomized 
questions HR/IR Randomization and LR Randomization.  
 
For HR/IR Randomization, approximately 170 evaluable HR/IR B-ALL patients 
are to be randomized between experimental (blinatumomab) and control 
(chemotherapy) arms after recovery from Block 1. As described in Section 9.3.1, 
the test of the randomization question has a power of 80.0% at a one-sided 
significance level of 2.5% to detect the desired improvement in 2-year DFS rate. 
The 170 evaluable HR/IR B-ALL patients are expected to take 3 years to be 
enrolled with the total rate of accrual to HR/IR Randomization to be 56 per year 
after adjusting for approximate 10% refusal rate to randomization. This estimate is 
based on the following estimates of annual accrual and dropout rate from past 
studies AALL01P2, AALL02P2, AALL0433 and ADVL04P2: 
 
 
Early 
marrow 
Early 
IEM 
Late 
marrow 
Late 
IEM 
# entering study 
60 
5 
44 
28 
Rate of MRD ≥ 0.1% 
- 
- 
38% 
12% 
Rate of not dropping out prior 
to block 2 (due to toxicity 
and/or treatment failure) 
70% 
70% 
90% 
90% 
# eligible for randomization 
42 
3 
15 
3 
 
For LR randomization, approximately 206 evaluable LR B-ALL patients are to be 
randomized between experimental (blinatumomab) and control (chemotherapy) 
arms after recovery from Block 1. As described in Section 9.3.2, the test of the 
randomization question has a power of 80.4% at a one-sided significance level of 
5% to detect the desired improvement in 3-year DFS rate. The 206 evaluable LR 
B-ALL patients are expected to accrue over 5.6 years with total rate of accrual to 
LR Randomization to be 37 per year after adjusting for approximate 10% refusal 
rate to randomization. This estimate is based on the following estimates of annual 
accrual and dropout rate from past studies AALL01P2, AALL02P2, AALL0433 
and ADVL04P2: 
 
 
Late marrow 
Late IEM 
# entering study 
44 
28 
Rate of MRD < 0.1% 
62% 
88% 

 
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Rate of not dropping out prior to block 2 (due to 
toxicity and/or treatment failure) 
80% 
80% 
# eligible for randomization 
22 
20 
 
Therefore, in order to enroll 170 and 206 evaluable patients for HR/IR and LR 
Randomization respectively, a total of 195 early marrow/IEM and 403 late 
marrow/IEM patients are expected be accrued at the beginning of the study. 
 
9.2.3 
Extension of accrual duration for both the LR cohort and the HR/IR cohort 
(Amendment #8) 
 
With Amendment #8, for both the LR cohort and the HR/IR cohort, the accrual 
duration will be extended until 10/31/2019, provided that there is no prolonged 
interruption of study enrollment.  
 
The AALL1331 study has demonstrated a steady accrual rate for both the LR 
cohort and the HR/IR cohort. The observed accrual rate is approximately 53 
patients/year in the LR cohort, much faster than the anticipated 37/year, and is 50 
patients/year in the HR/IR cohort, slightly smaller than but very close to the 
anticipated 56/year. With the faster accrual rate in the LR cohort and steady 
observed accrual rate in HR/IR, we amend the accrual duration for both cohorts to 
be until 10/31/2019 to ensure that the primary analyses maintain sufficient 
statistical power for the LR cohort and that the timing of completion of accrual be 
the same between the two cohorts. This amendment in accrual target will increase 
the power of statistical analyses and the sensitivity of the study, help us to gather 
more accurate information regarding the treatment regimens, and will not cause 
delay in addressing the primary objectives of the study or delay in opening the 
planned successor trial to AALL1331 (AALL1821).  AALL1331 is the first 
pediatric ALL study to substitute blocks of immunotherapy for conventional 
chemotherapy and the increased power of the analyses may be very beneficial in 
moving this general approach forward in future studies. 
 
9.2.3.1  The LR Cohort 
For the LR cohort, the study was originally designed to have 
approximately power of 0.80 to detect a hazard ratio of 0.55 with a one-
sided logrank test and Type I error of 0.05, which corresponds to an 
increase in 3-year DFS rate from 73% in the control arm to 84% in the 
experimental arm. This cohort was planned to enroll a total of 206 
randomized, evaluable patients. It was expected to accrue for 5.6 years, 
with 3 years of additional follow-up after completion of enrollment. With 
the observed accrual rate of 53 patients/year, the anticipated accrual 
completion date (ACD) with the original sample size of 206 is 
approximately 03/2019, and the anticipated analysis date (AAD) is 3 years 
after that, i.e., 03/2022. 
 
Given the faster-than-expected observed accrual rate, if this cohort follows 
the original plan to enroll 206 evaluable patients and have 3 years of 
additional follow-up, the power of the study will be smaller than planned 
due to the shorter average follow-up time among the patients. This is 

 
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demonstrated by the comparison of the dotted black line to the solid red 
line in the figure below. As shown by the dotted black line, with the 
observed accrual rate of 53/year, the study will only have  power of 0.77 
to detect a hazard ratio of 0.55, smaller than the planned power of 0.80. 
 
The faster observed accrual rate in the LR cohort gives us the opportunity 
to address this issue by enrolling more patients, resulting in an increase in 
the power of the analysis, an increase in the sensitivity of the study, and 
the ability to gather more accurate information regarding the treatment 
regimens. With Amendment #8, we extend the accrual duration for the LR 
cohort to be until 10/31/2019. This will increase the number of evaluable 
patients from 206 to approximately 236. With this extended accrual 
duration, the ACD and AAD will be 10/2019 and 10/2022, respectively 
(please see Section 9.3.2.1 for more details on the primary analysis with 
Amendment #8). (Note that the AAD of 10/2022 is still earlier than the 
AAD had the accrual rate been the assumed 37 patients/year.) With 236 
evaluable patients, the study will have approximately power of 0.83 to 
detect a hazard ratio of 0.55, and power of 0.75 to detect a hazard ratio of 
0.59.  
 
The following table presents a comparison in characteristics of the trial for 
the LR cohort under the scenarios of (1) the original accrual target with 
the expected accrual rate, (2) the original accrual target with the observed 
accrual rate, and (3) the extended accrual duration with Amendment #8. 
  
 
Characteristics 
Original 
Accrual Target 
(assuming 
expected 
accrual rate) 
Original 
Accrual Target 
 (with observed 
accrual rate) 
Extended  
Accrual 
Duration 
(Amendment 
#8) 
1 
Accrual rate 
37 pts/year 
53 pts/year 
53 pts/year 
2 
Sample size 
206 
206 
236 
3 
Accrual completion date (ACD) 
06/2020 
03/2019 
10/2019 
4 
Anticipated analysis date (AAD) 
06/2023 
03/2022 
10/2022 

 
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5 
Power of detecting a hazard ratio 
of 0.55 (corresponding to 3-year 
DFS of 84% vs. 73%) 
0.80 
0.77 
0.83 
6 
Power of detecting a hazard ratio 
of 0.59 (corresponding to 3-year 
DFS of 83% vs. 73%) 
0.72 
0.69 
0.75 
7 
Sample size for evaluation of 
toxicities and biologic aims 
-- 
-- 
Increased by 
14% 
8 
Delay in addressing primary 
aim, compared to the original 
accrual target 
-- 
-- 
No delay 
9 
Timing of completion of accrual 
compared to the HR/IR cohort  
-- 
5~6 more months 
of accrual if 
without 
amendment of 
accrual target of 
the two cohorts.  
The same as 
the HR/IR 
cohort with 
Amendment 
#8. 
 
 
9.2.3.2  The HR/IR Cohort 
For the HR/IR cohort, the study was originally designed to have 
approximately power of 0.80 to detect a hazard ratio of 0.58 with a one-
sided logrank test and Type I error of 0.025, which corresponds to an 
increase in 2-year DFS rate from 45% in the control arm to 63% in the 
experimental arm. This cohort was planned to enroll a total of 170 
randomized, evaluable patients. It was expected to accrual for 
approximately 3 years, with 2 years of additional follow-up after 
completion of enrollment. With the original sample size of 170 patients, 
the ACD is approximately 10/2018, and the AAD is 2 years after that, i.e., 
10/2020. 
 
If staying with the originally planned accrual target, the HR/IR 
randomization would be closed approximately 5-6 months earlier than the 
LR cohort. After closure of the HR/IR randomization, we would need to 
continue to enroll patients with late relapses to fulfill the accrual target for 
the LR cohort. A subset of patients with late relapses would be assigned 
the IR group at the completion of the induction therapy, and would 
subsequently need to be taken off therapy due to the closure of the HR/IR 
randomization.  
 
To avoid having to reject patients from further protocol therapy, with 
Amendment #8, we extend the accrual duration for HR/IR so that this 
cohort will complete accrual at the same time as the LR cohort. That is, 
we extend accrual duration of HR/IR to be until 10/31/2019, the same as 
the LR cohort. We plan that the primary analysis for the HR/IR cohort be 
conducted approximately 1 year later (please see Section 9.3.1.1 for more 
details on the primary analysis with Amendment #8). Hence the AAD will 
be approximately 10/2020. Given that the protocol therapy duration for 
HR/IR patients is typically 7 months, by 10/2020 all patients in the HR/IR 
cohort should have completed protocol therapy. This AAD is the same as 
the AAD for HR/IR if we did not amend the accrual target.  

 
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In summary, the increased accrual target of the HR/IR cohort will give us 
the same timing of completion of accrual between the HR/IR cohort and 
the LR cohort, without causing any delay in addressing the primary 
objectives.  The increased accrual target will also improve the sensitivity 
of this cohort and increase the power to detect a smaller difference in 
treatment effect between the experimental arm vs. the control arm. As 
shown in the figure below, the sample size of 220 evaluable patients will 
increase the power to detect a hazard ratio of 0.58 from 0.80 to 0.85.  
 
The following table presents a comparison in characteristics of the trial for 
the HR/IR cohort under the scenarios of (1) the original accrual target, and 
(2) the extended accrual duration with Amendment #8. 
 
 
Characteristics 
Original  
Accrual Target 
Extended  
Accrual 
Duration 
(Amendment #8) 
1 
Sample size 
170 
220 
2 
Accrual completion date (ACD) 
10/2018 
10/2019 
3 
Anticipated analysis date (AAD) 
10/2020 
10/2020 
4 
Power of detecting a hazard ratio 
of 0.58 (corresponding to 2-year 
DFS of 63% vs. 45%) 
0.80  
0.85 
5 
Sample size for evaluation of 
toxicities and biologic aims 
-- 
Increased by 29% 
6 
Delay in addressing primary 
aim, compared to the original 
accrual target 
-- 
No delay 
7 
Timing of completion of accrual 
compared to the LR cohort  
5~6 months ahead if 
without amendment 
of accrual target of 
the two cohorts.  
The same as the 
LR cohort with 
Amendment #8. 
 
 

 
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9.2.3.3  Accrual target (Amendment #8) 
With Amendment #8, both the LR cohort and the HR/IR cohort will enroll 
until 10/31/2019, provided that there is no prolonged interruption of study 
enrollment. Based on the observed accrual rates, it is anticipated, but not 
required, that we will enroll approximately a total of 220 randomized 
HR/IR patients and a total of 236 randomized LR patients.  By 10/31/2019, 
it is expected that the total accrual on this study will not surpass 700 
patients, including patients who are not eligible for or refuse 
randomization.  
 
9.3 
Statistical Analysis Methods 
9.3.1 
HR/IR Randomization for HR and IR relapse patients 
9.3.1.1 Primary endpoint: intent-to-treat DFS 
 
The original design (Activation Protocol) 
The primary efficacy analysis for HR/IR Randomization will be an intent-
to-treat comparison of the DFS curves between the randomized arms based 
on the Log-rank test. All HR/IR relapse patients who are not deemed as 
treatment failures at the end of Block 1 will be eligible for HR/IR 
Randomization. The randomization will occur upon recovery from 
Block 1 of therapy, and will be stratified as described in Section 9.2. From 
the past studies of AALL01P2, AALL02P2 and ADVL04P2, the overall 
2-year DFS rate for HR/IR patients was approximately 45%. Although 
most events are projected to occur within 2 years, events continue to occur 
in subsequent years, and hence an exponential distribution is considered 
more appropriate than a cure-rate model for comparing survival curves for 
this cohort of patients at the time of final analysis. Assuming a minimum 
of 2 years of follow up, an estimate of 170 evaluable patients will need to 
be randomized to achieve the goal of 18% improvement in 2-year DFS 
rate with blinatumomab over the expected 2-year DFS rate of 45% with 
chemotherapy backbone alone, with 80.0% power at a one-sided 
significance level of 2.5%, which represents a 42.1% reduction in hazard 
rate. The power calculations are based on the assumption of proportional 
hazards and using the log rank test. 
 
Interim analysis will be conducted to monitor for efficacy and futility. The 
efficacy stopping boundaries to be used will be based on the O’ Brien-
Fleming spending function. The futility boundaries are based on testing 
the alternative hypothesis at the 0.024 level.62 This monitoring rule can be 
applied to any interim analysis schedule and maintains the overall 
significance level of 0.025. Assuming exponential distribution and the 
final analysis is performed at the 2 years after the completion of 
enrollment, the expected maximum number of events to be observed is 
estimated to be 109. The first interim analysis will be performed after 36 
events have been observed. The cumulative power to detect the desired 
improvement is approximately 78%. The sample of monitoring boundaries 
for efficacy and futility with 3 interim analyses are given in the table 
below. 
 

 
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Looks 
# of events 
Information 
Efficacy 
Boundary 
Futility 
Boundary 
1 
36 
33% 
3.731 
-0.392 
2 
73 
67% 
2.504 
0.280 
3 
109 
100% 
1.994 
1.994 
 
Re-design for the HR/IR cohort (Amendment #8) 
 
Summary of the original design 
For the HR/IR cohort, the study was originally designed to have 
approximately power of 0.80 to detect a hazard ratio of 0.58 using a one-
sided logrank test with Type I error of 0.025, which corresponds to an 
increase in 2-year DFS rate from 45% in the control arm to 63% in the 
experimental arm. This cohort was originally planned to enroll a total of 
170 randomized, evaluable patients. It was expected to accrual for 
approximately 3 years, with 2 years of additional follow-up after 
completion of enrollment.  
 
Extended accrual duration and increased sample size 
With the extended accrual duration, the HR/IR cohort will continue to 
enroll until 10/31/2019. Based on the observed accrual rate of 50 
patients/year, this extended accrual duration will lead to a sample size of 
approximately 220 randomized patients in the HR/IR cohort. As initially 
planned, the primary analysis on efficacy will be based on a one-sided 
logrank test, with one-sided Type I error of 0.025. The primary analysis is 
planned to be conducted 1 year after completion of accrual provided that 
the expected total number of events is observed by then. Otherwise the 
primary analysis will be conducted when the expected total number of 
events is observed, or at 1.5 years after completion of accrual, whichever 
comes first. Assuming exponential distribution for the survival function, 
with 4.4 years of enrollment and 1 year of additional follow-up, the 
expected total number of events is 131. With the sample size of 220, the 
study will have approximately power of 0.85 to detect a hazard ratio of 
0.58. 
 
Interim analysis performed to date 
One interim analysis of DFS has been conducted for the HR/IR cohort 
using data freeze as of 12/31/2017. At the time of this first interim analysis, 
the observed number of events was 39 (35.8% of the information based on 
the original full information of 109 events), and the alpha (Type I error) 
that was spent was 0.00018. The first interim analysis did not cross either 
the efficacy or futility boundaries. 
 
Amended statistical monitoring plan for DFS 
With the extension of the accrual duration, the full information now 

 
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increases from the original 109 events to 131 events. With the increased 
expected number of events, the first interim analysis was actually 
conducted when we had 29.8% of information (rather than 35.8%), and 
the alpha that would have been spent would be 0.00004 instead of 0.00018. 
That is, more alpha was spent in the first interim analysis.   
 
A new interim monitoring plan for the future looks for the HR/IR cohort 
was developed by an independent statistician.  
 
The new monitoring plan for the HR/IR cohort accounts for the alpha-
spending that has already occurred.63,64 Specifically, with the new 
monitoring plan, the overall alpha to be expended is the original 
significance level minus the alpha expended with the initial interim 
monitoring that has been conducted.63,64 In the case of the HR/IR cohort, 
given that for the first look the alpha expended was 0.00018, the remaining 
alpha of 0.02482 can be used for the new monitoring plan. A monitoring 
plan that includes two more looks (the second look and the final look) was 
developed using the O’Brien-Fleming boundaries,65,66 with an overall 
significance level of 0.02482, scheduled at 66.4% and 100% of the total 
expected information. This way the cohort-wide significance level of 
0.025 is maintained. The futility boundaries are based on testing the 
alternative hypothesis at the 0.024 level.62 The boundaries are shown in 
the following table.  
 
 
 
Original Efficacy Boundaries 
New Efficacy Boundaries 
Futility 
Looks 
# of 
Events 
Inf. 
Time 
Upper 
Boundary 
of Z value 
Nominal 
Alpha 
Cumu. 
Alpha 
Inf. Time 
Revised 
Upper 
Boundary 
of Z value 
Nominal 
Alpha 
Cumu. 
Alpha 
Overall 
alpha 
Futility 
Boundary 
of Z value 
1 (done) 
39 
35.8% 
3.568  
0.00018 0.00018 
29.8% 
 
 
 
0.00018 
-0.327 
2 
87 
 
 
 
 
66.4% 
2.519 
0.00588 0.00588 0.00606 
0.363 
3 
131 
 
 
 
 
100% 
1.995 
0.02301 0.02482 
0.025 
1.995 
 
Confirmatory follow-up analysis of DFS of the HR/IR randomized 
cohort (Amendment #10)  
On 09/18/2019, the COG DSMC has recommended closing accrual to the 
HR/IR arms of AALL1331 and releasing the results of the HR/IR cohort 
to the study committee. This recommendation is primarily based on the 
significantly more favorable tolerability profile of the experimental 
(blinatumomab) arm, coupled with trending or superior DFS and OS of 
the blinatumomab arm (per interim analyses performed using data as of 
06/30/2019). DSMC has recommended that HR/IR patients assigned to the 
control arm (Arm A) who are at an appropriate point in their treatment 
program (prior to receiving Block 3) be offered the opportunity to cross 
over to the experimental arm (Arm B) to receive blinatumomab.  
 

 
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The following table summarizes the analysis of DFS (the second look) 
using data as of 06/30/2019. 
 
 
 
 
Original Efficacy Boundaries 
New Efficacy Boundaries 
Futility 
Observed 
Z Statistic 
Looks Data Cutoff 
# of 
Events 
Inf. 
Time 
Upper 
Boundary 
of Z value 
Nominal 
Alpha 
Cumu. 
Alpha 
Inf. Time 
Revised 
Upper 
Boundary 
of Z value 
Nominal 
Alpha 
Cumu. 
Alpha 
Overall 
alpha 
Futility 
Boundary 
of Z value 
1  
12/31/2017 
39 
35.8% 
3.568  
0.00018 0.00018 
29.8% 
 
 
 
0.00018 
-0.327 
1.233 
2 
06/30/2019 
80 
 
 
 
 
61.1% 
2.644 
0.00409 0.00409 0.00427 
0.267 
1.649 
 
A confirmatory follow-up analysis comparing DFS of the control arm vs. 
the experimental arm will be conducted using the 12/31/2020 data freeze 
or when 131 events are observed, whichever occurs earlier. This 
confirmatory analysis will use the HR/IR patients randomized on or prior 
to 06/30/2019 (103 in the control arm and 105 in the experimental arm).  
 
9.3.1.2 Secondary Endpoint: Intent-to-treat OS 
From the past studies of AALL01P2, AALL02P2 and ADVL04P2, the 3-
year OS rate for HR/IR patients was approximately 48%, and most deaths 
occurred within the first 3 years. Therefore, a cure-rate model with 
exponential distribution assumed during the first 3 years followed by a flat 
curve is considered for OS analysis. An interim OS analysis will be 
conducted at the time of the final DFS analysis, i.e. when all the 
170 randomized patients are followed up for 2 years. Assuming 
17% improvement in 3-year OS rate with blinatumomab over the expected 
3 – year OS rate of 48% with chemotherapy backbone alone, approximate 
70 deaths are to be observed by the time of the interim OS analysis. The 
power to detect such improvement at a one-sided significance level of 
2.5% is approximate 61% based on the log-rank test. 
 
If DFS analysis meets its target level of improvement (i.e. one-sided 
p – value < 0.025), the formal OS analysis will be performed at at 1 year 
after the interim OS analysis, by which time approximate 74 deaths are to 
be observed. The power to detect the above desired improvement is 
approximately 63%. 
 
Power of the analysis of OS with the extended accrual duration 
(Amendment #8) 
With the accrual duration extended to 10/31/2019, the power of the 
analysis of OS for the HR/IR cohort will be approximately 0.67 if 
conducted at 1 year after completion of accrual, and will be approximately 
0.72 if conducted at 2 years after completion of accrual.  
 
Confirmatory follow-up analysis of OS of the HR/IR randomized cohort 
(Amendment #10)  
A confirmatory follow-up analysis comparing OS of the control arm vs. 
the experimental arm will be conducted at the time of the confirmatory 
analysis of DFS, as well as one year following it. Same as for DFS, this 

 
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analysis will also be utilizing the HR/IR patients randomized on or prior 
to 06/30/2019 (103 in the control arm and 105 in the experimental arm).  
 
9.3.1.3 Secondary endpoint: MRD+ rates 
MRD comparisons (using an MRD+ threshold of 0.01%) will be 
performed at the end of Blocks 2 and 3 for marrow relapse patients 
participating in HR/IR Randomization. From past experience with studies 
AALL01P2, ADVL04P2, AALL07P1 and AALL0433, we anticipate that 
over the 3 years of the study, there will be 56 patients per arm evaluable 
for the MRD comparison at the end of Block 2 and 50 patients per arm 
evaluable for the MRD comparison at the end of Block 3 (see table below 
for derivation). 
 
 
Early 
marrow 
Late marrow with 
MRD ≥  0.1% 
Total 
# randomized on HR/IR 
Randomization (per arm) 
61 
24 
85 
Rate of not dropping out 
prior to end Block 2 
63% 
75% 
 
# evaluable for end Block 2 
MRD testing 
38 
18 
56 
Rate of not dropping out 
prior to end Block 3 
89% 
88% 
 
# evaluable for end Block 3 
MRD testing 
34 
16 
50 
 
Further, we anticipate that the rates of MRD ≥ 0.01% in the control arm 
will be 67% (67% for early and 68% for late) at the end of Block 2 and 
47% (43% for early and 55% for late) at the end of Block 3. A two-sample 
Fisher’s exact test of proportions (one-sided, alpha = 5%) will be used to 
test the hypothesis that the proportion of patients who are MRD+ on each 
experimental arm (with blinatumomab) is smaller than the control arm 
(without blinatumomab) at the end of Block 2 and 3. The corresponding 
power to detect various degrees of reduction in MRD+ rates is shown in 
the table below: 
 
 
Expected # per 
arm with 
successful MRD 
determination 
% MRD+ 
(control 
arm) 
Reduction in MRD+ rates 
(investigational arm) 
10% 
15% 
20% 
25% 
End Block 2 
56 
67% 
22.6% 
41.8% 
63.2% 
81.2% 
End Block 3 
50 
47% 
19.2% 
37.1% 
59.5% 
79.8% 
 
With the accrual duration extended to 10/31/2019, the analysis on MRD+ 
rates should have more statistical power. 
 
 

 
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9.3.1.4 Safety monitoring (Activation Protocol) 
According to the past study ALLR3, the cumulative toxic death rate of 
Blocks 2 and 3 of chemotherapy was estimated to be 4% (1.6% for Block 2 
and 2.7% for Block 3). The toxic death rate is expected to be lower in the 
experimental arm than the control arm because the myelosuppressive 
cytotoxic 
chemotherapy 
blocks 
are 
replaced 
with 
targeted 
immunotherapy. Therefore, toxic deaths will be closely monitored on all 
patients enrolled to each arm of HR/IR Randomization separately through 
blocks 2 and 3 of therapy. HR/IR Randomization will be temporarily 
closed for detailed review and possible therapy modifications if the 
number of toxic deaths in either arm is greater than or equal to that 
specified in the table. The boundary of toxic death was computed based 
on Pocock-type spending function at one-sided 20% significant level. 
 
Looks 
# evaluable 
patients 
Information 
Pocock boundary of 
excessive toxic death 
Excessive toxic 
death rate 
1 
28 
33% 
4 
14.29% 
2 
57 
67% 
5 
8.77% 
3 
85 
100% 
7 
8.24% 
 
Either arm of HR/IR Randomization will be rejected for excessive toxicity 
if the number of observed toxic deaths is greater than or equal to the 
corresponding boundary at any interim analysis. The actual power (based 
on exact binomial test) of declaring an arm too toxic are approximately 
95.2%, 80.8%, 47.2% and 10.1% when the true toxic death rate is 13%, 
10%, 7% and 4%, respectively. 
 
In addition, occurred during Block 2 and 3 of chemotherapy the toxic 
deaths and all toxicities of all grades between the two arms will be 
monitored/compared during the study. If the toxic death rate or the rate for 
any specific toxicity is significantly higher on the blinatumomab arm 
compared to the control arm (ALLR3 backbone), the data will be reviewed 
for possible suspension of the randomization and modification of therapy. 
 
9.3.1.5  Amended Safety Monitoring (Amendment 6) 
As of April 2017, there have been 4 deaths during blocks 2 and 3, among 
47 randomized patients on Arm A. Of these, three deaths occurred in 14 
AYA patients (ages 17, 23, and 26 years), with a death rate of 21.4%. The 
death rate among the younger patients is 1/33 (3%). The published 
UKALLR3 clinical trial only enrolled patients up to 18 years of age at the 
time of first relapse.  Hence the toxic death rate from that study (used as 
the baseline rate on this study), was based on a younger population than 
those enrolling on AALL1331. About 15% of enrollments on this study 
are currently greater than 18 years old. Based on prior studies in COG and 
other groups, it is known that the risk of toxic deaths may be higher in 
older patients relative to younger ones.  
 

 
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Based on this, the monitoring for toxic deaths during Blocks 2 and 3, 
among HR/IR patients randomized to Arm A, has been modified to apply 
only to patients ≤ 18 years of age at enrollment. The modified rule is given 
in the table below. 
 
Monitoring (HR/IR 
patients ≤18 years 
of age on Arm A) 
#Evaluable patients 
Pocock Boundary 
of Excessive Toxic 
deaths 
4-40 
4 
41-57 
5 
58-72 
6 
 
With this rule, the probability of stopping due to excessive toxic deaths is 
12% if the true toxic death rate is 4%, 48% if the true rate is 7%, and 79.2% 
if the true rate is 10%.  
 
Since it is estimated that only about 13 patients on each arm will be >18 
years of age at enrollment, separate stopping rules for this subset would 
not have much power (~74% at a true rate of 30%, or 13% power at a true 
rate of 10%). Instead of a formal monitoring rule for AYA patients, 
continuous monitoring will be done, such that any death occurring among 
the older patients, after the proposed supportive care changes are initiated, 
will trigger a study committee review and communication to the COG 
Data Safety Monitoring Committee.  
 
With Amendment #8, more patients will be enrolled in the HR/IR cohort. 
The above safety monitoring rule on toxic deaths will be implemented 
until the originally planned sample size of 170 evaluable patients are 
enrolled and completed protocol treatment. If the toxic death rates are not 
concerning with the 170 patients, then no formal statistical monitoring rule 
on toxic deaths will be implemented for the remaining patients who will 
be enrolled in this cohort. However, informal continuous monitoring of 
occurrences of toxic deaths will continue to be conducted. 
 
9.3.2 
LR Randomization for LR relapse patients 
9.3.2.1 Primary endpoint: intent-to-treat DFS from randomization 
The original design (Activation Protocol) 
The primary efficacy analysis for LR Randomization will be an intent-to-
treat comparison of the DFS curves between the randomized arms based 
on the Log-rank test. All late B-ALL marrow and IEM relapse patients 
with end Block 1 MRD < 0.1% who are not deemed to be treatment 
failures at the end of Block 1 or Block 2 will be eligible for LR 
Randomization . For IEM patients, uninterpretable MRD (due to lack of 
diagnostic marker) will be considered to be MRD negative. The 
randomization will occur upon recovery from Block 2 of therapy, and will 
be stratified as described in Section 9.2. Data from past studies suggest 
that most events are to occur within 3 years, but events continue to occur 
in subsequent years, and hence an exponential distribution is considered 

 
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more appropriate than a cure-rate model for comparing survival curves for 
this cohort of patients at the time of final analysis. An estimate of 206 
evaluable patients will be randomized 1:1 (103 evaluable patients per arm) 
between 
randomized 
experimental 
(blinatumomab) 
and 
control 
(chemotherapy) arms. Assuming a minimum of 3-years of follow up, this 
sample size estimate is based on a goal of achieving a 11% improvement 
in 3-year DFS rate with blinatumomab over the expected 3-year DFS rate 
of 73% with chemotherapy backbone alone, with 80.4% power at a one-
sided significance level of 5%, which represents a 44.6% reduction in the 
hazard rate. The power calculations are based on the assumption of 
proportional hazards and using the log rank test. 
 
Interim analysis will be conducted to monitor for efficacy and futility. The 
efficacy stopping boundaries to be used will be based on the O’ Brien-
Fleming spending function. The futility boundaries are based on testing 
the alternative hypothesis at the 0.039 level.62 This monitoring rule can be 
applied to any interim analysis schedule and maintains the overall 
significance level of 0.05. Assuming exponential distribution and the final 
analysis is performed at the 3 years after the completion of enrollment, the 
expected maximum number of events to be observed is estimated to be 75. 
The first interim analysis will be performed after 25 events have been 
observed. The cumulative power to detect a difference is approximately 
80%. The sample of monitoring boundaries for efficacy and futility with 3 
interim analyses are given in the table below. 
 
Looks 
# of events 
Information 
Efficacy Boundary 
Futility 
Boundary 
1 
25 
33% 
3.202 
-0.312 
2 
50 
67% 
2.140 
0.288 
3 
75 
100% 
1.695 
1.695 
 
 
 
Re-design for the LR cohort (Amendment #8) 
 
Summary of the original design 
For the LR cohort, the study was originally designed to have 
approximately power of 0.80 to detect a hazard ratio of 0.55 using a one-
sided logrank test with Type I error of 0.05. The hazard ratio of 0.55 
corresponds to an increase in 3-year DFS rate from 73% in the control arm 
to 84% in the experimental arm, assuming exponential distribution in 
survival function. This cohort was originally planned to enroll a total of 
206 randomized, evaluable patients. It was expected to accrue for 5.6 
years, with 3 years of additional follow-up after completion of enrollment.  
 
Extended accrual duration and increased sample size 
With the extended accrual duration, the LR cohort will continue to enroll 
until 10/31/2019. Based on the observed accrual rate of 53 patients/year, 
this extended accrual duration will lead to a sample size of approximately 

 
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236 randomized patients in the LR cohort. As initially planned, the 
primary analysis on efficacy will be based on a one-sided logrank test, 
with one-sided Type I error of 0.05. The primary analysis will be 
conducted 3 years after completion of enrollment or when the expected 
total number of events is observed, whichever comes first. Assuming 
exponential distribution for the survival function, with 4.4 years of 
enrollment and 3 years of additional follow-up, the expected total number 
of events is 80. With the sample size of 236, the study will have 
approximately power of 0.83 to detect a HR of 0.55. 
 
Amended statistical monitoring plan for DFS 
With the extended accrual duration, the full information increases from the 
original 75 events to 80 events. The new interim monitoring plan, 
developed by an independent statistician, accounts for the alpha-spending 
that has already occurred.63,64 Specifically, with the new monitoring plan, 
the overall alpha to be expended is the original significance level (0.05) 
minus the alpha expended with the first interim monitoring that has been 
conducted (0.00068).63,64  That is, the remaining alpha of 0.04932 can be 
used for the new monitoring plan. A monitoring plan that includes two 
more looks (the second look and the final look) was developed using the 
O’Brien-Fleming monitoring boundaries,65,66 with an overall significance 
level of 0.04932, scheduled at 66.25% and 100% of the total expected 
information. This way the cohort-wide significance level of 0.05 is 
maintained. The futility boundaries are based on testing the alternative 
hypothesis at the 0.039 level.62 The boundaries are shown in the following 
table.  
 
 
 
New Efficacy Boundaries 
Futility 
Looks 
# of 
Events 
Inf. Time 
Revised 
Upper 
Boundary 
of Z value 
Nominal 
Alpha 
Cumu. 
Alpha 
Overall 
alpha 
Futility 
Boundary 
of Z value 
2 
53 
66.25% 
2.151 
0.01573 0.01573 0.01641 
0.361 
3 
80 
100% 
1.702 
0.04462 0.04932 
0.05 
1.702 
 
9.3.2.2 Secondary Endpoint: Intent-to-treat OS 
From past studies suggest that most events for LR patients are to occur 
within 4 years after randomization and the 4-year OS rate is estimated to 
be 77%. Therefore, a cure-rate model with exponential distribution 
assumed during the first 4 years followed by a flat curve is considered for 
OS analysis for LR randomized patients. An interim OS analysis will be 
conducted at the time of the final DFS analysis, i.e. when all the 206 
randomized patients are followed up for 3 years. Assuming 10% 
improvement in 4-year OS rate with blinatumomab over the expected 4-
year OS rate of 77% with chemotherapy backbone alone, approximate 36 
deaths are to be observed by the time of the interim OS analysis. The 

 
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power to detect such improvement at a one-sided significance level of 5% 
is approximate 60% based on the log-rank test. 
 
If DFS analysis meets its target level of improvement (i.e. one-sided p-
value < 0.05), the formal OS analysis will be performed at 1 year after the 
interim OS analysis, by which time approximate 37 deaths are to be 
observed. The power to detect the above desired improvement is 
approximately 61%. 
 
Power of the analysis of OS with the extended accrual duration 
(Amendment #8) 
With the accrual duration extended to 10/31/2019, the power of the 
analysis of OS for the LR cohrt will be approximately 0.63 if conducted at 
3 years after completion of accrual, and will be approximately 0.64 if 
conducted at 4 years after completion of accrual.  
 
9.3.2.3 Monitoring for severe toxicities and toxic deaths 
According to the past study of ALLR3, the cumulative toxic death rate of 
Block 3, Continuation and Maintenance chemotherapy was estimated to 
be 4% (2.7% for Block 3 and 1.5% for Continuation and Maintenance). 
The toxic death rate is expected to be lower in the experimental arm than 
the control arm because the myelosuppressive Block 3 is replaced with 
targeted immunotherapy. Therefore, toxic deaths will be closely 
monitored on all patients enrolled on to each arm of LR Randomization 
separately from the start of Block 3 of therapy to the completion of 
protocol therapy. LR Randomization will be temporarily closed for 
detailed review and possible therapy modifications if the number of toxic 
deaths in either arm is greater than or equal to that specified in the table 
below. The boundary of toxic death was computed based on Pocock-type 
spending function at one-sided 20% significant level.  
 
Looks 
# evaluable 
patients 
Information 
Pocock boundary of 
excessive toxic death 
Excessive toxic 
death rate 
1 
34 
33% 
4 
11.76% 
2 
69 
67% 
6 
8.70% 
3 
103 
100% 
7 
6.80% 
 
Either arm of LR Randomization will be rejected for excessive toxicity if 
the number of observed toxic deaths is greater than or equal to the 
corresponding boundary at any interim analysis. The actual power (based 
on exact binomial test) of declaring an arm too toxic are approximately 
98.7%, 90.9%, 61.5% and 14.4% when the true toxic death rate is 13%, 
10%, 7% and 4%, respectively. 
 
In addition, during Block 3, Continuation 2 (Week 1 - 5) and Maintenance 
(Week 6 - 10) the toxic deaths and all toxicities of all grades between the 
two arms will also be monitored/compared. If the toxic death rate or the 
rate for any specific toxicity is significantly higher on the blinatumomab 

 
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arm compared to the control arm, the data will be reviewed for possible 
suspension of the randomization and modification of therapy.  
 
The potential for late adverse effects due to long term depletion of CD19+ 
normal lymphocytes following blinatumomab treatment is unknown. We 
will monitor for lymphocyte recovery and late events related to delayed 
recovery. Since HR/IR/TF patients go to HSCT soon after blinatumomab, 
it would be difficult to make sense of lymphocyte recovery/late events 
after blinatumomab for them. However, the LR patients that are 
randomized to +/- blinatumomab and do not proceed to HSCT serve as an 
excellent population to monitor for these delayed adverse effects. For all 
LR 
patients, 
we 
will 
collect 
absolute 
lymphocyte 
counts 
(ALC)/lymphocyte subset counts (total T and B cells) and data regarding 
late infections and progressive multifocal leukoencephalopathy (PML) 
after each 12-week maintenance cycle and every 3 months after 
completion of therapy for 1 year. The peripheral B-cell recovery rates and 
rates of late events by randomized arms will be monitored and compared 
descriptively between the two randomized arms every 6 months in the 
biannual study progress report and DSMC report. 
 
With Amendment #8, more patients will be enrolled in the LR cohort. The 
above safety monitoring rules on severe toxicities and toxic deaths will be 
implemented until the originally planned sample size of 206 evaluable 
patients are enrolled and completed protocol treatment. If the toxic death 
rates are not concerning with the 206 patients, then no formal statistical 
monitoring rule on severe toxicities and toxic deaths will be implemented 
for the remaining patients who will be enrolled in this cohort. However, 
informal continuous monitoring of occurrences of toxic deaths will 
continue to be conducted. 
 
9.3.3 
Pilot intervention for very high risk subset of HSCT recipients based on MRD and 
aGVHD 
 
9.3.3.1 Primary endpoint 
The primary endpoint of this non-randomized exploratory pilot 
intervention (accelerated taper of immune suppression) is feasibility and 
safety, with “success” defined as < 25% rate of Grade III-IV aGVHD and 
< 5% rate of treatment-related mortality (TRM) associated with the 
accelerated taper. We anticipate that 36 patients will meet the criteria to 
receive the intervention. We will calculate the observed rates of 
Grade III – IV aGVHD and TRM among this subset with 95% confidence 
intervals and compare descriptively to our target rates. 
 
9.3.3.2 Exploratory endpoint 
As secondary endpoints, we will calculate the percent of patients able to 
wean off immunosuppression without significant aGVHD (future 
intervention group), DFS of intervention group (vs. similar pts in 
ASCT0431 historical controls), rate of conversion from MRD+ to MRD- 
among preMRD-/postMRD+ subset (correlated with DFS), aGVHD rates 

 
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post-intervention (correlated with DFS). These data will be analyzed 
descriptively. 
 
9.3.3.3 Safety monitoring 
The toxic death and Grade 3+ GVHD rates will be closely monitored for 
the subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-HSCT 
with no acute graft versus host disease (aGVHD) who undergo accelerated 
taper of immune suppression during the study. According to past studies, 
the cumulative toxic death rate was estimated to be 5% and the cumulative 
incidence rate of Grade 3+ GVDH was approximately 25%. 
 
The safety stopping boundaries to be used for toxic death and Grade 3+ 
GVHD, respectively, will be based on the Pocock-type spending function 
at one-sided 20% significance level. Assuming 85% of evaluable HR/IR 
patients will proceed to HSCT study and approximately 25% of them will 
have MRD ≥ 0.01% pre- and/or post-HSCT with no evidence of aGVHD, 
an estimate of 36 patients will be monitored in this subset. The intervention 
(accelerated taper of immune suppression) will be temporarily closed for 
detailed review and possible therapy modifications if the number of toxic 
deaths or the number of Grade 3+ GVHD is greater than or equal to that 
specified in the corresponding table below. 
 
Table for toxic death monitoring boundary: 
Looks 
# evaluable 
patients 
Information 
Pocock boundary 
of excessive toxic 
deaths 
Excessive 
toxic death 
rate 
1 
12 
33% 
3  
25.00% 
2 
24 
67% 
4  
16.67% 
3 
36 
100% 
4 
11.110% 
 
The intervention will be rejected for excessive toxicity death if the number 
of observed toxic deaths is greater than or equal to the corresponding 
boundary at any interim analysis. The actual power (based on exact 
binomial test) of declaring the intervention too toxic are approximately 
88.5%, 71.1%, 41.6% and 10.9% when the true toxic death rate is 17%, 
13%, 9% and 5%, respectively. 
 
Table for Grade 3+ GVHD monitoring boundary: 
Looks 
# evaluable 
patients 
Information 
Pocock boundary 
of excessive 
toxicity 
Excessive 
toxicity rate 
1 
12 
33% 
6 
50.00% 
2 
24 
67% 
10  
41.67% 
3 
36 
100% 
13 
36.11% 
 
The intervention will be rejected for excessive Grade 3+ GVHD if the 
number of observed Grade 3+ GVHD is greater than or equal to the 
corresponding boundary at any interim analysis. The actual power (based 
on exact binomial test) of declaring the intervention too toxic are 
approximately 96.4%, 80.5%, 45.9% and 13.2% when the true rate of 
Grade 3+ GVHD is 49%, 41%, 33% and 25%, respectively. 

 
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See Appendix XII for guidelines for establishing organ stage and overall 
grade of acute GVHD.  
 
With Amendment #8, the above monitoring of toxic deaths and Grade 3+ 
GVHD in the subset of HSCT patients with MRD ≥ 0.01% pre- and/or 
post-HSCT with no aGVHD who undergo accelerated taper of immune 
suppression during the study will continue to be conducted until the HR/IR 
cohort meet the original planned accrual target of 170 evaluable patients.  
After that, no formal monitoring of toxic deaths or Grade 3+ GVHD will 
be conducted in this subset of patients. However, informal continuous 
monitoring of occurrences of toxic deaths will continue to be conducted. 
 
9.3.4 
Treatment Failure (TF) patients who are non-randomly assigned to blinatumomab 
Point estimate and the corresponding exact 95% confidence interval based on 
Clopper-Pearson’s method will be provided to estimate the hematologic CR , the 
rate of MRD < 0.01%, and the proportion treatment failure patients able to proceed 
to hematopoietic stem cell transplant (HSCT). 
 
The toxic death will be closely monitored for TF patients who are non-randomly 
assigned to blinatumomab. According to past studies, an approximate 60 (10%) of 
enrolled patients will be deemed as TF, and the cumulative toxic death rate is 
estimated to be 6%. The safety stopping boundaries to be used for toxic death will 
be based on the Pocock-type spending function at one-sided 20% significance 
level. The intervention for TF patients will be temporarily closed for detailed 
review and possible therapy modifications if the number of toxic deaths is greater 
than or equal to that specified in the corresponding table below. 
 
Table for toxic death monitoring boundary: 
Looks 
# evaluable 
patients 
Information 
Pocock boundary of 
excessive toxicities 
Excessive toxic 
death rate 
1 
12 
20% 
3 
25.00% 
2 
24 
40% 
4 
16.67% 
3 
36 
60% 
5 
13.89% 
4 
48 
80% 
6 
12.50% 
5 
60 
100% 
7 
11.67% 
The intervention will be rejected for excessive toxicity death if the number of 
observed toxic deaths is greater than or equal to the corresponding boundary at any 
interim analysis. The actual power (based on exact binomial test) of declaring the 
intervention too toxic are approximately 85.9%, 67.1%, 39.1% and 12.9% when 
the true toxic death rate is 15%, 12%, 9% and 6%, respectively. 
 
With Amendment #8, after monitoring toxic death rates in 60 evaluable TF 
patients, no further formal monitoring of toxic deaths among TF patients will be 
conducted. However, informal continuous monitoring of occurrences of toxic 
deaths will continue to be conducted. 
 

 
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9.3.5 
Blinatumomab related reportable adverse event (RAE) 
A reportable adverse event (RAE) with respect to blinatumomab is defined in 
Section 5.2. The reporting period case report form (CRF) for each blinatumomab 
course will specifically collect data regarding blinatumomab RAEs. Due to limited 
experience with blinatumomab, very little information is available estimate the 
expected incidence of blinatumomab RAEs. We will prospectively monitor the 
blinatumomab RAE rate on monthly study committee calls, and will report the 
blinatumomab RAE rate every 6 months in the biannual study progress report and 
DSMC report. RAE rates ≥ 10% will be of particular concern and will prompt 
discussion with the DSMC. 
 
9.3.6 
Monitoring for infection rate of 96-hour bag changes in Blinatumomab 
administration (Amendment #2) 
The rate of Grade 3 or higher relevant infections (defined as sepsis, bacteremia, 
device or catheter-related infection) will be monitored among patients who 
received blinatumomab with the infusion bag changed up to 96 hours. We will 
consider 96 hour bag change acceptable if the infection rate is 5% or less. All 
Grade 3 or higher relevant infections will be evaluated every six months and the 
infection rate will be tested to determine whether the true rate is greater than 5% 
using exact one-sided one-sample binomial test, and the results will be presented 
to DSMC. If at one of scheduled analyses, the one-sided p-value of the test is less 
than 0.05, the 96 hour bag change would be considered unacceptable and the 
DSMC will be consulted regarding whether the bag change frequency should be 
changed back to 48 hours. The two-sided 90% confidence interval for the infection 
rate will also be provided. 
 
9.3.7 
Monitoring for infection rate of 7-day bag changes in Blinatumomab 
administration (Amendment #8) 
 
Amendment #8 incorporates the allowance of a 7-day (168 hours) bag change 
schedule for Blinatumomab. This infusion schedule is added as an additional 
option to the existent 24-hour, 48-hour, and 96-hour infusion schedules.  
 
To ensure safety of using the 7-day bag change schedule, after the activation of 
this amended protocol, the rate of grade 3 or higher relevant infections (defined as 
sepsis, bacteremia, device or catheter-related infection) will be monitored among 
patients weighing ≥ 22 Kg who are enrolled after activation of the amended 
protocol and randomized to receive blinatumomab.  
 
We will conduct monthly monitoring of rate of relevant infections of grade 3+ 
using a Bayesian safety monitoring approach. Based on the observed accrual rate, 
we expect that every month we will have approximately 4 to 5 patients randomized 
to the blinatumomab arms (LR and HR/IR cohorts combined), and that the majority 
of them will be using 7-day bag change schedule. For this monitoring we will 
assume that from the date of the activation of this amended protocol, every patient 
weighing ≥ 22 Kg who are enrolled and randomized to receive blinatumomab will 
be using 7-day bag change schedule. We expect that the rate of grade 3+ infections 
related to the use of 7-day bag change schedule is 5% or less. 
 

 
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We assume that the number of patients experiencing relevant grade 3+ infections 
among those who use 7-day bag change schedule follows a binomial distribution, 
and that the probability for a patient to have relevant infections has a prior 
distribution of Beta(0.05,0.95). The first interim monitoring of infections for 7-day 
bag change will be undertaken after an initial 6 patients have received at least 1 
cycle of blinatumomab using 7-day bag change schedule and have AE data 
reported in Medidata RAVE, which is expected to occur 3 to 4 months after the 
activation of the amended protocol. After that, we will conduct monthly interim 
monitoring of the infection rate. 
 
At each interim monitoring, the posterior distribution of the probability for a 
patient to experience relevant grade 3+ infection (𝑝𝑖𝑛𝑓𝑒𝑐𝑡𝑖𝑜𝑛) will be calculated. If 
it is >95% likely that 𝑝𝑖𝑛𝑓𝑒𝑐𝑡𝑖𝑜𝑛 > 5%, the study committee will conduct toxicity 
review related to 7-day bag change,  consider the necessity of changing the bag 
change frequency back to 96 hours, and report the analysis results to DSMC. A 
simulation study showed that the probability for the rule to be triggered is 
approximately 0.97, 0.84, 0.50 and 0.10 when the true rate of relevant grade 3+ 
infection is 20%, 15%, 10% and 5%, respectively. 
 
9.4 
Gender and Minority Accrual Estimates 
The gender and minority distribution of the study population is expected to be (Activation 
Protocol): 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
85 
79 
164 
Not Hispanic or Latino 
225 
209 
434 
Ethnic Category:  Total of All Participants 
310 
288 
598 
Racial Category 
American Indian/Alaska Native 
5 
3 
8 
Asian 
12 
14 
26 
Black or African American 
35 
22 
57 
Native Hawaiian or Other Pacific  Island 
2 
1 
3 
White 
256 
248 
504 
Racial Categories:  Total of All Subjects 
310 
288 
598 
* 
These totals must agree 
This distribution was derived from past studies on AALL01P2, AALL02P2, ADVL04P2 and 
AALL0433. 
 
The gender and minority distribution of the study population is expected to be (Amendment 
#8): 
 
Accrual Targets 
Sex/Gender 

 
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Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
99 
93 
192 
Not Hispanic or Latino 
263 
245 
508 
Ethnic Category:  Total of All Participants 
363 
337 
700 
Racial Category 
American Indian/Alaska Native 
5 
4 
9 
Asian 
14 
16 
30 
Black or African American 
41 
26 
67 
Native Hawaiian or Other Pacific  Island 
3 
1 
4 
White 
300 
290 
590 
Racial Categories:  Total of All Subjects 
363 
337 
700 
This distribution was derived from past studies on AALL01P2, AALL02P2, ADVL04P2 and 
AALL0433. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Response Criteria  
See definitions in Section 3.3. 
 
 

 
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply 
• 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent 
and a commercial agent on the same study arm, but the commercial agent is 
given for a period of time prior to starting the investigational agent, 
expedited reporting of adverse events that occur prior to starting the 
investigational agent would follow the guidelines for commercial agents. 
Once therapy with the investigational agent is initiated, all expedited 
reporting of adverse events follow the investigational agent reporting 
guidelines. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 

 
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considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol. 
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered to be serious AEs. 
 
11.4.3 Death 
Reportable Categories of Death 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: Newborn death occurring during the first 28 days after birth. 
• 
Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression: in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should 
be submitted. 
 

 
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Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours. 
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy. 
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy 
• 
Myelodysplastic syndrome 
• 
Treatment related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
There is a possibility that the sperm of male patients treated on studies 
involving possible teratogenic agents may have been damaged. For this 

 
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reason, pregnancy in partners of men on study needs be reported 
and followed in the same manner as a patient pregnancy. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days after birth”, should be reported expeditiously as 
Grade 4 “Death neonatal” under the “General disorders and 
administration” SOC, when the death is the result of a patient 
pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death. 
 
11.5 
Reporting Requirements for Specialized AEs 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
 

 
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EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner. 
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database. 
 
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate 

 
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treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 
(301)   897 – 7497. 
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site. 
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS 
within 24 hours of learning of the event, followed by a complete expedited report 
within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event. 
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration. 
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours. 
 
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event. 
 
Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines. 
 

 
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Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 897-7404. 
 
Also: Fax or email supporting documentation to COG for all IND studies (fax # (310) 640-
9193; email: COGAERS@childrensoncologygroup.org; Attention: COG CTEP-AERS 
Coordinator). 
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. This 
 
does not include hospitalizations that are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
 
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special Situations as 
Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE.  
 

 
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1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1 - 4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 
require expedited reporting. 
• 
Any blinatumomab-related AE that results in interruption of dosing as described 
in Section 5.2 requires expedited reporting. 
• 
Any Grade 3 or higher infection (defined as sepsis, bacteremia, device or catheter-
related infection) that occurs more than 30 days after the last administration of 
blinatumomab and has an attribution of possible, probable, or definite must also 
be reported via CTEP-AERS. 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this 
study. 
 
Commercial reporting requirements are provided in Table B. 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution.  Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent that can be attributed (possibly, probably, 
or definitely) to the agent and is not due to cancer recurrence must be reported via 
CTEP-AERS. 
 
 

 
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11.12 Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting is split into three categories: 
 
1. During all blinatumomab cycles as well as parallel control arm cycles, routine 
reporting will include all toxicities of all grades (see table).  
2. HSCT routine reporting will include All toxicities reported via CTEP-AERS and 
all Grade 4 and higher non-hematological Adverse Events 
3. During all other blocks of therapy, routine reporting will include all toxicities 
reported via CTEP-AERS and all Grade 3 and higher non-hematological 
Adverse Events (see table). 
 
ADVERSE EVENT REPORTING BY TREATMENT PHASE 
ALL PATIENTS  
REPORTING REQUIREMENT 
Block 1 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
HR/IR 
 
Arm A  
(Control) 
Arm B 
(Experimental) 
 
Block 2 
Blinatumomab: Cycle 1 
Grade 1-5 hematological and non-hematological 
Adverse Events 
Block 3 
Blinatumomab: Cycle 2 
Grade 1-5 hematological and non-hematological 
Adverse Events 
Bridging Therapy 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
HSCT 
HSCT 
Grade 4 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
LR  
 
Arm C 
(control) 
Arm D (Experimental)  
Block 2 
Block 2 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
Block 3 
Blinatumomab cycle 1 
Grade 1-5 hematological and non-hematological 
Adverse Events 
Continuation 1 
Continuation 1 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
Continuation 2 
(first 5 weeks – days 1-35) 
Blinatumomab cycle 2 
Grade 1-5 hematological and non-hematological 
Adverse Events 
Continuation 2 
(last 3 weeks – days 36-53) 
Continuation 2 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
Maintenance 
(first 5 weeks – days 1-35) 
Maintenance 
(second 5 weeks – days 36-
70) 
Blinatumomab cycle 3 
Grade 1-5 hematological and non-hematological 
Adverse Events 

 
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Maintenance (remainder) 
Maintenance (all) 
Grade 3 and higher non-hematological Adverse Events 
and all toxicities reported via CTEP-AERS 
TF-Salvage Therapy 
 
Blinatumomab-S 1 
Grade 1-5 hematological and non-hematological 
Adverse Events 
Blinatumomab-S 2 

 
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12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
CTA/CRADA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
12.2.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study. Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI. If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement. A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
12.2.2 For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party 
Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 

 
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the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
12.2.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
12.2.4 When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
12.2.5 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
12.2.6 Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 

 
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13.0 
SPECIAL STUDIES AND SPECIMEN REQUIREMENTS 
 
13.1 
Banking for Future Research (optional) 
For cases with a limited amount of tissue available for analysis, please prioritize specimen 
for tissue banking. Samples will be collected at different time points. See Section 7.2 for 
time points.  
 
This study is designed to provide material for banking for the purpose of performing 
retrospective studies to refine risk stratification, identify new targets for therapy, identify 
biomarkers to predict response, and to link host polymorphisms with various disease 
characteristics and toxicities. See Appendix VI for details. 
 
Sample Collection Procedures  
A Specimen Transmittal Form should accompany every shipment of specimen(s) to the COG 
Reference Laboratory. Please complete one form per patient per shipment. 
 
Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol 
specific form. 
 
Shipping Media (SM) 
Samples for the Reference Laboratories are to be collected in shipping media (SM) in 
special 15 mL conical tubes. The SM contains RPMI with EDTA as the anticoagulant. 
These tubes will be prepared in the Molecular Reference Laboratory and shipped in batches 
to each participating institution, where they can be stored frozen at -20°C until use. Tubes 
are stable for 3 months if refrigerated and stable for 1 year if frozen. To request prepared 
and pre-packaged sample shipping tubes, order tubes through the Biopathology Center kit 
management system https://ricapps.nationwidechildrens.org/KitManagement/.  
 
Please note: The receiving institutions are strongly encouraged to make requests for sample 
tubes well in advance of their first patient registration on AALL1331; it will not be possible 
to expedite shipping because of prohibitive costs.  
 
Bone Marrow/Peripheral Blood Collection Procedures for Reference Laboratories:  
a. Collect BM/PB into a syringe and transfer the specimen immediately into the SM tube 
with RPMI/EDTA. 
b. Mix well. At least 2 mL and up to 5 mL of BM/PB can be placed in 1 SM tube. If you 
don’t have SM tubes, you can place the BM/PB into large purple EDTA tubes that are 
commonly available in most hospitals. However, the viability of the cells is greatly 
enhanced in the SM tubes. 
c. For BM, use multiple syringes and tubes as necessary. Reposition the BM aspirate 
needle at least once during the diagnostic procedure to ensure the maximum quality of 
BM. DO NOT SHIP SYRINGES. 
d. Label each tube with COG registration number, patient name and date of birth, 
collection date, institution and type of specimen (bone marrow). 
e. Samples are to be shipped at room temperature except for international samples that 
are expected to be delayed for more than 48 hours – place a cold pack (not ice pack) in 
shipment. 
NOTE: Enrollment APEC14B1 is ENCOURAGED, but NOT REQUIRED. APEC14B1 only 
require a single cell bank specimen (i.e. not separate AALL1331 and APEC14B1 specimens). 

 
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NOTE: For patients who are not having a BM for medical reasons at diagnosis or other 
time points and have an absolute blast count of at least 1,000/μL, PB may be submitted to 
the Reference Laboratories instead of BM. Submit 2 mL of PB for each 1 mL of required 
marrow. 
 
Reference Laboratory – Shipping Address (including Saturday delivery): 
 
COG Leukemia Biospecimen Bank 
Nationwide Children’s Hospital 
575 Children’s Crossroads, Room WB2255 
Columbus, OH 43215 
Phone: (614) 722-2866 
Fax: (614) 722-2887 
Email: mglab@nationwidechildrens.org 
 
All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery 
before 10 am). Use the COG FedEx account number, which may be found at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf. 
Notify Laboratory of each Saturday delivery (email or phone) and remember to mark 
“For Saturday Delivery” on the FedEx paperwork.  
 
13.2 
Local Bone Marrow: Central review of cytogenetics/FISH 
Bone marrow aspiration to confirm relapse (and/or to detect potential marrow disease in 
presumed isolated extramedullary relapse patients) is required for study entry. 
Morphologic, immunophenotypic, & cytogenetic/FISH analysis should be performed by 
the local institution. Cytogenetic analysis should include FISH for any cytogenetic 
abnormalities known from the patient‘s original leukemia if applicable. All FISH should 
be performed on uncultured, directly-harvested cells or unstimulated overnight cultured 
cells if the former is not possible. FISH for abnormalities shown by cytogenetics to be 
unique to the relapse specimen should also be done on directly harvested cells or 
unstimulated overnight cultured cells if the former is not possible. Cytogenetic/FISH 
analysis must be performed at a COG approved cytogenetics lab and cases will be reviewed 
retrospectively by the COG Cytogenetics Committee.  
 
Please see the following link for a list of COG approved cytogenetics labs: 
https://www.cogmembers.org/site/admin/default.aspx 
 
Required Material:  
a) Two original karyotypes of different cells from each abnormal clone or of two normal 
cells when no abnormalities are found; full-size metaphase images of the karyotypes 
cells. 
b) A completed COG Cytogenetics Reporting Form and FISH Form (if done). These 
reporting forms are available on the AALL1331 protocol web page. Electronic 
submission of the karyotypes/FISH images is required. 
 
Shipping: The review materials on each case should be sent to the COG ALL Cytogenetic 
Coordinators within 4 weeks of study entry. If the institution is west of the Mississippi 
River, send these materials to Dr. Andrew Carroll (University of Alabama). If the 

 
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institution is east of Mississippi River (except Minnesota and Wisconsin, which go to Dr. 
Carroll), send all materials to Dr. Nyla Heerema (The Ohio State University). 
 
Western Laboratory – Shipping Address: 
Dr. Andrew Carroll, Ph.D. 
Ph.D. Department of Genetics 
University of Alabama at Birmingham 
720 20th St. So. Kaul Bldg. Room 314B 
Birmingham, AL 35294 
Phone: 205-934-0665 
Fax: 205-934-1078 
Email: acarroll@ uab.edu 
 
Eastern Laboratory – Shipping Address: 
Dr. Nyla Heerema, Ph.D. 
Professor and Director of Cytogenetics 
The Ohio State University 
Division of Clinical Pathology 
Hamilton Hall, Room 167 
1645 Neil Ave. Columbus, OH 43210 
Phone: 614-292-7815 
Fax: 614-292-7072 
Email: Nyla.Heerema@osumc.edu 
 
13.3 
Bone Marrow for Central Flow-Immunophenotyping and MRD (required) 
Immunophenotyping will be done on fresh bone marrow specimens collected at study 
entry (see Section 7.1). Minimal residual disease will be detected using 6 color flow 
cytometry (Dr. Michael Borowitz, Johns Hopkins University) on fresh bone marrow 
specimens collected during therapy at various designated time points (see Section 7.1).  
Sample Collection Procedures  
A Specimen Transmittal Form should accompany every shipment of specimen(s) to the COG 
Reference Laboratory. Please complete one form per patient per shipment. 
 
Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol 
specific form. 
 
Shipping Media (SM) 
Samples for the Reference Laboratories are to be collected in shipping media (SM) in 
special 15 mL conical tubes. The SM contains RPMI with EDTA as the anticoagulant. 
These tubes will be prepared in the Molecular Reference Laboratory and shipped in batches 
to each participating institution, where they can be stored frozen at -20°C until use. Tubes 
are stable for 3 months if refrigerated and stable for 1 year if frozen. To request prepared 
and pre-packaged sample shipping tubes, order tubes through the Biopathology Center kit 
management system https://ricapps.nationwidechildrens.org/KitManagement/. 
 
Please note: The receiving institutions are strongly encouraged to make requests for 
sample tubes well in advance of their first patient registration on AALL1331; it will NOT 
be possible to expedite shipping because of prohibitive costs. 
 
Bone Marrow Collection Procedures for Reference Laboratories: 

 
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a. Collect BM into a syringe and transfer the specimen immediately into the SM tube 
with RPMI/EDTA. 
b. Mix well. At least 2 mL and up to 5 mL of BM can be placed in 1 SM tube. If you 
don’t have SM tubes, you can place the BM into large purple EDTA tubes that are 
commonly available in most hospitals. However, the viability of the cells is greatly 
enhanced in the SM tubes. 
c. Use multiple syringes and tubes as necessary. Reposition the BM aspirate needle at 
least once during the diagnostic procedure to ensure the maximum quality of BM. DO 
NOT SHIP SYRINGES. 
d. Label each tube with COG registration number/Biopathology number, patient name 
and date of birth, date, institution and type of specimen (bone marrow). 
e. Samples are to be shipped at room temperature except for international samples that 
are expected to be delayed for more than 48 hours – place a cold pack (not ice pack) in 
shipment. 
 
NOTE: For patients who are not having a BM for medical reasons at diagnosis or other 
time points and have an absolute blast count of at least 1,000/μL, PB maybe submitted to 
the Reference Laboratories instead of BM. Submit 2 mL of PB for each 1 mL of BM 
required. 
 
Please note: Specimens will be shipped to the COG Reference Laboratory at Johns Hopkins 
(Eastern) ONLY. 
 
Reference Laboratory – Shipping Address (including Saturday delivery): 
Michael Borowitz, MD, PhD 
Flow Cytometry Laboratory, Johns Hopkins Medical Institutions 
Weinberg Building – Room 2300 
401 N. Broadway 
Baltimore, MD 21287 
Phone: 410-614-2968 
Fax: 
410-502-1493 
Email: mborowit@jhmi.edu 
 
All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery 
before 10 am). Use the COG FedEx account number, which may be found at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf. 
Notify Laboratory of each Saturday delivery at 410-614-2968 or via email at 
kbowles3@jhmi.edu 
 
13.4 
Bone Marrow for CRLF2 expression (optional) 
We will quantify surface CRLF2 expression by flow cytometry and correlate with outcome. 
This assay will be done in conjunction with the immunophenotyping performed at study 
entry in Dr. Mike Borowitz’s lab at Johns Hopkins University (see Section 13.3). For 
details, refer to Appendix IX. 
 
Sample Collection Procedures  
NOTE: A separate specimen is NOT REQUIRED. Please note on the specimen transmittal 
forms that accompany the required immunophenotyping specimen whether the patient has 
consented for the optional CRLF2 expression assay. 
 

 
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13.5 
Blinatumomab Pharmacodynamics (PD) (optional) 
Immunopharmacologic testing will be performed using blood and bone marrow specimens 
in consenting patients treated with blinatumomab during the first exposure to 
blinatumomab in an effort to identify biomarkers of blinatumomab response. For details, 
refer to Appendix X. 
 
NOTE: All patients will be offered participation in this study at Block 1, prior to treatment 
assignment/randomization. Bone marrow samples will be drawn on all consenting patients 
at end Block 1. If the patient is subsequently randomized or assigned to treatment with 
blinatumomab (Arm B, Arm D, or Salvage Therapy), the Block 1 bone marrow sample will 
be analyzed and subsequent blood samples should be obtained. If the patient is randomized 
to treatment on the control arm (Arm A or Arm C), the Block 1 bone marrow sample will 
be destroyed and no further samples will be collected. 
 
Sample Collection Procedures  
A Specimen Transmittal Form should accompany every shipment of specimen(s) to the 
Brown Laboratory. Please complete one form per patient per shipment. 
 
In the event that the infusion is interrupted, the peripheral blood collection should likewise 
be delayed to account for the interruption. i.e. collect the timed sample after X days of 
infusion rather than X days from start of infusion.  
 
Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol 
specific form. 
 
Blood and marrow collection schedule (see Section 7.2) 
• 
Bone Marrow (1 sample, 5-10mL in sodium heparin tube) 
o End Block 1 (All patients) 
o End Block 2 (LR patients on Arm D only) 
 
• 
Blood during first blinatumomab cycle (7 samples, 3mL each in sodium heparin tubes)  
o Day 1 
- 
0 hr (just prior to start of blinatumomab infusion) 
- 
6 hr 
- 
12 hr 
o Day 2 
o Day 7 
o Day 14 
o Day 21 
 
Samples should be shipped at room temperature. 
 
Brown Laboratory – Shipping Address (including Saturday delivery): 
Dr. Patrick Brown 
Johns Hopkins Oncology 
Cancer Research Building I, Room 262 
1650 Orleans Street 
Baltimore, MD 21231 

 
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Laboratory phone:  410-955-8688 
Pager no: 
410-434-0732 
E-mail: 
pbrown2@jhmi.edu 
 
All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery 
before 10 am). Use the COG FedEx account number, which may be found at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf. 
 
Saturday deliveries are permissible. If a Saturday delivery is required, please notify Dr. 
Brown of the planned shipment via email (pbrown2@jhmi.edu) PRIOR to the time of 
shipment and clearly mark the package “For Saturday Delivery”. 
 
13.6 
Protein Cell Stress Pathways (optional) 
Note: Isolated extramedullary relapse patients are not eligible for this sub-study.  
 
This study is designed to analyze two specific aims: 1) To determine if specific protein 
expression profiles, as determined by reverse-phase protein lysate array (RPPA) analysis 
and phospho-flow analysis, correlate with therapy response and 2) To determine if 
alterations in specific cell stress proteins (such as the UPR) during chemotherapy can 
identify low risk patients with “high risk” protein signatures. For details, refer to 
Appendix XI. 
 
Consenting patients will have peripheral blood samples (5mL for those ≥ 10kg, 3 mL for 
those < 10 kg) collected at 0 hours (prior to start of Block 1 systemic chemotherapy), and 
at 2 time points after the initiation of therapy (6 hours and 24 hours after the first dose of 
Block 1 systemic chemotherapy) to examine for changes in protein expression patterns. 
Blood samples for RPPA using sucrose centrifugation and (if necessary) the lymphoblast 
population will be isolated by either bead technology or flow cytometry. Sample collected 
for phospho-flow will be analyzed directly from whole blood. Sorted lymphoblasts will be 
made into lysates for RPPA analysis prior to freezing. Remaining samples will be frozen 
as pellets for protein analysis. 
 
Eligible samples: 
Sample should be sent to the Horton lab only if the patient has an initial absolute blast 
count of at least 1,000 lymphoblasts/µL. To calculate the absolute blast percentage, 
multiply the total WBC by the % peripheral blasts: 
(WBC)(% blast)(1000) = absolute blast count/µL 
 
Example: 
If the patient has a WBC of 10 and 50% blasts, the absolute blast count is: 
(10)(.5)(1000) = 5000/µL 
 
If the initial % blasts is unknown, send samples only if the total WBC is more than 10,000 
and notify the Horton lab of the % blast as soon as available (contact info provided below). 
 
Sample Collection Procedures 
A Specimen Transmittal Form should accompany every shipment of specimen(s) to the 
Horton Laboratory. Please complete one form per patient per shipment. Please note: The 
AALL1331 Specimen Transmittal Form should be used. This is a protocol specific form. 
 
 

 
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Sample collection time points: 
 
Day 1, Hour 0 
(before start of systemic 
chemotherapy) 
Day 1, Hour 6-8 
Day 1, Hour 24 
Peripheral 
Blood 
(Block 1 
only) 
• 
3 – 5 mL# in CellSave 
Preservative Tube* 
• 
3mL in heparin tube 
• 
3mL in CellSave 
Preservative 
Tube* 
• 
3mL in heparin 
tube 
• 
3mL in CellSave 
Preservative 
Tube* 
• 
3mL in heparin 
tube 
# 5 mL for those ≥ 10kg, 3 mL for those < 10kg 
* CellSave tubes will be provided by the Horton lab to each institution upon IRB 
approval. To obtain more CellSave tubes, contact the Horton lab at the numbers 
provided below. If the CellSave tubes are not available, submit entire 6 mL sample in 
2 heparin tubes. Note that the sample integrity is greatly enhanced by the use of 
CellSave tubes.  
 
Store samples in refrigerator until shipment, and use Thermosafe with ice pack (or 
similar Styrofoam shipping containers with sufficient ice packs if these are not available at 
your site.) These containers maintain biology samples at a constant temperature and are 
strongly recommended for biology sample shipment, particularly in warm weather months. 
 
Horton Laboratory – Shipping Address (including Saturday delivery): 
Dr. Terzah Horton c/o Gaye Jenkins 
Feigin Center, Room 760.01 
1102 Bates St. 
Baylor College of Medicine 
Houston, TX 77030 
Phone: (832) 824-4676 or (832) 824-4269 
Email tmhorton@txccc.org 
 
All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery 
before 10 am). Use the COG FedEx account number, which may be found at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf. 
 
The Horton lab can accept Saturday shipments if we are contacted ahead of time. 
Please contact Gaye Jenkins or Dr. Horton (832-824-4676 or 832-824-4269) for 
alternative address and shipping information for Saturday delivery. 
 
 
13.7 
Blinatumomab Immunogenicity Assessment (Required) 
(See lab manual on protocol webpage for sample collection and shipping details) 
 
Blinatumomab is a novel protein therapeutic under clinical development. As outlined in 
the Draft Guidance: Immunogenicity Assessment for Therapeutic Protein Products (Feb 
2013) pre-specified immunogenicity sampling will be performed to evaluate and mitigate 
risk (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM338856.pdf).  
 
Blood samples for the assessment of blinatumomab immunogenicity will be collected to 
determine whether anti-idiotype antibodies directed against blinatumomab have been 

 
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developed. Screening for these antibodies will be done by ELISA assay on ECL Basis 
(electrochemiluminescence), and binding will be confirmed with a Biacore assay to 
measure protein-protein interaction and binding affinity. 
 
In a tiered approach patient samples are initially tested in a screening assay. Samples that 
produce signals above a certain screening cut point (classified as “positive”) may be 
subjected to a confirmatory assay. The screening assay is designed to minimize false 
negatives, so positive screening assays need to be confirmed as positive. These are 
performed using the same format as the screening assay. A comparison of patient serum in 
the presence and absence of excess blinatumomab is used to confirm or deny the existence 
of anti blinatumomab antibodies. The screening and confirmation assay in the context of 
blinatumomab clinical studies will be performed according to an internal standardized 
protocol using a validated assay. 
 
Immunoassay-positive samples will be analyzed in a third step using a cell based 
blinatumomab-mediated cytotoxicity assay to determine if the detected antibodies have 
neutralizing properties. Detection of neutralizing anti-blinatumomab antibodies relies on a 
validated bioassay measuring changes in the biologic activity of blinatumomab triggered 
by the presence of the antibody. 
 
Blood Serum samples for antibody testing are being collected on all patients randomized 
to receiving blinatumomab for the measurement screening of anti-blinatumomab binding 
antibodies. Samples testing positive for binding antibodies will also be tested for 
neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity 
and presence of immune complexes. The ‘cell-based assay’ for neutralizing antibody 
detection tests patient sera in a model cell based system. This does not require patient cells 
or additional serum to be collected. Both the screening and the neutralizing assays are well-
established at the Amgen Research Munich laboratory. 
 
COG will be notified of any positive neutralizing antibody results to blinatumomab. If 
results are not provided, no neutralizing antibodies to blinatumomab have been detected. 
Patients who test positive for neutralizing antibodies to blinatumomab at the final 
scheduled study visit will be asked to return for additional follow-up testing. This testing 
is to occur approximately every three months starting from when the site has been notified 
of the positive result, until: (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least one year (± 4 weeks) post administration 
of blinatumomab. All follow-up results, both positive and negative will be communicated 
to COG. More frequent testing (e.g. every month) or testing for a longer period of time 
may be requested in the event of safety-related concerns. Follow-up testing is not required 
where it is established that the subject did not receive blinatumomab. Patients who test 
positive for binding, non-neutralizing antibodies and have clinical sequelae that are 
considered potentially related to an anti-blinatumomab antibody response may also be 
asked to return for additional follow-up testing. 
 
13.8 
Blinatumomab PK (required) 
Please see the Lab Manual posted on the protocol web page for sample collection and 
shipping details. 
 

 
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14.0 
RADIATION THERAPY GUIDELINES FOR ALL PATIENTS 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved 
COG RT facilities (per COG administrative policy: Other Membership: Radiation 
Oncology Paritipcation Requirements). 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
14.1 
General Guidelines 
The objective of this protocol is to compare the benefits and risks of Blinatumomab in the 
treatment of first relapse B-ALL. Patients eligible for this study will undergo risk 
classification after an initial block of chemotherapy (Block 1). Risk classification and the 
indications for irradiation will be based on site of first relapse, time to first relapse, MRD 
status following Block1 chemotherapy and clinical response to chemotherapy (when 
testicular leukemia is present at protocol entry). 
 
Patients determined to be low risk (LR) after Block 1, will receive additional chemotherapy 
(Block 2) post randomization to a control arm or an experimental arm. The experimental 
arm includes blinatumomab. Both the control and experimental arms include maintenance 
chemotherapy to complete the respective regimens. LR patients with testicular leukemia at 
protocol entry will receive testicular irradiation (2400cGy) during Block2 if they do not 
have a clinical complete response after Block1. LR patients with CNS leukemia at protocol 
entry will receive cranial irradiation (1800cGy) during maintenance chemotherapy. 
 
Intermediate Risk (IR) and High Risk (HR) patients will proceed to protocol-specified 
hematopoietic stem cell transplant (HSCT). Selected patients that do not respond to Block1 
and HR and IR patients that do not respond to the control arm will receive blinatumomab 
in a separate treatment arm and may proceed to HSCT depending on their response to 
Blinatumomab provided they do not have a history of CNS leukemia (CNS3) at or after 
protocol entry. IR/HR patients with testicular leukemia at protocol entry will receive 
testicular irradiation (2400cGy) during the first cycle of Blinatumomab (experimental arm) 
if they do not have a complete response after Block1. IR/HR patients with testicular 
leukemia who have a complete clinical response to Block 1 will receive supplemental 
testicular irradiation (600cGy) sequentially with total body irradiation (TBI). IR/HR 
patients with CNS leukemia at protocol entry will receive supplemental cranial irradiation 
(600cGy) sequentially with TBI. Supplemental irradiation refers to irradiation of any site 
performed sequentially with TBI. 
 
Treatment failure (TF) patients are select patients that do not respond to Block1 and HR 
and IR patients that do not respond to the control arm. They will receive Blinatumomab in 
a separate treatment arm and may proceed to HSCT depending on their response to 
Blinatumomab provided they do not have a history of CNS leukemia (CNS3) at or after 
protocol entry. They may also receive testicular or cranial irradiation therapy when 
indicated. TF patients after block1 will receive testicular irradiation (2400cGy) during their 
first course of Blinatumomab. TF patients with testicular leukemia who have a complete 
clinical response to Block1 will receive supplemental testicular irradiation (600cGy) 

 
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sequentially with total body irradiation (TBI). TF patients after block2 with CNS leukemia 
at protocol entry will receive supplemental cranial irradiation (600cGy) sequentially with 
TBI. 
 
Because there is no consensus on fractionated TBI or supplemental irradiation regimens, 
the radiation therapy guidelines for this study were designed to promote protocol 
participation and match guidelines used at the majority of approved transplant institutions 
and evolved from guidelines developed for other COG protocols. Questions about these 
guidelines should be directed to the radiation therapy coordinator or principal investigator. 
Complete clinical response refers only to the testes. Supplemental irradiation refers to 
irradiation of any site performed sequentially with TBI. 
 
14.1.1 Required Benchmark and Questionnaires 
Radiation therapy will be administered using photons or electrons according to 
treatment site. All centers administering TBI must have completed the TBI 
benchmark for the specific TBI technique to be used for patients treated on this 
study. Benchmark instructions are available at the IROC Rhode Island website: 
https://www.qarc.org/.  
 
The calibration of therapy units used in this protocol must be verified by IROC 
Houston (RPC) (http://irochouston.mdanderson.org). 
 
14.2 
Indications for Radiation Therapy 
14.2.1 Total Body Irradiation 
TBI is indicated as part of the preparative regimen for IR/HR patients undergoing 
HSCT. 
14.2.1.1 
Supplemental cranial irradiation is indicated for HSCT patients with a 
history of CNS leukemia at protocol entry and shall be given 
sequentially. 
 
14.2.1.2 
Supplemental testicular irradiation is indicated for HSCT patients with 
the diagnosis of testicular leukemia and complete response after Block1 
and shall be given sequentially. Those with testicular leukemia and 
without complete response after Block1 will not require supplemental 
testicular irradiation because they will have already received 2400cGy 
earlier in the regimen. 
 
14.2.1.3 
Patients who require irradiation to extra-medullary sites other than 
brain and testes should contact the Study Chair. 
 
14.2.2 Cranial Irradiation 
LR patients with a history of CNS leukemia at protocol entry should receive cranial 
irradiation. Cranial irradiation will be given between the first and second 12 week 
blocks of Maintenance chemotherapy. This corresponds to Week 40 for LR 
patients treated on the control arm and Week 54 for LR patients treated on the 
experimental arm. IR/HR patients will receive supplemental cranial irradiation 
sequentially with TBI prior to HSCT. Exceptions to the use of cranial irradiation 
include concerns about additional effects due to patient age, history of prior cranial 

 
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irradiation and history or imaging evidence of CNS toxicity including 
leukoencephalopathy, stroke and necrosis. 
 
14.2.3 Testicular Irradiation 
Patients with persistent testicular leukemia at the end of Block 1 will receive 2400 
cGy of testicular radiation during either Block 2 chemotherapy (for LR patients 
and HR/IR patients randomized to the control arm) or during blinatumomab (for 
HR/IR patients randomized to the experimental arm and TF patients after Block 1). 
Prior testicular irradiation will not be a contraindication to supplemental testicular 
irradiation on this protocol. 
 
14.3 
Timing 
14.3.1 All patients who might require irradiation should be seen in consultation by a 
radiation oncologist in advance of treatment. The purpose of the consultation is to 
participate in planning the sequence of treatment and to determine the need for 
extra medullary (cranial, testicular and other) and supplemental irradiation in 
conjunction with HSCT. 
 
14.3.2 The timing of TBI and supplemental irradiation will be determined in part by the 
TBI fractionation regimen. Supplemental irradiation should precede TBI and be 
performed during weekdays. 
 
14.4 
Emergency Irradiation 
There may be instances when radiation therapy has been administered prior to enrollment 
on this protocol because of potentially life-threatening or function-threatening 
extramedullary involvement. Although it is not expected that prior treatment would make 
total body irradiation contraindicated, it should be considered when describing to the 
patient or parent the potential complications of treatment on this protocol. 
 
14.5 
Equipment and Methods of Delivery 
Treatment Site 
Photons 
Electrons 
TBI 
Any Energy 
 
Cranial Irradiation 
4 or 6MV 
 
Testicular Irradiation 
Any Energy 
Any Energy 
Any energy for photons or electrons can be used as long as the skin and target dose 
requirements are met. 
 
14.6 
Treatment Volumes 
14.6.1 Total Body Irradiation 
The entire body will be treated including the head and feet in one field. Care should 
be taken to insure that the patient is entirely within the 90% isodose line of the 
beam and not in the penumbra region. 
 

 
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14.6.2 Cranial Irradiation 
The treatment site consists of the entire brain and intracranial subarachnoid volume 
as well as the optic nerves and the posterior halves of the optic globes. The caudal 
border shall be the C2/3 vertebral interspace. 
 
14.6.3 Testicular Irradiation 
The treatment site consists of the testes in the scrotal sac. 
 
14.7 
Target Dose 
14.7.1 Dose Definition 
Photon and electron dose is to be specified in centigray (cGy)-to-muscle. 
 
14.7.2 Prescribed Dose, Fractionation and Dose Rate for TBI 
TBI may be administered with either of the following two regimens: 
• 
1200 cGy administered over 3 consecutive treatment days (Days -7, 
- 6, - 5) at 200cGy BID 
• 
1200 cGy administered over 4 consecutive treatment days (Days -8, -7, 
- 6, -5) at 150cGy BID 
 
Allowable but not preferred TBI regimen: 
• 
1320 cGy given over 4 consecutive treatment days (Days -8, -7, -6, -5) at 
165 cGy BID 
 
Important considerations for TBI: 
• 
Effort should be made to avoid interruptions in TBI administration 
• 
The inter-fraction interval shall be no less than 5 hours between treatments 
(start to start) 
• 
A mid-plane dose rate of between 6 and 15 cGy per minute is required 
 
14.7.3 Prescribed Dose and Fractionation for Cranial Irradiation 
14.7.3.1 LR patients will receive 1,800 cGy administered in 10 daily fractions of 
180 cGy during Maintenance chemotherapy. 
 
14.7.3.2 IR/HR patients will receive 600 cGy administered in 3 daily fractions of 
200 cGy immediately before TBI 
 
14.7.4 Prescribed Dose and Fractionation for Testicular Irradiation (testicular leukemia at 
protocol entry) 
14.7.4.1 LR patients will not receive testicular irradiation if a complete clinical 
response is observed after Block1. 
 

 
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14.7.4.2 LR patients will receive 2400 cGy testicular irradiation administered in 
12 daily fractions of 200 cGy during Block 2 if a complete clinical 
response is not observed after Block 1. 
 
14.7.4.3 IR/HR patients will receive 600 cGy administered in 3 daily fractions of 
200 cGy immediately before TBI if complete clinical response is 
observed after Block 1. 
 
14.7.4.4 IR/HR patients will receive 2400 cGy testicular irradiation administered 
in 12 daily fractions of 200 cGy During Block 2 if a complete clinical 
response is not observed after Block 1. 
 
14.7.5 Prescribed dose and fractionation for testicular irradiation (testicular leukemia not 
present at protocol entry) 
14.7.5.1 Supplemental testicular irradiation of 400 cGy in 1 or 2 daily fractions 
prior to or during TBI may be administered according to institutional 
preference but is not required. 
 
14.8 
Treatment Technique 
14.8.1 TBI 
Supine and prone, lateral decubitus, upright seated and standing positions are 
allowed. Treatment will be delivered with equally weighted parallel opposed 
portals. Each treatment will include both fields. All treatment techniques and 
patient positions should meet the criteria on dose, dose rate, and dose uniformity. 
Beam spoilers or other equally effective devices may be used to increase skin dose 
to meet the dose uniformity requirements. Changes in patient positioning after the 
patient has started TBI must be documented. Changes in lung blocking and dose 
recalculation should be reported. 
 
14.8.2 TBI - Lung Shielding 
Lung shielding is mandated to restrict the lung dose (see Section 14.9.1). Lung 
shielding to achieve dose reduction should conform to the following guidelines: 
• 
The lateral edges will be 1.0 – 1.5 cm inside the inner border of the ribs; 
• 
The inferior edges will be 1.0 – 1.5 cm superior from the dome of the apex of 
the diaphragm; 
• 
The superior borders will be 1.0 – 1.5 cm below the clavicles; 
• 
The medial border 2.0 – 2.5 cm lateral to edges of the thoracic vertebral bodies. 
• 
No contouring of the lung shields will be done around the hilum unless there 
is residual hilar adenopathy in which case the margins around the hilar 
abnormality will be 1.0 – 1.5 cm. When utilized, lung blocks should be 
employed for sequential treatments starting with the first treatment.  
• 
Compensatory electron boost of the portion of the chest wall shielded by the 
lung blocks is not required. 
 

 
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14.8.3 Cranial Irradiation 
Supine treatment is recommended with immobilization appropriate for the age of 
the child. Two opposed lateral equally weighted photon beams are preferred. The 
fields shall extend at least 1 cm beyond the periphery of the scalp. Customized 
field-shaping is required with blocks that are at least 5 HVL thick. Alternatively, a 
multi-leaf collimator may be used provided the leaf width is less than or equal to 
5 mm. 
 
Lens sparing techniques are encouraged with 1 of 2 techniques: 
• 
Angling of the 2 lateral fields in the anterior direction (RAO/LAO) using 
the lateral canthus markers to “flatten” the beam edge. Shielding blocks 
are used to block the anterior halves of the eyes, the nose, and mouth. 
• 
Set the central axes of the horizontal cranial beams so that they are aligned 
to the lateral canthi (half-beam blocking technique). The anterior edges of 
the beams are defined by an external block or by an independently 
controlled collimator and meet at a point 1 cm anterior to the frontal lobe 
meninges. Shielding blocks cover the anterior halves of the eyes and 
protect the nose and mouth. 
 
14.8.4 Testicular Irradiation 
The patient shall be treated in the supine position. Field shaping for photons and 
electrons will be done with either customized cerrobend blocking or multi-leaf 
collimation. The testes may be supported posteriorly and, if possible, extended 
caudally in order to minimize perineal irradiation. The penis should be excluded 
from the field. 
 
14.9 
Organs at Risk 
14.9.1 Normal tissue sparing for TBI 
Restricting the lung dose to ≤ 800 cGy is required on this protocol. This 
requirement applies to both AP/PA and lateral treatments.. Institutions are allowed 
to use their preferred method of beam attenuation to achieve the dose reduction to 
lungs. The lung dose shall be reported as reference point C for lateral treatments 
and reference point D for AP/PA treatments (see Section 14.10.1.2). It should be 
reported on the TBI Summary form. 
 
14.9.2 Normal tissue sparing for cranial irradiation 
• 
Lens sparing techniques, as outlined in Section 14.8.3, are encouraged. 
 
14.9.3 Normal tissue sparing for testicular irradiation 
• 
Techniques for sparing perineum and penis are outlined in Section 14.8.4. 
 
14.10 Dose Calculation and Reporting 
14.10.1 Dose calculations for TBI 
14.10.1.1 Suggested Methods for Dose Calculations for TBI 

 
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The TBI percent depth dose (PDD) or Tissue Maximum Ratio (TMR) 
and output factors may be measured under TBI treatment conditions for 
a range of phantom sizes to establish the database for TBI beam-on time 
calculations and to validate the calculation method. Measurements of 
entrance and exit dose at the center of a phantom equivalent to the size 
of the typical patient are performed and compared to the calculated dose. 
If differences are found, additional correction factors should be 
introduced to the calculation method. The prescription point is defined 
as the point along the longitudinal axis of the patient at the mid-plane at 
the level of the umbilicus (Point E below). Tissue inhomogeneity 
correction is not required in the calculation of dose to the prescription 
point. 
 
14.10.1.2 Dose Calculations and Measurements to Selected Anatomical Reference 
Points for TBI 
Prescription Point:  
The following reference points will be determined: 
The calculated and measured doses to selected anatomical points must 
be submitted to IROC RI as part of the quality assurance documentation: 
 
(Point A - Head) This reference point is defined along the longitudinal 
axis of the skull at the greatest mid-separation (immediately superior to 
the nasal bridge). The depth should be taken as midway between the 
entrance and exit points of the opposed radiation beams. 
 
(Point B – Neck) This reference point is defined along the patient’s 
longitudinal axis at the level of C3/C4 (approximate mid-neck, but 
chosen for the thinnest mid-separation of the neck). The point is taken 
to be midway between the entrance and exit point of the beam. 
 
(Point C - Mid-mediastinum) For APPA: The point is in the center of 
the chest along the sagittal plane midway between the anterior and 
posterior surfaces (Usually at the level of the carina). For opposed 
laterals: this point is located midway between the entrance and exit 
points of the beams at the level of the carina. Calculations at this 
reference point should include lung shielding if present. 
 
(Point D – Mid-Lung) APPA only: This reference point is centered in 
the middle of the right or left lung (both medial/lateral and 
cephalocaudad directions). The depth should be taken as midway 
between the entrance and exit points of the opposed radiation beams. 
Calculations at this reference point should include lung shielding if 
present. 
 
(Point E – Umbilicus) This is the PRESCRIPTION POINT. This point 
is located along the patient’s longitudinal axis at the level of the 
umbilicus and midway between the entrance and exit points of the 
opposed beams. 
 

 
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(Point F – Hip or Pelvis) This reference point is defined at the level 
approximately 1 cm superior to pubic symphysis midway between the 
entrance and exit points of the beam. 
 
(Point G - Knee) This reference point is defined along the midline in the 
mid-plane of the knee at the level of the patella. 
 
(Point H -Ankle) This reference point is defined along the midline at the 
mid-plane of the ankle at the level of the lateral malleolus. 
 
14.10.1.3 Lung Dose Calculation 
Tissue heterogeneity must be accounted for in the calculation of dose to 
lung. The preferred method is use of CT to enable use of CT numbers in 
the calculation. Alternatively, other methods as developed by the 
participating institution may be used. Lung density value estimates, 
based on methods adopted by treating institutions, may be incorporated 
into the dose calculation. The methodology used by each participating 
institution for lung dose determination will be evaluated as part of the 
benchmark approval process. 
 
14.10.2 Dose Uniformity and Treatment Site Coverage 
14.10.2.1 TBI Dose Uniformity and Treatment Site Coverage 
The TBI fields should be set up to cover the patient’s entire body without 
any part of the patient extending into the penumbra region. The dose 
difference between the prescription point and each reference point (see 
separate guidance for lung dose in Section 14.9.1) shall be within ± 10% 
of the prescribed dose. The calculated dose to the lung shall be in 
accordance with the lung dose requirements specified in Section 14.9. 
To limit overall total lung dose to ≤ 800 cGy, partial transmission lung 
blocks can be used. For AP/PA treatments the lung blocks may be placed 
in both AP and PA fields or alternatively in just the AP or PA field alone. 
 
14.10.2.2 Cranial Irradiation Dose Uniformity and Treatment Site Coverage 
The prescription point for the cranial treatment is at or near the center of 
the field. Regardless of the location of the central axis, the dose should 
be prescribed at the center of the cranial volume –midway between the 
points of maximum separation. The variations of dose within the 
treatment site shall be within +7%, -5% of the dose to the prescription 
point. 
 
14.10.2.3 Testicular Irradiation Dose Uniformity and Treatment Site Coverage 
The scrotum should be treated with en face electrons with the 
prescription depth covered by the 90% isodose. If electron beam is used 
for testicular irradiation, the prescription should include the beam 
energy and the dose coverage. Photon irradiation is allowed. 
 

 
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14.10.3 Tissue heterogeneity 
There shall be no required correction for tissue heterogeneity for the cranial and 
testicular treatment. 
 
14.10.4 Interruption of therapy 
Excluding weekends and holidays, supplemental cranial irradiation, testicular 
irradiation and fractionated TBI should be continuous. All efforts should be made 
not to have treatment delay or interruption. Once patients have begun testicular 
treatment, they should immediately proceed to TBI for transplantation. If 
interruptions occur, the radiation therapy coordinator should be notified. 
 
14.11 Quality Assurance Documentation and Review 
There are no on-treatment review or image submission requirements for this study. A post-
treatment review will be conducted by IROC RI.  
 
Within 1 week of the completion of radiotherapy, the following data shall be submitted for 
TBI and/or cranial and testicular irradiation: 
 
• 
TBI Summary Form for Total Body Irradiation. 
• 
Measured and/or calculated doses for the TBI reference points. 
• 
A copy of the radiotherapy record including the prescription, and daily and 
cumulative doses for all treated sites including TBI and supplemental sites (cranial, 
testicular). 
• 
The "RT-2 Radiotherapy Total Dose Record" forms must be completed for cranial 
and testicular irradiation. 
• 
If the treatment technique differs from an approved benchmark, a new benchmark 
must be completed and approved (see Section 14.1.1). 
 
Data should be sent by email to the IROC Rhode Island QA Center: 
datasubmission@qarc.org 
 
Questions regarding the dose calculations or documentation should be directed to the COG 
Protocol Dosimetrist at the IROC Rhode Island QA Center. 
Email: physics@qarc.org 
Phone: (401) 753-7600 
 
14.12 Definitions of Deviation in Protocol Performance 
14.12.1 TBI 
14.12.1.1 Deviations for prescription dose 
Deviations for TBI Dose 
Variation Acceptable: 
• 
The dose to the prescription point and to any of the reference 
points (except points C and D lung dose points) differs from the 
protocol specified dose by >10% or <15%. 
 

 
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Deviation Unacceptable: 
• 
The dose to the prescription point and to any of the reference 
points (except points C and D lung dose points) differs from the 
protocol specified dose by >15%. 
 
14.12.1.2 Deviations for TBI Dose Rate 
• 
A dose rate exceeding 15cGy/min will be considered as an 
unacceptable deviation. 
 
14.12.1.3 Deviations for Lung Dose 
• 
The dose to the lungs (reference points C and D) that is < 700 cGy 
or > 900 cGy will be considered an unacceptable deviation. 
 
14.12.2 Deviations for Cranial Irradiation Dose 
Variation Acceptable: 
• 
The dose to the prescription point differs from the protocol specified dose 
by > 6 but ≤ 10%. 
 
Deviation Unacceptable: 
• 
The dose to the prescription point differs from the protocol specified dose 
by >10%. 
 
14.12.3 Deviations for Testicular Irradiation Dose 
Variation Acceptable: 
• 
The dose to the prescription point differs from the protocol specified dose 
by > 6% but ≤ 10%. 
 
Deviation Unacceptable: 
• 
The dose to the prescription point differs from the protocol specified dose 
by > 10%. 
 
 

 
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APPENDIX I: SUPPORTIVE CARE 
NOTE: For blinatumomab-specific supportive care guidelines, please refer to Section 5.2. 
 
General Guidelines  
Aggressive supportive care improves outcome. The following guidelines are intended to give general 
direction for optimal patient care and to encourage uniformity in the treatment of this study population. 
Notify Study Chair of any unexpected or unusually severe complications. Please also see the COG 
Supportive Care Guidelines at: https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines. 
 
Blood Components  
Blood products should be irradiated following current FDA guidelines.  
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components.  
 
Red Blood Cells (RBC)  
Transfusion with RBC is indicated to correct severe or symptomatic anemia or acute blood loss. In the 
setting of extreme hyperleukocytosis investigators should be mindful that peripheral red blood cells (PRBC) 
may contribute to hyperviscosity.  
 
Platelets  
Transfusion with platelets is indicated to correct bleeding manifestations and may be indicated for severe 
thrombocytopenia without bleeding particularly prior to an invasive procedure.  
 
Special Guidelines During Induction (Block 1) 
Patients may experience profound myelosuppression and immune suppression during this time. Since 
steroids may mask fever as well as other components of the inflammatory response, sepsis during Induction 
may be associated with very mild and subtle symptoms. Caregivers must also be made aware that patients 
may experience very rapid clinical deterioration. This suggests the need for a supportive care network that 
can recognize and respond to sudden changes in a patient‘s condition. In addition it should be noted that 
serious toxic events may have an intestinal component. Patients with subtle GI symptoms should be 
monitored very closely. Taken together, the risks of significant morbidity and mortality, including sudden 
death in patients with relapsed leukemia, are sufficient to strongly recommend hospitalization during 
remission Induction, until patients show consistent neutrophil recovery and transfusion needs that are 
deemed to be manageable in the outpatient setting. 
 
Tumor Lysis Syndrome  
In this population with ALL, rapidly assess patients clinically and by appropriate laboratory parameters for 
evidence of symptomatic hyperleukocytosis, tumor lysis syndrome, and coagulopathy. Suggested studies 
to be obtained prior to initiating antileukemia therapy include complete blood count (CBC), prothrombin 
and activated partial thromboplastin times, fibrinogen, D-dimer, and serum electrolytes, including 
creatinine, BUN, uric acid, phosphorous, and calcium. Continued monitoring of these studies should be 
carried out at suitable intervals until abnormalities have resolved or the risk has abated. Begin allopurinol 
at a dose of 300 mg/m²/day or 10 mg/kg/day (maximum 800 mg/day) in 2-3 divided doses and continue 
until peripheral blasts and extramedullary disease are reduced. In some situations it may be appropriate to 
use rasburicase. Hydrate at 2,400 – 3,000 mL/m²/day (potassium should not be added to hydration fluids) 
to maintain urine output > 100 mL/m²/hour until peripheral blasts and extramedullary disease are reduced.  
 
 

 
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Infection Prophylaxis  
Patients undergoing transplantation for ALL on this protocol are at high risk for infection. This risk may be 
increased due to infections that occur during the intensive chemotherapy most patients will receive prior to 
stem cell transplant on this protocol. Centers should be especially mindful of this as they choose anti-
bacterial, anti-fungal, anti-viral, and PCP prophylactic regimens. Aside from well established screening 
approaches for CMV, centers may wish to consider routine screening for other viral pathogens such as 
Adenovirus or HHV-6. Any prophylaxis regimen chosen must be the same for patients on both arms of the 
protocol. Special considerations should be given for antifungal prophylaxis (see below). 
 
Supportive Care for Patients Age 15 Years and Older 
It is recommended that adolescent and young adult (AYA) patients enrolled on this protocol (defined as 
patients between the ages of 15 and 31 years) be monitored in the hospital during Block 1, Block 2 and 
Block 3 of chemotherapy until they show signs of bone marrow recovery (specifically evidence that the 
absolute neutrophil count (ANC) is rising for 2 successive days) and the patient is afebrile and clinically 
stable. If a patient should experience profound myelosuppression at any other time, there should also be a 
very low threshold to hospitalize AYA patients with inpatient management continued until there is evidence 
of bone marrow recovery. Antibiotic prophylaxis against Gram-positive and Gram-negative organisms (e.g. 
levofloxacin) may be considered during these hospitalizations until patients meet the criteria for discharge. 
If the patient should develop febrile neutropenia while on antibiotic prophylaxis, the patient should be 
started on broad-spectrum intravenous antibiotics per institutional guidelines. Antifungal prophylaxis may 
also be considered during periods of myelosuppression. Options include an echinocandin such as 
caspofungin or micafungin, or an azole. Azole antifungal agents (i.e., fluconazole, itraconazole, 
posaconazole, voriconazole) given concurrently with vincristine may increase the risk of neurotoxicity. 
Investigator caution is advised if azole antifungals are used. If antibiotic and/or antifungal prophylaxis is 
utilized, consultation with Infectious Disease may be considered. 
 
Pneumocystis jiroveci 
All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 2.5 mg/kg/dose 
(maximum dose 160 mg/dose) by mouth twice daily on 2 or 3 sequential days per week. For patients allergic 
to or experiencing excessive myelosuppression with TMP/SMX, alternative prophylaxis with dapsone 
(2 mg/kg/day by mouth, maximum dose 100 mg/day), aerosolized pentamidine (300 mg/q month ≥ 5 years 
of age), or atovaquone (4 - 24 month: 45 mg/kg/day; > 24 months: 30 mg/kg/day) by mouth may be 
considered. For children in whom TMP/SMX, dapsone, atovaquone, and inhaled pentamidine cannot be 
administered, IV pentamidine (4 mg/kg/dose IV every 2 to 4 weeks) should be given. (REF: Centers for 
Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic 
stem 
cell 
transplant 
recipients: 
a 
global 
perspective. 
(https://www.cdc.gov/mmwr/preview/
mmwrhtml/rr6002a1.htm)    
 
Varicella Vaccine  
May be given to the siblings of patients in remission and stable at the physician’s discretion. Varicella 
vaccination is not recommended for ALL patients during therapy.  
 
Gamma globulin  
If clinically indicated, IgG levels may be monitored throughout treatment. If the IgG level falls below age-
determined normal levels, IVIG at 400 mg/kg may be administered at the discretion of the investigator. 
Note of IVIG administration should be recorded on data form. 
 
Antifungals  
Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently with vincristine 
may increase the risk of neurotoxicity. Investigator caution is advised if azole antifungals are used. 

 
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Fluconazole and other azoles are expected to increase serum tacrolimus and sirolimus levels. Therefore, 
dosages of sirolimus and tacrolimus should be adjusted accordingly. Due to extreme interactions with 
sirolimus, voriconazole is contraindicated during sirolimus. Patients on voriconazole prior to transplant 
should have another drug substituted for voriconazole prior to starting sirolimus therapy. 
 
Hospitalization after High-Dose Cytarabine  
Empiric hospitalization after Day 8 of Induction 3 (intensively-timed Capizzi-II) until there is evidence of 
marrow recovery should be considered due to the risk of neutropenic sepsis; patients not hospitalized should 
be monitored very closely.  
 
Treatment of Established or Presumed Infections  
 
Fever with Neutropenia  
For patients with ANC < 500/μL or expected to fall to this level within the next 48 hours and an oral-
equivalent temperature ≥ 38.3°C once or between 38.0°C and 38.3°C twice within 12 hours, empiric broad 
spectrum antibiotics should be instituted after obtaining appropriate cultures. Patients who present with 
severe sepsis should have empiric antibiotic coverage widened to include resistant Gram-negative, Gram-
positive, and anaerobic bacteria. 
 
The risk of bacteremia and infectious mortality is higher during Induction and during profound neutropenia. 
For prolonged fever and neutropenia (≥ 96 hours), empiric antifungal therapy with either caspofungin or 
liposomal amphotericin B should be given during periods of anticipated prolonged neutropenia including 
induction. 
 
Also, please see the COG Fever and Neutropenia Guidelines at: 
https://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document_Dec_2017.pdf  
 
Use of filgrastim (G-CSF) 
Filgrastim may be used for severe infections with neutropenia, but routine use is discouraged.  
 
Filgrastim at a dose of 5 micrograms/kg/day given IV or subcutaneously is required for recipients of cord 
blood starting at Day +1 and continuing until patients are fully engrafted. Filgrastim is generally not 
necessary for BM/PBSC recipients and is not recommended, unless engraftment is delayed. 
 
Primary Varicella Infection (Chickenpox)  
Patients should be treated promptly with acyclovir 1500 mg/m²/day intravenously divided q8 hours, and 
monitored closely for the development of invasive systemic disease. 
 
Empiric Management of Pulmonary Infiltrates  
Pulmonary infiltrates should be evaluated with bronchoscopy and biopsy, lavage or open lung biopsy. If a 
procedure cannot be tolerated, begin empiric antifungal therapy given the high likelihood of fungal disease 
during Induction, Re-induction and periods of intensive chemotherapy (HDAraC). Empiric coverage should 
include treatment for gram-negative and positive bacteria, Legionella (erythromycin), Pneumocystis 
(TMP/SMX), and fungi (amphotericin) pending culture results. If fungal pulmonary disease is documented, 
surveillance radiographic imaging studies of the sinuses, abdomen/pelvis and brain are indicated. Surgical 
excision of pulmonary lesions should be considered at the discretion of the treating physician. Treatment 
of fungal infections with amphotericin B and/or other antifungal agents will be at the discretion of the 
treating physician. Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently 
with vincristine may increase the risk of neurotoxicity. Investigator caution is advised if azole antifungals 
are used.  

 
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Management of Mucositis/Perirectal Cellulitis  
Mucositis should be managed with IV hydration and hyperalimentation if indicated, effective analgesia, 
broad-spectrum gram-positive and gram-negative antibiotic therapy and empiric antiviral and antifungal 
therapy as indicated. Management of perirectal cellulitis should include broad-spectrum antibiotic therapy 
with dual gram-negative coverage as well as anaerobic coverage (i.e. ceftazidime + aminoglycoside + 
metronidazole; or piperacillin-tazobactam + aminoglycoside), Sitz baths, a strong barrier technique and 
effective analgesia. 
 
Prevention and Management of Chemotherapy-induced Nausea and Vomiting (CINV) 
Please refer to the COG Endorsed guidelines on prevention and management of CINV at: 
https://childrensoncologygroup.org/downloads/COG_SC_CINV_Guidelines_Document_Feb_2018.pdf  
 
The routine use of steroids including dexamethasone, as an antiemetic is discouraged but may be 
appropriate in select patients with demonstrated intolerance to higher-dose chemotherapeutic agents. 
 
Gastrointestinal (GI) Protection 
While patients are on steroid therapy, consider using an H2 receptor antagonist (e.g., ranitidine, 
famotidine). 
 
Constipation  
As vincristine may cause severe constipation, prophylactic stool softeners/laxatives (per investigator’s 
discretion) are recommended during all phases in which VCR is given.  
 
 
 

 
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APPENDIX II:  THERAPY DELIVERY MAPS 
 
APPENDIX II-A 
Block 1 (All patients) 
Block 1 therapy is common to all patients on study  
 
Patient COG ID number 
  
 
 
 
DOB  
Block 1 lasts 4 weeks (28 days). Please see Section 4.2 for treatment details. This therapy delivery map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal Methotrexate (IT MTX) 
IT 
Age (yrs) 
Dose 
1-1.99 
8 mg 
2-2.99 
10 mg 
3-8.99 
12 mg 
≥9 
15 mg 
1 
ALL PATIENTS 
 
 
Note age-based dosing 
a. Hx, PE [VS/Wt (BSA)] 
b. CBC/diff/platelets 
c. Local BM evaluation% 
d. BM for Immunophenotyping 
e. CSF cell count, cytospin1 
f. Bilirubin, ALT & creatinine, 
BUN 
g. Echocardiogram 
h. Pregnancy test 
i. Testicular Exam & Testicular 
biopsy, if indicated® 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for details.  
 
Optional studies 
j 
Banking for future research  
k 
Protein cell stress pathways  
l. 
CRLF2 expression 
m. BM sample for 
Blinatumomab PD  
 
 
See Section 7.2 for details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Intrathecal Methotrexate (IT MTX) 
 
 
IT 
Age (yrs) 
Dose 
1-1.99 
8 mg 
2-2.99 
10 mg 
3-8.99 
12 mg 
≥9 
15 mg 
8  
CNS1/2 ONLY 
 
*For CNS2: Continue weekly until 2 clear csf 
samples are obtained i.e. CNS1 
 
Note age-based dosing 
Intrathecal Triple Therapy (ITT): 
Methotrexate (MTX)/ 
Hydrocortisone (HC)/Cytarabine 
(ARAC) 
 
 
IT 
Age (yrs) 
Dose 
1-1.99 
MTX:8mg,  
 
HC: 8mg,  
 
ARAC: 16mg 
2-2.99 
MTX: 10mg 
 
HC: 10 mg 
 
ARAC: 20 mg 
3-8.99 
MTX: 12 mg 
 
HC: 12 mg 
 
ARAC: 24 mg 
≥9 
MTX: 15 mg 
 
HC: 15 mg 
 
ARAC: 30 mg 
8, 15, 22 
CNS3 ONLY 
 
 
Note age-based dosing 
MitoXANTRONE (MITOX) 
IV over 15-30 
minutes 
10 mg/m²/dose 
1, 2 
Administer through the tubing of a freely 
infusing solution of D5W or 0.9% NaCl 
Dexamethasone (DEX) 
PO 
10 mg/m²/dose BID 
1-5, 15-19 
Total Daily Dose 20 mg/m²/day divided BID 
Cap dose at 40 mg per day. 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
1.5 mg/m² 
1, 8, 15, 22 
+Or infusion via minibag as per institutional 
policy. Maximum dose: 2mg 
Pegaspargase (PEG-ASP) 
IV over 1-2 
hours 
2500 International 
units/m²/dose 
3, 17 
Administer through the tubing of a freely 
infusing solution of D5W or 0.9% NaCl 
 
 

 
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APPENDIX II-A 
Block 1 (All patients) 
Block 1 therapy is common to all patients on study  
 
Patient COG ID number 
  
 
 
 
DOB  
Ht _________cm  
Wt _________kg  
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
IT MTX 
ALL PATIENTS 
____mg 
IT MTX 
CNS1/2 ONLY* 
____mg 
ITT 
CNS3 ONLY 
____mg 
MITOX 
 
____mg 
DEX 
 
___mg 
VCR 
 
____mg 
PEG-ASP 
 
____IU 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
a, b, c% d-i, l$,j+ 
 
 
 
1 
_____mg 
 
 
____mg 
____mg 
 
 
 
 
____mg 
 
k¥ 
 
 
 
2 
 
 
 
____mg 
 
 
 
 
 
 
3 
 
 
 
 
 
____IU 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
8 
 
_____mg 
_____mg 
 
 
____mg 
 
b, e, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
15 
 
_____mg* 
_____mg 
 
____mg 
 
____mg 
 
b, e*, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
____IU 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
22 
 
_____mg* 
_____mg 
 
 
____mg 
 
b, e*, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
b, c, e^, f, i®,j+, m 
 
 
 
 
 
Begin next course based on Day 29 risk assignment and treatment randomization. IR/HR patients are not eligible for post-Induction treatment 
and will be removed from protocol therapy at the end of Induction. LR patients will be randomized to Arm C (control arm) or Arm D 
(experimental arm). All LR patients (Arm C and Arm D) receive Block 2 therapy (Section 4.3, APPENDIX II-B). Treatment failures post-
Block 1 with M3 marrow without residual CNS disease (CNS1) are eligible for treatment with at least 2 blocks of Salvage Therapy 
(Blinatumomab-S) (Section 4.7, APPENDIX II-F); treatment failures with residual CNS disease (CNS2/3), irrespective of marrow status will 
be off protocol therapy. See Section 4.3 for further details on time frame for end-Block 1 evaluations and criteria to fulfill prior to subsequent 
therapy. 
*For CNS2 patients, continue weekly until 2 clear CSF (CNS1) samples are obtained; can be a max of 4 (Days 1, 8, 15 and 22). If still unclear, patients 
are treatment failures and will be off protocol therapy regardless of marrow status.  
^ A diagnostic LP should be performed on Day 29 for CNS2 or CNS3 patients for whom clearance of CSF blasts has not yet been documented. 
®  Testicular biopsy is only done in the setting of persistent testicular enlargement. Patients with persistent testicular leukemia at the end of Block 1 who are 
deemed treatment failure (TF) will receive 2400 cGy of testicular radiation during Blinatumomab. 
$ No separate specimen needed-cell pellet from required central flow MRD assays will be used (see Section 13.4 for complete details). 
¥ PB before and after chemotherapy on Day 1 of Block 1 (see Section 13.6) for complete details). 
% BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse patients should include morphology, 
immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis must be performed at a COG approved cytogenetics lab and cases will be reviewed 
retrospectively 
+ Bone marrow: at Baseline and End Block 1. Peripheral blood: At Baseline and End Block 1. (See Section 13.1 for complete details) 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 

 
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APPENDIX II-B Block 2  
Block 2 therapy is for all LR patients post Block-1 (Arm C and Arm D)  
 
Patient COG ID number 
 
 
 
DOB  
Block 2 lasts 4 weeks (28 days). Block 2 should begin after receipt of risk assignment according to timing outlined in Section 4.2.7. All patients can proceed with Day 1 of Block 2 without awaiting 
count recovery (must be no later than 5 calendar days after callback). Patients with M1 marrow after Block 1 should await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to 
beginning Day 8 ID MTX; Patients with M2 marrow after Block 1 should not await recovery prior to beginning Day 8 ID MTX. All patients should await count recovery to ANC ≥ 500/µL and 
platelets ≥ 50,000/µL prior to beginning Day 15 cyclophosphamide and etoposide. Please see Section 4.3 for treatment details. This Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
3 mg/m²/dose BID 
1-5 
Total Daily Dose: 6 mg/m2/day, divided BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
Local BM evaluation 
d 
BM for MRD evaluation 
e 
CSF cell count, cytospin1 
f 
Bilirubin, ALT & creatinine, 
 
BUN 
g 
Testicular Exam 
 
Optional studies 
h 
Banking for future research 
i 
Bone Marrow for Blinatumomab 
PD (Arm D ONLY) 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for details.  
 
 
 
See Section 7.2 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
1.5 mg/m²/dose 
1 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Intrathecal Methotrexate (IT 
MTX) 
 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
8  
CNS 1/2 ONLY 
 
Note age-based dosing 
 
When IT therapy and ID MTX are scheduled for the same 
day, deliver the IT therapy within 6 hours of the beginning 
of the IV MTX infusion (hour -6 to +6, with 0 being the start 
of the MTX bolus). 
Intrathecal Triple Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
8, 22 
 
CNS3 ONLY. 
 
Note age-based dosing. 
 
 
Intermediate Dose 
Methotrexate (ID MTX) 
IV over 36 hours 
1000 mg/m²/dose 
8 
See Section 5.8 for admin guidelines. 
 
Leucovorin (LCV) 
PO/IV 
15 mg/m²/dose Q6H 
10, 11 
48 hours after the start of ID MTX infusion. See Section 5.8 
for admin guidelines 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International units/m²/dose 
9 or 10* 
*Administer 4 hours after completion of Day 8 IV MTX.  
Cyclophosphamide (CPM) 
IV over 15-30 mins. 
440 mg/m²/dose 
15-19 
 
Etoposide (ETOP) 
IV over 60-120 mins. 
100 mg/m²/dose 
15-19 
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during Block 2 therapy. See Section 14.2 for details of TRT. 
 
 

 
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APPENDIX II-B Block 2  
Block 2 therapy is for all LR patients post Block-1 (Arm C and Arm D)  
 
Patient COG ID number 
 
 
 
DOB  
 
Ht _________cm  
 
Wt _________kg  
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
DEX. 
 
____mg 
VCR 
 
____mg 
IT MTX 
CNS1/2 ONLY 
____mg 
ITT 
CNS3 ONLY 
______mg 
ID MTX 
 
___mg 
LCV 
 
___mg 
PEG-ASP 
 
___IU 
CPM 
 
___mg 
ETOP 
 
___mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
 
 
 
1 
____mg 
____mg 
 
 
 
 
 
 
 
a, b, f 
 
--- 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
8 
 
 
____mg 
____mg 
____mg^ 
 
 
 
 
b, e, f 
 
 
 
9 
 
 
 
 
 
 
____IU* 
 
 
 
 
 
 
10 
 
 
 
 
 
____mg 
 
 
 
 
 
 
 
11 
 
 
 
 
 
____mg 
 
 
 
 
 
--- 
 
 
15 
 
 
 
 
 
 
 
____mg& 
____mg& 
b, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
____mg 
 
 
 
 
 
b, e#, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
 
 
b,c,d,f,g,h+,i 
 
 
 
 
Following count recovery, LR patients randomized to Arm C receive Block 3 therapy (Section 4.4, APPENDIX II-C), and LR patients randomized to Arm D rece
Blinatumomab Block 1: Cycle 1 therapy (Section 4.15, APPENDIX II-M. 
^ All patients with M1 marrow are recommended to await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 8 ID MTX. Day 8 
treatment must begin no later than 14 calendar days after giving the Day 1 vincristine and dexamethasone to continue to receive protocol therapy. 
& Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 15 cyclophosphamide and etoposide. 
+ Peripheral blood: End Block 2 (See Section 13.1 for complete details) 
*Administer 4 hours after completion of Day 8 IV MTX. (Day 9 or 10) 
# CNS3 ONLY 
 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 
 

 
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APPENDIX II-C 
Block 3 
Block 3 therapy is for all LR patients randomized to the control arm (Arm C). 
 
Patient COG ID number 
 
DOB  
Block 3 lasts 4 weeks (28 days) and starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL. Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22 
ID MTX. See Section 4.4 for treatment details. This Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO (May be given IV) 
3 mg/m²/dose BID 
1-5 
Total Daily Dose: 6 mg/m2/day, divided BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
Local BM evaluation 
d 
BM for MRD evaluation 
e 
CSF cell count, cytospin1 
f 
Bilirubin, ALT & creatinine, 
 
BUN 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further details. 
 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m²/dose 
1 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Cytarabine (ARAC) 
IV over 3 hours 
3000 mg/m²/dose Q12H 
1, 2, 8, 9 
 
Asparaginase (Erwinia)  
IM or IV over 1 hour 
25, 000 International units/m²/dose 
2, 4, 9, 11, 23 
See Section 4.4 for administration guidelines.  
• On Days 2 and 9, Erwinia should be given 4 hours 
after last cytarabine infusions. 
• On Day 23, Erwinia is to be given 4 hours after the 
completion of the Day 22 MTX infusion. 
Intermediate Dose 
Methotrexate (ID MTX) 
IV over 36 hours 
1000 mg/m²/dose 
22 
See Section 5.8 for admin guidelines. 
 
 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose  
24, 25 
48 hours after the start of ID MTX infusion. See 
Section 5.8 for admin guidelines 
Intrathecal Methotrexate 
(IT MTX) 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
1 All Patients 
 
 
22 CNS 1/2 ONLY 
 
When IT therapy and ID MTX are scheduled for the 
same day, deliver the IT therapy within 6 hours of the 
beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Note age-based dosing 
Intrathecal Triple Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
22  
CNS3 ONLY 
 
When ITT therapy and ID MTX are scheduled for the 
same day, deliver the ITT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, 
with 0 being the start of the MTX bolus). 
 
Note age-based dosing 
 
 

 
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APPENDIX II-C 
Block 3 
Block 3 therapy is for all LR patients randomized to the control arm (Arm C). 
 
Patient COG ID number 
 
DOB  
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
Date Due 
Date 
Given 
Day 
DEX. 
 
____mg 
VCR 
 
____mg 
ASP 
ERWINIA 
____IU 
ID MTX 
 
___mg 
LCV 
 
____mg 
ARAC 
 
____mg   ____mg 
IT MTX 
All Patients 
______mg 
IT MTX 
CNS1/2 ONLY 
______mg 
ITT 
CNS3 ONLY 
______mg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
 
 
1 
____mg 
____mg 
 
 
 
____mg   ____mg 
____mg 
 
 
a, b, e, f 
 
 
 
2 
 
____IU 
 
 
____mg   ____mg 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
____IU 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
____mg   ____mg 
 
 
 
b, f 
 
 
 
9 
 
 
____IU 
 
 
____mg   ____mg 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
____IU 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
b, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
____mg^ 
 
 
 
____mg 
____mg 
b, e, f 
 
 
 
23 
 
 
____IU 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
____mg 
 
 
 
 
 
 
 
 
25 
 
 
 
 
____mg 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
 
 
b, (c, d)* f 
 
 
 
Following count recovery ANC ≥ 500/µL and platelets ≥ 50,000/µL. HR/IR Treatment Failures post-Block 3 have the option of receiving 2 blocks of Salvage Therapy –
Blinatumomab-S (Sections 4.7, 4.8, APPENDIX II-F, II-G). LR patients randomized to Arm C receive Continuation 1 therapy (Section 4.11, Appendix II-I). 
^ Await count recovery until ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22 ID MTX.  
*HR/IR Patients ONLY. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 
 
 

 
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APPENDIX II-D Blinatumomab Block - Cycle 1 (HR/IR Patients in Arm B ) 
This therapy is the 1st cycle of therapy with blinatumomab for the HR/IR patients assigned to the experimental arm (Arm B)  
 
Patient COG ID number 
 
DOB  
Blinatumomab Block-Cycle 1 lasts 5 weeks (35 Days). For patients with M1 marrow, treatment begins when ANC ≥ 500/µL and platelets ≥ 50,000/µL and must begin no later 
than 14 calendar days after risk assignment for patient to continue to receive protocol therapy. For patients with M2 marrow, treatment begins without awaiting count 
recovery, and must be no later than 5 calendar days after callback. See Section 4.5 for treatment details. This Therapy Delivery Map is on two (2) pages.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab (BLIN) 
 
Do not use 
commercial supply 
IV 
15 micrograms/m²/day  
1-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
BM (Local evaluation & 
 
MRD) 
d 
CSF cell count, cytospin1 
e 
Bilirubin, ALT & 
creatinine, BUN 
f 
Peripheral blood for PK 
g 
Peripheral blood for 
Immunogenicity 
 
Optional studies 
h 
Blinatumomab PD 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further 
details. 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
 
Dexamethasone 
(DEX) 
PO or IV 
5 mg/m2  (max 20 mg) 30 to 60 minutes 
prior to the start of the Blinatumomab 
infusion 
1 
Start prior to blinatumomab therapy 
Intrathecal 
Methotrexate (IT 
MTX) 
 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
15, 29 
CNS1/2 ONLY 
 
Note age-based dosing 
Intrathecal Triple 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
15, 29 
CNS3 ONLY 
 
 
Note age-based dosing 
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during Blinatumomab Block – Cycle 1. See 
Section 14.2 for details of TRT. 
 
 
 

 
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APPENDIX II-D Blinatumomab Block - Cycle 1 (HR/IR Patients in Arm B ) 
This therapy is the 1st cycle of therapy with blinatumomab for the HR/IR patients assigned to the experimental arm (Arm B)  
 
Patient COG ID number 
 
DOB  
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Date Due 
Date 
Given 
Day 
BLIN 
 
____mcg 
DEX 
 
____mg  
IT MTX 
CNS1/2 ONLY 
______mg 
ITT 
CNS3 ONLY 
______mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mcg 
____mg  
 
 
a*, b, e, h+,g$ 
 
 
 
2 
 
 
 
f&,h+ 
 
 
 
--- 
 
 
 
 
 
 
 
7 
 
 
 
h+ 
 
 
 
8 
 
 
 
b, e,  
 
 
 
--- 
 
 
 
 
 
 
 
14 
 
 
 
f&, h+ 
 
 
 
15 
 
____mg 
____mg 
b, d, e 
 
 
 
--- 
 
 
 
 
 
 
 
21 
 
 
 
h+ 
 
 
 
22 
 
 
 
b, e,  
 
 
 
--- 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29 
 
 
____mg 
____mg 
b, c, d, e 
 
 
 
30-35 
Rest Period 
 
 
 
 
Following count recovery, start next cycle, Blinatumomab Block Cycle 2 (Section 4.6, APPENDIX II-E). Treatment failures will be taken off 
protocol therapy. 
+Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete 
details). 
 
$ Prior to (Hour 0) first blinatumomab infusion (see Section 13.7 & lab manual for details)  
& See lab manual for collection and shipping details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 
 

 
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APPENDIX II-E Blinatumomab Block - Cycle 2 (HR/IR Patients in Arm B) 
This therapy is the 2nd cycle of therapy with blinatumomab for the HR/IR patients assigned to the experimental arm (Arm B) 
 
Patient COG ID number 
 
DOB  
Blinatumomab Block-Cycle 2 lasts 5 weeks (35 Days) and begins when ANC ≥ 500/µL and platelets ≥ 50,000/µL. See Section 4.6 for treatment details. This Therapy Delivery Map is on one (1) page.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab (BLIN) 
Do not use commercial 
supply 
IV 
15 micrograms/m²/day 
1-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
BM (Local evaluation & MRD) 
Intrathecal Methotrexate 
(IT MTX) 
 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
8, 29 
CNS1/2 ONLY 
 
Note age-based dosing 
d 
CSF cell count, cytospin1 
e 
Bilirubin, ALT & creatinine, BUN 
f 
Peripheral blood for 
 
Immunogenicity 
 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Intrathecal Triple 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
8, 29 
CNS3 ONLY 
 
 
Note age-based dosing 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
BLIN 
 
____mcg 
IT MTX 
CNS1/2 ONLY 
______mg 
ITT 
CNS3 ONLY 
______mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
1 
____mcg 
 
 
a*, b, e 
 
 
 
--- 
 
 
 
 
 
 
8 
____mg 
____mg 
b, d, e 
 
 
 
--- 
 
 
 
 
 
 
15 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
22 
 
 
b, e 
 
 
 
--- 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
____mg 
____mg 
b, c, d, e,f$ 
 
 
 
30-35 
Rest Period 
 
 
 
Following count recovery, patients will proceed to HSCT (Section 4.9). See Section 4.10, Appendix II-H for suggested bridging therapy in the event that 
HSCT is delayed. Treatment failures will be taken off protocol therapy. 
$ In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
 
& See lab manual for collection and shipping details 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 

 
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APPENDIX II-F Blinatumomab-S: Cycle 1 (Treatment Failure) 
This therapy is the 1st cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients 
classified as treatment failures who have not previously had blinatumomab on study. 
 
Patient COG ID number 
 
DOB  
Blinatumomab-S: Cycle 1 lasts 5 weeks (35 Days). See Section 4.7 for treatment details. This Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab 
(BLIN) 
Do not use 
commercial supply 
IV 
5 micrograms/m²/day  
15 micrograms/m²/day  
1-7 
8-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
CSF cell count, 
cytospin1 
d 
Bilirubin, ALT & 
creatinine, BUN 
e 
Local BM evaluation 
f 
BM for MRD- pre 
HSCT  
g 
Peripheral blood for PK 
h 
Peripheral blood for 
Immunogenicity 
 
Optional studies 
i 
Blinatumomab PD 
 
 
 
1 Obtain with each IT/ITT 
 
 
See Section 7.0 for further 
details. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
 
Dexamethasone 
(DEX) 
PO or IV 
5 mg/m2  (max 20 mg) 30 to 60 minutes prior to the 
start of the Blinatumomab infusion 
1, 8 
Start prior to blinatumomab 
therapy on Day 1 and prior to 
step dose on Day 8. 
Intrathecal 
Methotrexate (IT 
MTX) 
 
 
 
 
IT 
Age (yrs) 
Dose 
1-1.99  
8 mg 
2-2.99  
10 mg 
3-8.99  
12 mg 
≥9 
 
15 mg 
15 
 
Note age-based dosing 
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during the 1st cycle of Blinatumomab-S therapy. See Section 14.2 for 
details of TRT. 
 
 

 
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APPENDIX II-F Blinatumomab-S: Cycle 1 (Treatment Failure) 
This therapy is the 1st cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients 
classified as treatment failures who have not previously had blinatumomab on study. 
 
Patient COG ID number 
 
DOB  
 
Ht _________cm  
 
 
Wt _________kg  
 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
BLIN 
____mcg days 1-7 
____mcg days 8-28 
DEX 
 
____mg  
IT MTX 
 
______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mcg days 1-7 
____mg 
 
a*, b, d, i+,h$ 
 
 
 
2 
 
 
g& 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
i+ 
 
 
 
8 
____mcg days 8-28 
____mg 
 
b, d 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
14 
 
 
b, c, d, g&, i+ 
 
 
 
15 
 
____mg 
 
 
 
 
16 
 
 
 
 
 
 
21 
 
 
b, d, i+ 
 
 
 
22 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
b, d, e, f+++ 
 
 
 
30-35 
Rest Period 
 
 
 
 
See Section 4.7.6 for criteria for proceeding to HSCT (Section 4.9) or to Blinatumomab-S: Cycle 2 (Section 4.8, APPENDIX II-G)  
+ Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete 
details). 
$ Prior to (Hour 0) first blinatumomab infusion. In cases where blinatumomab treatment will not continue to Cycle 2, collect additional sample at end of Cycle 1. (see 
Section 13.7 and lab manual for details) 
& See lab manual for collection and shipping details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
+++ Pre-HSCT evaluation  
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  
 
 

 
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APPENDIX II-G Blinatumomab-S: Cycle 2 (Treatment failure) 
This therapy is the 2nd cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients 
classified as treatment failures who have not previously had blinatumomab on study. 
 
Patient COG ID number 
 
DOB  
Blinatumomab-S: Cycle 2 lasts 5 weeks (35 Days) and starts no earlier than Day 36 after the beginning of Blinatumomab-S: Cycle 1.. See Section 4.8 for treatment details. This 
Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab 
(BLIN) 
 
Do not use 
commercial supply 
IV 
15 micrograms/m²/day 
1-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
Local BM evaluation 
d 
CSF cell count, cytospin1 
e 
Bilirubin, ALT & creatinine,  BUN 
f 
BM for MRD- pre HSCT 
g 
Peripheral blood for 
 
Immunogenicity 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Intrathecal 
Methotrexate (IT 
MTX) 
 
 
IT 
Age (yrs) 
Dose 
1-1.99  
8 mg 
2-2.99  
10 mg 
3-8.99  
12 mg 
≥9 
 
15 mg 
8, 29 
 
Note age-based dosing 
 
 
 

 
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APPENDIX II-G Blinatumomab-S: Cycle 2 (Treatment failure) 
This therapy is the 2nd cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients 
classified as treatment failures who have not previously had blinatumomab on study. 
 
Patient COG ID number 
 
DOB  
 
Ht _________cm  
 
 
Wt _________kg  
 
 
BSA _________m2 
Date Due 
Date 
Given 
Day 
BLIN 
 
______mcg 
IT MTX 
______mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mcg 
 
a*, b, e 
 
 
 
--- 
 
 
 
 
 
8 
____mg 
b, d, e 
 
 
 
--- 
 
 
 
 
 
15 
 
b, e 
 
 
 
--- 
 
 
 
 
 
22 
 
b, e 
 
 
 
--- 
 
 
 
 
 
29 
 
____mg 
b, c, d, e,g$, 
f+++ 
 
 
 
30-35 
Rest Period 
 
 
 
 
 
 
See Section 4.8.5 for criteria for proceeding to HSCT (Section 4.9) or to Bridging Maintenance Therapy Section 4.10, Appendix II-H. 
Patients with M2/M3 marrow after Blinatumomab-S: Cycle 2 will be taken off protocol therapy. 
$ In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
+++ Pre-HSCT evaluation  
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  
 
 

 
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Appendix II-H Bridging Maintenance Therapy: Optional (HR/IR patients 
and TF patients that are eligible for HSCT) 
This therapy is only for HR/IR patients awaiting stem cell transplant therapy due to stem cell 
source or facility scheduling issues causing a lag time > 2 weeks after count recovery. Bridging 
therapy can be given for a maximum of 6 weeks, but does not need to be given the full 6 weeks if 
patient is ready for HSCT earlier. 
 
Patient COG ID number 
 
 
DOB  
This therapy lasts for a maximum of 6 weeks (42 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL. See Section 4.10 for treatment 
details. This therapy delivery map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m²/dose 
1, 22 
+ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
BM for MRD evaluation 
d 
BUN/creatinine 
e 
LFTs  
 
See Section 7.1c for Follow up 
observations.  
Mercaptopurine (MP) 
PO 
75 mg/m²/dose 
1-42 
 
Methotrexate (MTX) 
PO 
20 mg/m²/dose 
1, 8, 15, 22, 29, 36  
 
Ht _________cm  
 
 
Wt _________kg  
BSA _________m2 
Date Due 
Date Given 
Day 
VCR 
 
____mg 
MP 
 
___mg 
PO MTX 
 
______mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_____mg 
_____mg 
_____mg 
a, b, d,e 
 
 
 
--- 
 
 
 
 
 
 
8 
 
_____mg 
 
 
 
 
--- 
 
 
 
 
 
 
15 
 
_____mg 
 
 
 
 
--- 
 
 
 
 
 
 
22 
_____mg 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
29 
 
_____mg 
 
 
 
 
--- 
 
 
 
 
 
 
36 
 
_____mg 
 
 
 
 
--- 
 
 
 
 
 
 
42 
 
 
 
 
 
 
43 
 
c1 
 
1 Bone marrow for MRD evaluation must be repeated prior to the start of HSCT. 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  

 
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APPENDIX II-I Continuation1/2 (All LR patients) 
This therapy is for all LR patients and is the same for Continuation 1 and Continuation 2. 
 
Patient COG ID number 
 
 
DOB  
Continuation lasts 8 weeks and is given twice, for a total of 16 weeks. Begin when ANC ≥ 500/µL and platelets ≥ 50,000/µL. Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL 
prior to beginning Day 22 ID MTX. See Section 4.11 for treatment details. This therapy delivery map is for one cycle of Continuation and is on two (2) pages.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
3 mg/m²/dose BID 
1-5 
Total Daily Dose: 6 mg/m2/day, divided BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
CSF cell count, cytospin1 
d 
Bilirubin, ALT & 
creatinine, BUN 
 
 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further 
details 
 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m²/dose 
1 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Methotrexate (MTX) 
PO 
20 mg/m²/dose 
8, 15, 29, 36 
 
Intermediate Dose 
Methotrexate (ID MTX) 
IV over 36 hours 
1000 mg/m²/dose 
22 
CNS3 ONLY 
Methotrexate (MTX) 
PO 
25 mg/m²/dose Q6H x 4 doses 
22 
CNS1/2 ONLY  
 
Mercaptopurine (MP) 
PO 
75 mg/m²/dose daily 
1-42 
 
Leucovorin (LCV) 
IV/PO 
15 mg/m²/dose Q6H 
24, 25 
CNS3 ONLY Begin 48 hrs after the START of ID MTX 
infusion. 
Leucovorin (LCV) 
PO 
10 mg/m2/dose  Q6H x 2 
24 
CNS1/2  ONLY Begin 48 hrs after the START of day 22 
PO Methotrexate 
Cyclophosphamide (CPM) 
IV over 15-30 minutes 
300 mg/m²/dose 
43, 50 
See Section 4.11 and Appendix IV for administration 
guidelines. 
Etoposide (ETOP) 
IV over 60-120 minutes 
150 mg/m²/dose 
43, 50 
Thioguanine (TG) 
PO 
40 mg/m2/dose 
43-49 
Cytarabine (ARAC) 
IV over 1 – 30 minutes or SQ 
50 mg/m²/dose  
44-47, 51-54 
 
Intrathecal Methotrexate 
(IT MTX) 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
1, 43 
CNS1/2 ONLY 
 
Note age-based dosing 
Intrathecal Triple Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
1, 43  
CNS3 ONLY 
 
Note age-based dosing 
 

 
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APPENDIX II-I Continuation1/2 (All LR patients) 
This therapy is for all LR patients and is the same for Continuation 1 and Continuation 2. 
 
Patient COG ID number 
 
 
DOB  
Enter Cycle #: _____ 
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
DEX. 
 
 
___mg 
MP 
 
 
__mg 
VCR 
 
 
___mg 
PO 
MTX 
 
___mg 
PO MTX 
CNS1/2 
ONLY 
___mg 
ID MTX 
CNS3 
ONLY 
____mg 
LCV 
____mg 
ETOP 
 
 
___mg 
CPM 
 
 
___mg 
TG 
 
 
___mg 
ARAC 
 
 
___mg 
IT MTX 
CNS1/2 
ONLY 
___mg 
ITT 
CNS3 
ONLY 
___mg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
 
 
 
1 
___mg 
___mg 
__mg 
 
 
 
 
 
 
 
 
___mg 
___mg 
a, b, c,d 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
___mg 
 
 
 
 
 
 
 
 
 
b,d 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
___mg 
 
 
 
 
 
 
 
 
 
b,d 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22^ 
 
 
 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
 
 
 
 
 
b,d 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
____mg 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
____mg 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
___mg 
 
 
 
 
 
 
 
 
 
b,d 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
36 
 
 
___mg 
 
 
 
 
 
 
 
 
 
b,d 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
43^ 
 
 
 
 
 
 
 
___mg 
___mg 
___mg 
 
___mg 
___mg 
b, c,d 
 
 
 
44 
 
 
 
 
 
 
 
 
 
___mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
___mg 
___mg 
 
 
 
 
b, d 
 
 
 
51 
 
 
 
 
 
 
 
 
 
 
___mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
 
 
 
 
 
b,d 
 
Following Continuation 1, upon count recovery, LR patients randomized to Arm C will receive Continuation 2 therapy (Section 4.11, APPENDIX II-I), LR patients randomized to Arm D will receive 
Blinatumomab Block: Cycle 2 therapy (Section 4.16, APPENDIX II-N), 
Following Continuation 2, upon count recovery, LR patients randomized to Arm C will receive Maintenance Cycle 1 therapy (Section 4.12, Appendix II-J), LR patients randomized to Arm D will receive 
Blinatumomab Block: Cycle 3 therapy (Section 4.16, APPENDIX II-N), 
^ Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22 and Day 43 therapy. See Section 4.11 for details 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  

 
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Appendix II-J Maintenance Cycle 1 (All LR patients) 
This Maintenance therapy is for all LR patients (Arm C  and Arm D ) 
 
Patient COG ID number 
 
 
DOB  
Maintenance Cycle 1 lasts for 12 weeks (84 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL. See Section 4.12 for treatment details. This 
therapy delivery map is for Maintenance and is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
3 mg/m²/dose BID 
1-5, 29-33, & 57-61 
Total Daily Dose: 6 mg/m2/day, divided BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
CSF cell count, cytospin1 
d 
Bilirubin, ALT & creatinine, BUN 
e 
Absolute lymphocyte count with T and 
B subset quantification.2 
f 
Peripheral blood for Immunogenicity 
 
1 Obtain with each IT/ITT 
2 To be done at the end of each 12 week 
maintenance cycle and every 3 months after 
completion of therapy for 1 year. 
 
 
See Section 7.0 for further details. 
 
 
 
 
 
 
 
 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CAR 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
1.5 mg/m²/dose 
1, 29, 57 
+ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg 
Mercaptopurine (MP) 
PO 
75 mg/m²/dose daily 
1-84 
 
Methotrexate (MTX) 
PO 
20 mg/m²/dose weekly 
8, 15, 22, 29, 36, 43, 
50, 57, 64, 71, 78 
 
Intrathecal 
Methotrexate (IT MTX) 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
1 
CNS1/2 ONLY 
 
Note age-based dosing 
Intrathecal Triple 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
1 
CNS3 ONLY 
 
 
Note age-based dosing 
 
 
 

 
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Appendix II-J Maintenance Cycle 1 (All LR patients) 
This Maintenance therapy is for all LR patients (Arm C and Arm D) 
 
Patient COG ID number 
 
 
DOB  
Ht _________cm  
 
 
Wt _________kg  
BSA _________m2 
Date Due 
Date 
Given 
Day 
DEX. 
 
____mg 
VCR 
 
____mg 
MP 
 
___mg 
MTX 
 
______mg 
IT MTX 
CNS1/2 ONLY 
______mg 
ITT 
CNS3 ONLY ______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_____mg 
_____mg 
_____mg 
 
______mg 
______mg 
a, b, c, d,f$ 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
8 
 
 
______mg 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
15 
 
 
______mg 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
22 
 
 
______mg 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
29 
_____mg 
_____mg 
______mg 
 
 
a, b, d 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
36 
 
 
______mg 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
43 
 
 
______mg 
 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
50 
 
 
______mg 
 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
57 
_____mg 
_____mg 
______mg 
 
 
a, b, d 
 
 
 
58 
 
 
 
 
 
 
 
 
58 
 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
64 
 
 
______mg 
 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
71 
 
 
______mg 
 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
78 
 
 
______mg 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
a, b, d, e 
 
 
 
85 
Following Maintenance Cycle 1 therapy, CNS3 patients ONLY will receive CNS directed therapy with chemoradiation (Section 4.13, APPENDIX II-K). All other 
patients on Arm C and Arm D will continue with Maintenance Post-Cycle 1 therapy (Section 4.14, APPENDIX II-L) 
$ Arm D ONLY. Prior to start of Maintenance therapy for eligible patients (see Section 13.7 and lab manual for details) 
 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 

 
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APPENDIX II-K Maintenance Chemoradiation-CNS Directed Therapy (LR Patients) 
This therapy is for all CNS3 patients ONLY and is given between 1st and 2nd cycles of Maintenance 
therapy. 
 
 
Patient COG ID number 
 
DOB  
This CNS directed therapy lasts 3 weeks (21 days) and starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL (whichever occurs later). See Section 4.13 for treatment details. This Therapy 
Delivery Map is on one (1) page 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
5 mg/m²/dose BID 
1-7, 15-21 
Total Daily Dose: 10 mg/m2/day, divided 
BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
Bilirubin, ALT & creatinine, 
 
BUN 
 
 
 
See Section 7.0 for further details. 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m²/dose 
1, 8, 15 
+ Or infusion via minibag as per 
institutional policy 
 
Maximum dose: 2 mg 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International units/m²/dose 
1 
Administer through the tubing of a freely 
infusing solution of D5W or 0.9% NaCl 
Cranial Radiotherapy: Patients with CNS3 and isolated CNS relapse will receive cranial radiation during Maintenance, between Blocks 1 and 2. See 
Section 14.1 for details of cXRT. 
 
Enter Cycle #: _____ 
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
Date Due 
Date 
Given 
Day 
DEX. 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
________mg 
________mg 
_______IU 
a, b, c 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
________mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
15 
________mg 
________mg 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
Following chemoradiation, patients will receive Maintenance Post-Cycle 1 therapy (Section 4.14, APPENDIX II-L) when count parameters are met. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  

 
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APPENDIX II-L Maintenance Post Cycle 1 (All LR patients) 
This therapy is for all LR patients (Arm C  and Arm D ) 
 
Patient COG ID number 
 
 
DOB  
Maintenance Post Cycle 1 is given in 12 week cycles based on dose modifications for low counts and platelets. See Section 4.14 and Section 5.9 for details. This therapy delivery map is on two (2) 
pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
3 mg/m²/dose BID 
1-5, 29-33, & 57-61  
Total Daily Dose: 6 mg/m2/day, divided BID. 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
CSF cell count, cytospin1 
d 
Bilirubin, ALT & Creatinine, BUN 
e 
Absolute lymphocyte count with T 
and B subset quantification2 
 
1 Obtain with each IT/ITT 
2 To be done at the end of each 12 week 
maintenance cycle and every 3 months 
after completion of therapy for 1 year. 
 
See Section 7.0 for further details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m²/dose 
1, 29, 57  
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Methotrexate (MTX) 
PO 
20 mg/m²/dose  
1 
CNS3 ONLY 
Mercaptopurine (MP) 
PO 
75 mg/m²/dose daily 
1-84  
 
Methotrexate (MTX) 
PO 
20 mg/m²/dose weekly 
8, 15, 22, 29, 36, 43, 50, 
57, 64, 71, 78  
 
Intrathecal 
Methotrexate (IT MTX) 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
1  
CNS1/2 ONLY 
 
Note age-based dosing 
 
 

 
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APPENDIX II-L Maintenance Post Cycle 1 (All LR patients) 
This therapy is for all LR patients (Arm C  and Arm D)   
 
Patient COG ID number 
 
 
DOB  
Cycle # ____ 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Date Due 
Date 
Given 
Day 
DEX. 
 
____mg 
VCR 
 
____mg 
MTX (PO) 
CNS3 ONLY 
____mg 
MTX (PO) 
_____mg 
MP 
 
_____mg 
IT MTX 
CNS1/2 ONLY 
______mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
_____mg 
______mg 
 
_____mg 
______mg 
a, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
8 
 
 
 
______mg 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
29 
____mg 
_____mg 
 
______mg 
 
a, b, d 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
57 
____mg 
_____mg 
 
______mg 
 
a, b, d 
 
 
 
58 
 
 
 
 
 
 
 
 
59 
 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
 
----- 
 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
 
---- 
 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
a, b, d, e 
 
 
 
85 
Maintenance cycles are repeated in 12 week cycles based on dose modifications for low counts or low platelets until 2 yrs from start of Block 1 therapy for both 
male and female patients.  
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  
 

 
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APPENDIX II-M Blinatumomab Block - Cycle 1 (LR Patients in Arm D ) 
This therapy is the 1st cycle of therapy with blinatumomab for the LR patients randomized to Arm D 
 
Patient COG ID number 
 
DOB  
 
This cycle lasts 5 weeks (35 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL.. See Section 4.15 for treatment details. This Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab (BLIN) 
Do not use commercial 
supply 
IV 
15 micrograms/m²/day  
1-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
CSF cell count, cytospin1 
d 
Bilirubin, ALT & creatinine, BUN 
e 
Peripheral blood for PK 
f 
Peripheral blood for 
 
Immunogenicity 
 
Optional studies 
g 
Blinatumomab PD 
 
 
 
1 Obtain with each IT/ITT 
 
See Section 7.0 for further details. 
 
 
 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Dexamethasone (DEX) 
PO or IV 
 
5 mg/m2  (max 20 mg) 30 to 60 minutes prior 
to the start of the Blinatumomab infusion 
1 
Start prior to blinatumomab therapy 
Intrathecal Methotrexate 
(IT MTX) 
 
 
IT 
Age (yrs) Dose 
1-1.99 
 
8 mg 
2-2.99 
 
10 mg 
3-8.99 
 
12 mg 
≥9 
 
15 mg 
8, 29 
CNS1/2 ONLY 
 
Note age-based dosing 
Intrathecal Triple 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
 
 
 
IT 
Age (yrs)  
Dose 
1-1.99 
 
MTX:8mg,  
 
 
HC: 8mg,  
 
 
ARAC: 16mg 
2-2.99 
 
MTX: 10mg 
 
 
HC: 10 mg 
 
 
ARAC: 20 mg 
3-8.99 
 
MTX: 12 mg 
 
 
HC: 12 mg 
 
 
ARAC: 24 mg 
≥9 
 
MTX: 15 mg 
 
 
HC: 15 mg 
 
 
ARAC: 30 mg 
8, 29 
CNS3 ONLY 
 
 
Note age-based dosing 
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation. See Section 14.2 for details of TRT. 
 
 
 
 

 
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APPENDIX II-M Blinatumomab Block - Cycle 1 (LR Patients in Arm D ) 
This therapy is the 1st cycle of therapy with blinatumomab for the LR patients randomized to Arm D 
 
Patient COG ID number 
 
DOB  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date Due 
Date 
Given 
Day 
BLIN 
______mcg 
DEX 
______mg 
 
IT MTX CNS1/2 
ONLY 
______mg 
ITT CNS3 ONLY 
______mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mcg 
_____mg  
 
 
a*, b, d, g+,f$  
 
 
 
2 
 
 
 
e& g+ 
 
 
 
--- 
 
 
 
 
 
 
 
7 
 
 
 
g+ 
 
 
 
8 
 
____mg 
____mg 
b, c, d,  
 
 
 
--- 
 
 
 
 
 
 
 
14 
 
 
 
e& g+ 
 
 
 
15 
 
 
 
b, d 
 
 
 
--- 
 
 
 
 
 
 
 
21 
 
 
 
g+ 
 
 
 
22 
 
 
 
b, d 
 
 
 
--- 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29 
 
 
____mg 
____mg 
b, c, d 
 
 
 
30-35 
Rest Period 
 
 
 
36 
Following Blinatumomab Block: Cycle 1, patients receive Continuation 1 therapy (Section 4.11, APPENDIX II-I) when count parameters are 
met. 
+ Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete details). 
$ Prior to (Hour 0) first blinatumomab infusion (see Section 13.7 and lab manual for details) 
& See lab manual for details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines. 

 
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APPENDIX II-N 
Blinatumomab Block - Cycle 2 and 3 (LR Patients in Arm D) 
This therapy is Cycles 2 and 3 of therapy with blinatumomab for the LR patients randomized to Arm D 
 
Patient COG ID number 
 
DOB  
Blinatumomab Block: Cycles 2 & 3; each last 5 weeks (35 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50,000/µL. See Section 4.16 for treatment details. 
This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Blinatumomab (BLIN) 
Do not use commercial 
supply 
IV 
15 micrograms/m²/day  
1-28 
 
a 
Hx, PE [VS/Wt (BSA)] 
b 
CBC/diff/platelets 
c 
Bilirubin, ALT & creatinine, BUN 
d 
Peripheral blood for Immunogenicity 
 
 
See Section 7.0 for further details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
 
Enter Cycle #_________ 
 
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
BLIN 
 
____mcg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mcg 
a*, b, c 
 
 
 
--- 
 
 
 
 
8 
b, c 
 
 
 
--- 
 
 
 
 
15 
b, c 
 
 
 
--- 
 
 
 
 
22 
b, c 
 
 
 
--- 
 
 
 
 
28 
 
 
 
 
29 
 
b, c,d$ 
 
 
 
30-35 
Rest Period 
 
 
 
 
36 
Following Blinatumomab Block Cycle 2: LR B-ALL patients randomized to Arm D will receive Continuation 2 (Section 4.11, 
APPENDIX II-I) when count parameters are met. 
 
Following Blinatumomab Block Cycle 3: LR B-ALL patients randomized to Arm D will receive Maintenance Cycle 1 therapy- 
(Section 4.12, Appendix II-J) when count parameters are met. 
$Obtain at End Cycle 2. In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details 
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e 
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.  
 

 
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APPENDIX III:  MERCAPTOPURINE DOSING GUIDELINES 
MERCAPTOPURINE 75 mg/m2 
 
Note: The Mercaptopurine dosing nomograms in this appendix only apply to the tablet formulation. 
Body Surface Area (m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly Dose 
0.36 - 0.40 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.41 - 0.45 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.46 - 0.49 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.50 - 0.54 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.55 - 0.59 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.60 - 0.64 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.65 - 0.69 
1 tab / day 
350 mg/wk 
0.70 - 0.73 
1 tab / d x 6; 1½ tab / d x 1 
375 mg/wk 
0.74 - 0.78 
1 tab / d x 5; 1½ tab / d x 2 
400 mg/wk 
0.79 - 0.83 
1 tab / d x 4; 1½ tab / d x 3 
425 mg/wk 
0.84 - 0.88 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
0.89 - 0.92 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
0.93 - 0.97 
1½ tab / d x 6; 1 tab /d x 1 
500 mg/wk 
0.98 - 1.02 
1½ tab / day 
525 mg/wk 
1.03 - 1.07 
1½ tab / d x 6; 2 tab / d x 1 
550 mg/wk 
1.08 - 1.11 
1½ tab / d x 5; 2 tab / d x 2 
575 mg/wk 
1.12 - 1.16 
1½ tab / d x 4; 2 tab / d x 3 
600 mg/wk 
1.17 - 1.21 
2 tab / d x 4; 1½ tab / d x 3 
625 mg/wk 
1.22 - 1.26 
2 tab / d x 5; 1½ tab / d x 2 
650 mg/wk 
1.27 - 1.30 
2 tab / d x 6; 1½ tab / d x 1 
675 mg/wk 
1.31 - 1.35 
2 tab / day 
700 mg/wk 
1.36 - 1.40 
2 tab / d x 6; 2½ tab / d x 1 
725 mg/wk 
1.41 - 1.45 
2 tab / d x 5; 2½ tab / d x 2 
750 mg/wk 
1.46 – 1.49 
2 tab / d x 4; 2½ tab / d x 3 
775 mg/wk 
1.50 – 1.54 
2½ tab/ d x 4; 2 tab / d x 3 
800 mg/wk 
1.55 – 1.59 
2½ tab/ d x 5; 2 tab / d x 2 
825 mg/wk 
1.60 – 1.64 
2½ tab/ d x 6; 2 tab / d x 1 
850 mg/wk 
1.65 – 1.69 
2½ tab/ d 
875 mg/wk 
1.70 – 1.73 
2½ tab/ d x 6; 3 tab / d x 1 
900 mg/wk 
1.74 – 1.78 
2½ tab/ d x 5; 3 tab / d x 2 
925 mg/wk 
1.79 – 1.83 
2½ tab/ d x 4; 3 tab / d x 3 
950 mg/wk 
1.84 – 1.88 
3 tab/ d x 4; 2½ tab / d x 3 
975 mg/wk 
1.89 – 1.92 
3 tab/ d x 5; 2½ tab / d x 2 
1000 mg/wk 
1.93 – 1.97 
3 tab/ d x 6; 2½ tab / d x 1 
1025 mg/wk 
1.98 – 2.02 
3 tab/ d x 7 
1050 mg/wk 

 
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2.03 – 2.07 
3 tab/ d x 6; 3½ tab / d x 1 
1075 mg/wk 
2.08 – 2.11 
3 tab/ d x 5; 3½ tab / d x 2 
1100 mg/wk 
2.12 – 2.16 
3 tab/ d x 4; 3½ tab / d x 3 
1125 mg/wk 
2.17 – 2.21 
3½ tab/ d x 4; 3 tab / d x 3 
1150 mg/wk 
2.22 – 2.26 
3½ tab/ d x 5; 3 tab / d x 2 
1175 mg/wk 
2.27 – 2.30 
3½ tab/ d x 6; 3 tab / d x 1 
1200 mg/wk 
2.31 – 2.35 
3½ tab/ d x 7 
1225 mg/wk 
2.36 – 2.40 
3½ tab/ d x 6; 4 tab / d x 1 
1250 mg/wk 
2.41 – 2.45 
3½ tab/ d x 5; 4 tab / d x 2 
1275 mg/wk 
2.46 – 2.49 
3½ tab/ d x 4; 4 tab / d x 3 
1300 mg/wk 
2.50 – 2.54 
4 tab/ d x 4; 3½ tab / d x 3 
1325 mg/wk 
2.55 – 2.59 
4 tab/ d x 5; 3½ tab / d x 2 
1350 mg/wk 
2.60 – 2.64 
4 tab/ d x 6; 3½ tab / d x 1 
1375 mg/wk 
2.65 – 2.69 
4 tab/ d x 7 
1400 mg/wk 
2.70 – 2.73 
4 tab/ d x 6; 4½ tab / d x 1 
1425 mg/wk 
2.74 – 2.78 
4 tab/ d x 5; 4½ tab / d x 2 
1450 mg/wk 
2.79 – 2.83 
4 tab/ d x 4; 4½ tab / d x 3 
1475 mg/wk 
2.84 – 2.88 
4½ tab/ d x 4; 4 tab / d x 3 
1500 mg/wk 
2.89 – 2.92 
4½ tab/ d x 5; 4 tab / d x 2 
1525 mg/wk 
2.93 – 2.97 
4½ tab/ d x 6; 4 tab / d x 1 
1550 mg/wk 
2.98 – 3.00 
4½ tab/ d x 7 
1575 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated on actual BSA with no maximum 
dose. 
 
 
 

 
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APPENDIX IV:  THIOGUANINE DOSING GUIDELINES 
THIOGUANINE 40 mg/m2 
*Patients exceeding a BSA of 3 m2 should have their TG doses calculated on actual BSA with no maximum dose. 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 40 mg) 
Cumulative Weekly 
Dose 
0.27 – 0.3 
Use oral compounded suspension 
 
0.31 – 0.34 
Use oral compounded suspension 
 
0.35 – 0.38 
Use oral compounded suspension 
 
0.39 – 0.41 
Use oral compounded suspension 
 
0.42 – 0.45 
Use oral compounded suspension 
 
0.46 – 0.48 
Use oral compounded suspension 
 
0.49 – 0.54 
½ tab / d x 7 
140 mg/wk 
0.55 – 0.61 
½ tab / d x 6; 1 tab / d x 1 
160 mg/wk 
0.62 – 0.68 
½ tab / d x 5; 1 tab / d x 2 
180 mg/wk 
0.69 – 0.75 
½ tab / d x 4; 1 tab / d x 3 
200 mg/wk 
0.76 – 0.82 
 1 tab / d x 4; ½ tab / d x 3 
220 mg/wk 
0.83 – 0.89 
1 tab / d x 5; ½ tab / d x 2 
240 mg/wk 
0.9 – 0.96 
1 tab / d x 6; ½ tab / d x 1  
260 mg/wk 
0.97 – 1.04 
1 tab / d x 7 
280 mg/wk 
1.05 – 1.11 
1 tab / d x 6; 1½ tab / d x 1 
300 mg/wk 
1.12 – 1.18 
1 tab / d x 5; 1½ tab / d x 2 
320 mg/wk 
1.19 – 1.25 
1 tab/ d x 4; 1½ tab / d x 3 
340 mg/wk 
1.26 – 1.32 
1½ tab / d x 4; 1 tab / d x 3 
360 mg/wk 
1.33 – 1.39 
1½ tab / d x 5; 1 tab /d x 2 
380 mg/wk 
1.4 – 1.46 
1½ tab / d x 6; 1 tab / d x 1 
400 mg/wk 
1.47 – 1.54 
1½ tab /day 
420 mg/wk 
1.55 – 1.61 
1½ tab / d x 6; 2 tab / d x 1 
440 mg/wk 
1.62 – 1.68 
1½ tab / d x 5; 2 tab / d x 2 
460 mg/wk 
1.69 – 1.75 
1½ tab / d x 4; 2 tab / d x 3 
480 mg/wk 
1.76 – 1.82 
2 tab / d x 4; 1½ tab / d x 3 
500 mg/wk 
1.83 – 1.89  
2 tab / d x 5; 1½ tab / d x 2 
520 mg/wk 
1.9 – 1.96 
2 tab / d x 6; 1½ tab / d x 1 
540 mg/wk 
1.97 – 2.04 
2 tab / day 
560 mg/wk 
2.05 – 2.11 
2 tab / d x 6; 2½ tab / d x 1 
580 mg/wk 
2.12 – 2.18 
2 tab / d x 5; 2½ tab / d x 2 
600 mg/wk 
2.19 – 2.25 
2 tab / d x 4; 2½ tab / d x 3 
620 mg/wk 
2.26 – 2.32 
2½ tab / d x 4; 2 tab / d x 3 
640 mg/wk 
2.33 – 2.39 
2½ tab / d x 5; 2 tab / d x 2 
660 mg/wk 
2.4 – 2.46 
2½ tab / d x 6; 2 tab / d x 1 
680 mg/wk 
2.47 – 2.54 
2½ tab / d 
700 mg/wk 
2.55 – 2.61 
2½ tab / d x 6; 3 tab / d x 1 
720 mg/wk 
2.62 – 2.68 
2½ tab / d x 5; 3 tab / d x 2 
740 mg/wk 
2.69 – 2.75 
2½ tab / d x 4; 3 tab / d x 3 
760 mg/wk 
2.76 – 2.82 
3 tab / d x 4; 2½ tab / d x 3 
780 mg/wk 
2.83 – 2.89 
3 tab / d x 5; 2½ tab / d x 2 
800 mg/wk 
2.9 – 2.96 
3 tab / d x 6; 2½ tab / d x 1 
820 mg/wk 
2.97 – 3 
3 tab / d x 7 
840 mg/wk 
 

 
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APPENDIX V: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A trial to compare 2 ways to treat children with B-Lymphoblastic Leukemia (B-ALL) 
that has come back (relapsed) after the first treatment 
 
1. We have been talking with you about your illness, B-ALL. You have received treatment for this B-
ALL before. After doing tests, we have found that the cancer has come back in your bone marrow, 
brain or spinal cord, or testes. B-ALL that has come back after the first treatment is called relapse. 
 
2. We are asking you to take part in a research study because you have B-ALL that has relapsed. A 
research study is when doctors work together to try out new ways to help people who are sick. In this 
study we are trying to learn more about how to treat B-ALL when it has come back after the first time 
it was treated. During this study, we want to test whether the relapsed B-ALL responds better to 
combination chemotherapy or a new drug called blinatumomab. The treatment that you get will depend 
on a process called random assignment. Random assignment is a lot like flipping a coin and you will 
have an equal chance of getting both treatment options. 
 
3. Children and teens who are part of this study will be treated with either combination chemotherapy or 
a new drug called blinatumomab. It is possible that some children will get radiation to their brain or 
testes, depending on where the leukemia is found. Some children will also get a stem cell transplant. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is having the leukemia go 
away for as long as possible. But we don’t know for sure if there is any benefit of being part of this 
study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you might experience more side effects from 
the combination chemotherapy or blinatumomab. Another risk is that the therapy on this study might 
not be as effective as other options. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if there 
are ways to tell how the cancer will respond to treatment. These samples would be taken when other 
standard tests are being performed, so there would be no extra procedures. You can still be treated on 
this study even if you don't allow us to collect the extra blood samples for research. 
 
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A trial to compare 2 ways to treat children with B-Lymphoblastic Leukemia (B-ALL) 
that has come back (relapsed) after the first treatment 
 
1. We have been talking with you about your illness, B-ALL. You have received treatment for this B-
ALL before. After doing tests, we have found that the cancer has come back in your bone marrow, 
brain or spinal cord, or testes. B-ALL that has come back after the first treatment is called relapse. 
 
2. We are asking you to take part in a research study because you have B-ALL that has relapsed. A 
research study is when doctors work together to try out new ways to help people who are sick. In this 
study we are trying to learn more about how to treat B-ALL when it has come back after the first time 
it was treated. During this study, we want to test whether the relapsed B-ALL responds better to 
combination chemotherapy or a new drug called blinatumomab. The treatment that you get will depend 
on a process called random assignment. Random assignment is a lot like flipping a coin and you will 
have an equal chance of getting both treatment options. 
 
3. Children and teens who are part of this study will be treated with either combination chemotherapy or 
a new drug called blinatumomab. It is possible that some children will get radiation to their brain or 
testes, depending on where the leukemia is found. Some children will also get a stem cell transplant. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is having the leukemia go 
away for as long as possible. But we don’t know for sure if there is any benefit of being part of this 
study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you might experience more side effects from 
the combination chemotherapy or blinatumomab. Another risk is that the therapy on this study might 
not be as effective as other options. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if there 
are ways to tell how the cancer will respond to treatment. These samples would be taken when other 
standard tests are being performed, so there would be no extra procedures. You can still be treated on 
this study even if you don't allow us to collect the extra samples for research. 
 
 
 
 

 
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APPENDIX VI: ADDITIONAL INFORMATION FOR BANKING FOR FUTURE RESEARCH 
CORRELATIVE BIOLOGY STUDY 
 
a) Rationale 
The ability to collect leukemic and normal tissue samples for future research, and to link these samples to 
patient characteristics and outcomes, has been critical to recent seminal discoveries regarding the molecular 
basis of de novo ALL and relapsed ALL, and the relationship of  specific molecular lesions with outcomes 
and response to targeted therapies. In the context of this protocol, we will seek consent from participants to 
provide material for banking for the purpose of performing retrospective studies to refine risk stratification, 
identify new targets for therapy, identify biomarkers to predict response, and to link host polymorphisms 
with various disease characteristics and toxicities.  
 
b) Aims and methods 
These studies will be performed as stand-alone biology studies subject to review and approval in accordance 
with the NCTN policies. The following are general descriptions of the types of studies planned. 
 
• 
Leukemia genomic studies 
Modern genomic studies of high risk ALL have identified novel genetic alterations in ALL that are 
associated with treatment failure. In particular, high frequencies of mutations have been described in 
genes involved in B lymphocyte development (EBF1, IKZF1, PAX5) and signaling (BTLA, CD200, 
RAS) and in cell cycle regulation (CDKN2A/B, RB, TP53).67 Limited genomic analyses of paired 
diagnosis and relapse ALL samples have also shed light upon the early origin and clonal nature of such 
leukemia-associated mutations.68,69 Other yet-undiscovered mutations likely contribute the 
pathogenesis of this heterogeneous group of malignancies, and comprehensive prospective evaluation 
of the genetic landscape of relapsed ALL has not been performed. We hypothesize that integration of 
genomic profiling data will provide important insights regarding the molecular pathogenesis of relapsed 
ALL and may identify potential therapeutic targets or identify novel mechanisms of resistance within 
the context of the agents employed.70-72 
 
We hypothesize that high-throughput genome-wide profiling via multiple non-overlapping techniques 
provide a comprehensive genetic and epigenetic “fingerprint” and will identify key alterations that 
contribute to the pathogenesis and progression of relapsed ALL. We further hypothesize that integration 
of these approaches will allow discovery of alterations that may also be present in de novo ALL and 
could ultimately be used for initial risk stratification and new treatment approaches. 
 
Consenting patients will submit bone marrow and/or peripheral blood samples at study entry and, if 
applicable, at second relapse to the central COG Tissue Bank at Nationwide Children’s Hospital for 
storage of viably cryopreserved cells and for isolation nucleic acids, including DNA and RNA. Nucleic 
acids isolated from relapse specimens will be stored for potential use for genomic profiling, which will 
include single nucleotide polymorphism (SNP) arrays, array-based gene expression profiles and/or 
quantitative RT-PCR-based gene expression analyses, methylation arrays, and/or comprehensive 
sequencing approaches (e.g., RNA-seq, whole exome sequencing), depending on currently available 
technologies and funding sources. Banked specimens subsequently will be distributed from the 
reference laboratories to the laboratories performing the individual correlative biology studies. Results 
from these correlative biology studies may ultimately facilitate (a) enhanced refinement of risk 
stratification for patients with relapsed ALL, (b) detection of previously-unsuspected subset specificity 
of blinatumomab, and (c) generation of additional hypotheses with respect to the underlying biology of 
relapsed ALL. 
 

 
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• 
Host polymorphism studies 
There is substantial evidence that both inherited germline constitutional and somatically-acquired ALL-
specific genomic variation may contribute to variations in response.73-82 Blood samples obtained during 
remission are requested specifically for the purpose of providing constitutional (germline) DNA from 
each patient. Several efforts are anticipated for study of how genomic variation (SNPs, copy number 
variations, DNA methylation and insertions/deletions) in the constitutional DNA may be associated 
with phenotypes in ALL. The phenotypes could include those related to probability of cure, response, 
adverse events or classification. Techniques for interrogation of DNA variation are constantly evolving, 
and thus these techniques vary but may include candidate polymorphism testing (eg, via Taqman, 
GoldenGate, or PCR/RFLP assays), candidate gene sequencing (eg, via next-generation technologies 
coupled with exon capture) or whole-genome sequencing (eg, via next-generation technologies, with 
or without capture). 
 
• 
MRD by next generation sequencing (NGS) 
Next-generation sequencing (NGS) offers the potential for highly sensitive and standardized detection 
of minimal residual disease (MRD) in ALL. In comparison to current PCR methods, NGS assays do 
not require the laborious generation and validation of patient-specific primers, resulting in improved 
turn-around time and reduced cost, and may provide improved specificity by direct enumeration of 
leukemia-derived sequences. Current flow cytometric methods for MRD detection rely on relatively 
subjective assessments by trained interpreters and are about 1 log less sensitive than PCR-based 
methods. To determine the suitability of NGS methods for routine MRD assessment in a clinical trial 
setting, we will sequence the variable regions of IGH in pretreatment and post-treatment samples. Both 
the presence and the frequency of the MRD clone relative to the total IGH repertoire will be noted. 
 
 
 
 

 
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APPENDIX VII-A: CLINICAL SITE MANAGEMENT OF OUT-PATIENT TREATMENT 
USING CTEP-SUPPLIED BLINATUMOMAB 
 
• 
PREPARED IV INFUSION BAGS MAY NOT BE CHANGED BY THE STUDY SUBJECT 
• 
PREPARED INFUSION BAGS OR INTACT VIALS MUST NOT BE TRANSPORTED TO 
ANOTHER LOCATION BY THE STUDY SUBJECT 
 
AGENT PREPARATION AND ADMINISTRATION OPTIONS 
 
• 
Prepare all out-patient infusion bags at the registering/treating NCTN Network institution. Study 
subjects should return to the registering/treating institution for all infusion bag changes. 
 
• 
For study subjects that cannot return to the registering/treating institution for infusion bag 
exchanges, the next preference would be for another NCTN Network institution that is 
participating on the trial and is closer to the subject’s home take over responsibility for the 
study subject’s protocol participation. In such cases, transfer of the subject’s protocol registration 
to another participating investigator and institution should be considered.  
 
• 
If transferring the subject’s protocol registration to another participating investigator and trial site 
within the NCTN Network is not feasible, use of a local outpatient infusion center could be 
considered.  
 
a. First preference would be for all infusion bags to be prepared by the registering/treating 
institution and shipped via overnight courier delivery service in a 2o to 8oC pre-qualified 
shipping container to the local out-patient infusion center.  
 
b. The prepared infusion bags are stored at the local outpatient infusion center. The infusion 
center would perform each infusion bag change.   
 
c. If the local outpatient infusion center will not administer prepared infusion bags admixed 
by the registering/treating institution, the registering/treating institution may provide intact 
vials of blinatumomab to the local outpatient infusion center, with infusion bags prepared 
and administered by the local outpatient infusion center staff.   
 
d. In either case, the local outpatient infusion center would be managed as a satellite pharmacy 
of the registering/treating institution (see evaluation criteria below). 
 
e. If physical transport of intact vials of blinatumomab from the registering/treating institution 
to the local infusion center by registering/treating institution or local infusion center staff 
is not possible, CTEP will allow shipment of the vials from the registering/treating 
institution to the local infusion center via overnight courier delivery service in a 2o to 8oC 
pre-qualified shipping container.  
 
• 
If an outpatient infusion center is not an option, use of a home health care service provider can be 
considered.  
 
Note: If a home health care agency is being considered to prepare and change the blinatumomab 
infusion bag, the drug company that provides blinatumomab will cover the costs associated with 
a home health care agency providing these services.  
 

 
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a. The first preference would be for all outpatient infusion bags to be prepared by the 
registering/treating institution and shipped via overnight courier delivery service in a 2o to 
8oC pre-qualified shipping container to the servicing home health care agency.  
 
b. The prepared infusion bags are stored by the home health care agency and each individual 
infusion bag transported to the subject’s home by the home health care service nursing staff 
under refrigerated storage conditions for each infusion bag change. 
 
c. If home health care agency will not administer prepared infusion bags admixed by the 
registering/treating institution, the registering/treating institution may provide intact vials 
of blinatumomab to the home health care agency, with infusion bags prepared and 
administered by the home health care agency staff.   
 
d. In either case, the home health care agency would be managed as a satellite pharmacy of 
the registering/treating institution (see evaluation criteria below).  
 
e. If physical transport of intact vials of blinatumomab from the registering/treating institution 
to the home health care agency by registering/treating institution or home health care 
agency staff is not possible, CTEP will allow shipment of the vials from the 
registering/treating institution to the home health care agency via overnight courier 
delivery service in a 2o to 8oC pre-qualified shipping container.  
 
5. If all options above are not feasible, shipping the prepared infusion bags directly to patient’s 
home via overnight courier delivery service for administration by home healthcare agency staff 
is acceptable. 
 
a. The prepared infusion bags are to be shipped in a 2o to 8oC pre-qualified shipping container 
containing one infusion bag per box. Example 1, if you are making 2 x 48 hour infusion 
bags, each infusion bag will be shipped in a separate 2o to 8oC pre-qualified shipping 
container. Example 2, if you are making a 2 x 96 hour infusion bags, each infusion bag will 
be shipped in a separate 2o to 8oC pre-qualified shipping container. The infusion of the 2nd 
96 hour bag must be completed within 8 days (192 hrs) of preparation to avoid exceeding 
the expiration date. The number of infusion bags that may be prepared and shipped is 
dependent on the duration the shipping container used is qualified to maintain 2o to 8oC 
temperature. 
 
b. Patients should NOT open the shipping container upon arrival. Shipping containers are to 
be stored in a secured area away from reach of children or pets. 
 
c. Shipping containers must only be opened by the home health care service staff at the time 
of the infusion bag change. Only one shipping container should be opened at a time. If 
cold-chain management of the prepared infusion bag has been interrupted by opening of 
the shipping container or storage of the prepared infusion bag in the shipping container 
exceeds the duration of the qualified time the container will maintain 2o to 8oC temperature, 
the infusion bag should not be used.  
 

 
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The home health care service staff should immediately contact the registering/treating institution 
site pharmacy as indicated on the shipment form. Within 1 business day, the registering/treating 
institution site should send an email to the COG Industry Sponsored Trials office at 
istprogram@childrensoncologygroup.org 
with 
a 
copy 
to 
PMB/CTEP 
at 
PMBafterhours@mail.nih.gov to report all such occurrences of prepared, unusable infusion bags 
shipped to a patient’s home. 
 
d. Form documenting the time of packaging in the shipping container, duration of time the 
container will maintain 2o to 8oC temperature and verification that cold-chain management 
was maintained prior to administration must be included in each shipping container and 
returned to registering/treating institution for documentation purposes. (See Appendix VII-
B) 
 
e. Home health care service staff is to use GCP guidelines. 
 
EVALUATION OF POTENTIAL SATELLITE PHARMACY SITES 
 
When the registering/treating institution is considering use of a local infusion center or home health care 
agency as a satellite pharmacy, the following must be assessed by the registering/treating institution in 
relation to the suitability of the local infusion center or home health care agency: 
 
• 
Ability to appropriately store (temperature and security) the intact agent vials and/or prepared 
infusion bags. 
• 
Ability to provide documentation of controlled and monitored temperature storage conditions while 
the IND agent is in the local infusion center or home health care agency possession. 
• 
Availability of appropriately trained staff to prepare doses in compliance with USP <797> 
guidelines and the protocol, to label infusion bags according to the protocol instructions and to 
store agent doses under appropriate controlled temperature conditions.  
• 
For home health care agency services, the ability to transport each prepared dose individually to 
the subject’s home under appropriate controlled storage conditions or the ability to assess and 
confirm that cold-chain management of prepared infusion bags shipped to the subject’s home is 
maintained prior to administration. 
• 
Availability of appropriately trained staff to administer the prepared doses and perform the infusion 
bag changes according to the protocol. 
• 
Methods for proper disposal of the waste, empty vials, IV bags, etc. are in place. 
• 
Plan for return of unused intact vials to the registering/treating institution is in place. 
• 
Source documentation to confirm agent administration must be maintained by the local infusion 
center or home health care agency and must be provided to the registering/treating institution for 
incorporation into the patient’s medical/research records and for audit purposes. 
• 
Plan for handling missed doses is in place. 
• 
Agent accountability must be maintained via use of the NCI Drug Accountability Record Form 
(DARF).  The originating site must keep a Control DARF and the local infusion center or home 
health care agency would be required to maintain a Satellite DARF if receiving and storing supplies 
of intact vials or receiving and storing infusion bags prepared by the registering/treating institution. 
Maintenance of a Satellite DARF is not required by home health care agency staff for prepared 
infusions bags shipped to the subject’s home. 
• 
The DARF must be provided to the registering/treating institution for record keeping purposes and 
audits. 

 
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• 
Documentation of IRB coverage for the protocol must be maintained. The IRB of record for the 
site must be informed that the study subject may receive therapy administered by a non-research 
site (i.e., the local infusion center or home health care agency). 
 
TRAINING FOR ALL PARTICIPATING SITES 
 
The Lead Network Group for the trial must work with participating sites to: 
 
a. Implement a training process for participating NCTN Network sites regarding blinatumomab 
preparation and administration. Documentation of participating site training must be submitted 
via RSS as a protocol specific requirement at the time of site activation for participation on the 
trial. 
 
b. Develop a plan for participating NCTN Network sites to assess and train local outpatient 
infusion centers or home health care agency for patient treatment if required and document 
training of such sites. 
 
c. Have a training manual available for local outpatient infusion centers or home health care 
agencies on the clinical trial, appropriate agent preparation, handling and administration 
requirements and appropriate record keeping requirements. 
 
d. Create a definitive written communication plan for use between registering/treating institution 
and the local outpatient infusion centers or home health care agency on an ongoing basis during 
subject’s 
treatment 
regimen, 
including 
emergency 
contact 
information 
for 
the 
registering/treating institution and investigator. 
 
 
 
 

 
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APPENDIX VII-B: SHIPMENT OF BLINATUMOMAB IV BAG FROM SITE/PHARMACY TO 
PATIENT’S HOME 
To be completed by Site/Pharmacy: 
 
From: (Investigator Name, Address) 
To Patient: (Patient Initials, Study ID No) 
_________________ ;  ____________________ 
Patient Initials             Study ID Number 
Protocol No.: 
 
Prepare shipment of IV bag at 2°C to 8°C in validated/pre-qualified insulated shipper as per manufacturer 
instructions (see shipping container instructions). Please take care to use the applicable instructions for 
summer or winter package preparation, respectively. 
 
Date of packaging 
[DD/MMM/YYYY] 
Time of packaging 
[hh:mm] 
packed by 
(initials) 
 
Please tick the boxes and fill in the information below when preparing the IV bag shipment! 
 
□ Validated/pre-qualified shipping container duration of time 2°C to 8°C  temperature is 
maintained: ___________________________ hours 
□ Cooling elements for provided box used according to manufacturer’s instruction 
 
 
 
Confirmed by:   
 
(print name, signature) 
(date) 
 
 
 
To be completed by Ambulant/Home Care Service Provider: 
 
Shipment box unopened and content intact? 
YES 
 
NO 
 
 
IF NO, please comment_ 
 
 
 
 
 
Date and time shipment box opened:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      (date) 
 
 
 
(time) 
Confirmed by:   
 
(print name, signature) Amb. Care Service 
(date) 
 
Note: 
If content is not intact, please do not use IV bag and inform site immediately! 
If time box opened minus time of packaging exceeds the time duration the shipping 
container maintains 2°C to 8°C, please do not use IV bag and inform site 
immediately! 
 
 
CONFIDENTIAL 

 
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APPENDIX VIII: ADDITIONAL INFORMATION FOR MRD CORRELATIVE BIOLOGY 
STUDY 
 
a) Rationale 
Minimal residual disease is known to be a powerful prognostic factor in childhood ALL.1-5,12,20-22 Although 
the majority of work has been done in newly diagnosed ALL patients, several studies using both polymerase 
chain reaction methods13,14,16-18 and flow cytometry19,23 have shown that MRD is highly predictive of second 
marrow relapse.  
 
Flow cytometric MRD results will be used for the following purposes in this study:  
• 
For late B-ALL marrow and late B-ALL IEM patients, we will use end-Block 1 flow cytometric MRD 
levels of < 0.1% vs. ≥ 0.1% to define low risk group vs. intermediate risk group, respectively. The low 
risk group will be eligible for LR randomization. The intermediate risk group will be eligible for HR/IR 
Randomization. 
• 
For the LR patients participating in LR randomization, we will use end-Block 2 MRD levels of < 0.01% 
vs. ≥ 0.01% as a randomization stratification criteria to ensure balanced randomization. 
• 
For the IR and HR patients participating in HR/IR Randomization, we will use end-Block 1 MRD levels 
of <0.1% vs. ≥ 0.1% as a randomization stratification criteria to ensure balanced randomization. 
• 
For HR/IR Randomization patients proceeding to HSCT, we will use the end-Block 3/pre-HSCT MRD 
level, the peri-engraftment MRD level and the day +100 MRD level to determine eligibility for rapid 
tapering of immunosuppression.  
• 
In HR/IR Randomization, we will use flow cytometric MRD+ rates at the end of Blocks 2 and 3 as a 
secondary efficacy objective. 
 
Amendment #10 incorporates the High Risk/Intermediate Risk randomization closure. Effective 
September 18, 2019, accrual and randomization on the HR/IR arms closed. At completion of Block 1, if 
patient is found to be HR/IR the patient comes off protocol therapy.  
 
b) Technique 
Aliquots of fresh bone marrow specimens at study entry and during therapy at various designated time 
points (see study schema and TDMs) will be adjusted to suitable cell concentrations and stained with the 
following combinations of monoclonal antibodies in 6-color immunofluorescence: 
 
Tube 1: CD20-FITC/CD10-PE/CD38-PerCP-Cy5.5/CD58-APC/CD19-PE-Cy7/CD45-APC-Cy7 
Tube 2: CD9-FITC/CD13-PE+CD33-PE/CD34-PerCP-Cy5.5/CD10-APC/CD19-PE-Cy7/CD45-APC-
Cy7 
 
After incubation, samples will be lysed with ammonium chloride, fixed with 0.25% ultra pure 
formaldehyde, and washed once before analysis.  Samples will be run on a Becton Dickinson FACSCanto. 
A minimum of 750,000 events will be collected, and data will be analyzed by software developed by Dr. 
Brent Wood, University of Washington that facilitates the hierarchical gating strategy useful for identifying 
phenotypically aberrant cells. In cases in which the above panels are not informative for detecting abnormal 
cells, additional markers including but not limited to CD15 and TdT will be added to the panel to help 
identify MRD populations. In addition, if the administration of blinatumomab creates difficulties in 
identifying leukemic cells by virtue of CD19 expression, cytoplasmic CD79a and/or CD22 will be used to 
aid gating. 
 
 

 
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APPENDIX IX: ADDITIONAL INFORMATION FOR CRLF2 CORRELATIVE BIOLOGY 
STUDY 
a) Rationale 
Recent genomic studies of ALL have identified genomic alterations of CRLF2, which encodes the thymic 
lymphopoietin receptor (TSLPR) and which results in upregulation of CRLF2 as an important contributor 
to leukemic pathogenesis.3-5,7 Upregulation may occur by gene alterations, most often fusing CRLF2 to 
either P2RY8 or IGH@, as well as rarely, a CRLF2 point mutation (F232C),3-5,7 though there may also be 
as yet unrecognized mechanisms. In addition, patients with whose blasts show upregulated CRLF2 typically 
also have simultaneous activating mutations in kinase genes including IKZF1, JAK1 and JAK2, and as a 
result have abnormalities in signal transduction networks.3,4,7 Our results suggested high risk children with 
overexpressed CRLF2 as detected by PCR have very poor outcome irrespective of whether structural 
rearrangements can be identified,8 while other studies have suggested that this is only true of patients with 
P2RY8-CRLF2 translocations.2,9 Moreover, in our studies CRLF2 did not appear to be prognostically 
significant in standard risk patients.8 However, virtually nothing is known about CRLF2 overexpression in 
the relapse setting, and whether its expression has continued prognostic significance in this already poor-
risk group of patients. In addition, because of the underlying kinase abnormalities in this patient population, 
these patients are potentially ideal candidates for treatment with novel signal transduction inhibitors. 
Assessing CRLF2 expression may help to identify patients who might be candidates for specific therapy in 
trials that may be developed as these agents mature.  
 
b) Technique 
In conjunction with the immunophenotyping performed at study entry as a baseline for flow cytometric 
MRD testing, we will also quantify surface TSLPR expression and correlate with outcome. 
 
c) Specific Aims 
Aims:  
1) 
To determine if the frequency of high CRLF2 expression (which correlates with CRLF2 
genomic lesions) is higher in the first marrow relapse B-ALL patient population than in the 
initial diagnosis B-ALL patient population. 
 
2) 
To determine if first marrow relapse B-ALL patients with high CRLF2 expression have an 
inferior outcome to those without high CRLF2 expression. 
 
d) Power calculations 
Aim 1: Comparison of the frequency of CRLF2 expression among B-ALL patients in first marrow 
relapse to that in newly diagnosed B-ALL patients. 
 
From past COG studies for newly diagnosed B-ALL, it is estimated that 10% of standard risk (SR) and 
21% of high risk (HR) patients will relapse. Assuming there are 2/3 SR and 1/3 HR newly diagnosed 
patients, it is estimated that around 49% and 51% of patients in first relapse will be NCI SR and HR, 
respectively. Given that about 7% and 12% of the SR and HR patients have high level CRLF2 expression 
via flow cytometery, the overall rate of high CRLF2 expression (which correlates with genomic lesions) 
in newly diagnosed B-ALL patients is about 10%.  
 
The following table provides the power to detect a difference in rates of high CRLF2 expression between 
newly diagnosed and 1st relapse B-ALL patients when the rate of high CRLF2 expression of the 1st 
relapse patients is 13%, 15%, 18% and 20%  (i.e. RR=1.3, 1.5, 1.8 and 2.0), respectively. The power 
calculations are based on a one-sample exact test at 5% significance levels (one-sided).  A total of 426 
B-ALL marrow relapse ALL patients [180 early (CR1<36 months) and 246 late (CR1 ≥36 months)] 
were considered in this power calculation. 

 
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Significance 
Level 
Rate of high CRLF2 expression in relapse B-ALL 
pts  
(baseline rate = 10% among newly diagnosed pts) 
Power (%) 
5% 
13% 
60.0 
 
15% 
92.4 
 
18% 
99.9 
 
20% 
100.0 
 
Aim 2: Comparison of EFS in first marrow relapse B-ALL patients with high level CRLF2 expression 
vs. those without high level CRLF2 expression. 
 
It is anticipated that a total of 180 early (CR1<36 months) and 246 late (CR1 ≥36 months) marrow B-
ALL patients will be enrolled to AALL1331. According to past studies, the 3-year EFS of early and late 
marrow relapse patients are approximately 26% and 65%, respectively, giving an overall 3-year EFS of 
about 48%. Assuming the above rates of high-level CRLF2 expression and minimum 2 years of follow-
up, the table gives powers for comparing EFS between patient groups with and without high level 
CRLF2 expression. The power calculations are based on the one-sided log-rank test at the 5% 
significance level. 
 
Significance 
Level 
CRLF2 high rate for 
1st relapsed pre-B 
pts 
Sample Size 
3-year EFS rates 
Power 
CRLF2
+ 
CRLF2- 
CRLF2+ 
CRLF2- 
0.05 
0.13 
55 
371 
0.18 
0.52 
100.0 
 
0.13 
55 
371 
0.20 
0.52 
99.9 
 
0.13 
55 
371 
0.23 
0.52 
99.8 
 
0.13 
55 
371 
0.26 
0.51 
99.0 
 
0.13 
55 
371 
0.30 
0.51 
96.3 
 
0.13 
55 
371 
0.33 
0.50 
88.8 
 
0.13 
55 
371 
0.36 
0.50 
77.7 
 
0.13 
55 
371 
0.39 
0.49 
55.1 
 
0.15 
64 
362 
0.18 
0.53 
100.0 
 
0.15 
64 
362 
0.20 
0.53 
100.0 
 
0.15 
64 
362 
0.23 
0.52 
99.9 
 
0.15 
64 
362 
0.26 
0.52 
99.6 
 
0.15 
64 
362 
0.30 
0.51 
97.5 
 
0.15 
64 
362 
0.33 
0.51 
93.5 
 
0.15 
64 
362 
0.36 
0.50 
81.2 
 
0.15 
64 
362 
0.39 
0.50 
65.0 
 
0.18 
77 
349 
0.18 
0.55 
100.0 
 
0.18 
77 
349 
0.20 
0.54 
100.0 
 
0.18 
77 
349 
0.23 
0.53 
100.0 
 
0.18 
77 
349 
0.26 
0.53 
99.9 
 
0.18 
77 
349 
0.30 
0.52 
99.1 
 
0.18 
77 
349 
0.33 
0.51 
95.7 
 
0.18 
77 
349 
0.36 
0.51 
88.8 

 
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0.18 
77 
349 
0.39 
0.50 
69.6 
 
0.20 
85 
341 
0.18 
0.56 
100.0 
 
0.20 
85 
341 
0.20 
0.55 
100.0 
 
0.20 
85 
341 
0.23 
0.54 
100.0 
 
0.20 
85 
341 
0.26 
0.54 
100.0 
 
0.20 
85 
341 
0.30 
0.53 
99.6 
 
0.20 
85 
341 
0.33 
0.52 
97.8 
 
0.20 
85 
341 
0.36 
0.51 
90.6 
 
0.20 
85 
341 
0.39 
0.50 
72.1 
 
 
 

 
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APPENDIX X: ADDITIONAL INFORMATION FOR BLINATUMOMAB 
PHARMACODYNAMICS CORRELATIVE BIOLOGY STUDY 
 
a) Rationale 
For patients with relapsed/refractory ALL, response patterns to blinatumomab are essentially binary. Some 
patients have a striking response, with a systemic cytokine release syndrome (CRS, most notably IL-6) 
accompanying clearance of leukemic blasts and culminating in an MRD-negative remission, and others do 
not respond.10,11,83 For patients that have received blinatumomab in the setting of MRD positivity (i.e., with 
very low tumor burden), response rates are generally higher and significantly less likely to be associated 
with CRS.4,5 Attempts to correlate responses with various peripheral blood parameters (such as ALC and 
T-cell subset quantitation) have been largely unsuccessful in either setting, although the patient numbers 
have been limited.3 
  
The bone marrow microenvironment contains various immunologic components that have been shown to 
either enhance or suppress cytotoxic T-cell effector response to tumor antigens. The bone marrow serves 
as a reservoir of memory T-cells with heightened antigen specificity compared to peripheral blood memory 
T-cells, and the bone marrow microenvironment is capable of effectively priming naïve T-cell responses.84-
86 However, the bone marrow is also a reservoir for suppressive regulatory CD4/CD25/FOXP3+ T-cells (T 
regs).87 Comparative studies of bone marrow vs. peripheral blood in patients with myeloma have shown 
that marrow-infiltrating lymphocytes (MILs) are more effectively activated and expanded and are more 
capable of tumor-specific cytotoxicity than peripheral blood lymphocytes (PBLs).88 In addition, bone 
marrow contains myeloid-derived suppressor cells (MDSCs) that have been shown to preferentially capture 
and present tumor associated antigens to T regs, resulting in tumor tolerance, and preventing the capture 
and presentation of these antigens by dendritic cells to activate tumor-specific cytotoxic effector T-cells.89 
IL-6 is among the key mediators that skews the marrow T-cell repertoire from T regs to cytotoxic effector 
T-cells.90 
 
As has been suggested by previous studies, lymphocyte populations and cytokine profiles in the peripheral 
blood may also provide insight into responses3 and adverse effects11. Since our study will include more 
patients than any blinatumomab trial to date, our study may be particularly well-suited to detect these 
associations. 
 
b) Hypotheses and specific aims 
The overall objective of this correlative study is to generate new knowledge regarding the mechanisms that 
determine the observed heterogeneity of clinical responses to blinatumomab in relapsed ALL, for which 
there are currently no biomarkers. While this study is preliminary and will not by itself establish biomarkers 
of blinatumomab response, it may identify putative biomarkers that can then be evaluated for validation in 
future studies. 
We hypothesize that the balance of enhancing vs. suppressive components of the cytotoxic T-cell effector 
response in the bone marrow microenvironment  (which we will directly measure using flow cytometry and 
single-cell RNA sequencing, and infer functionally using ex-vivo response assays) may be playing a 
particularly important role in determining the presence or absence of clinical response to blinatumomab. 
Specifically, we hypothesize that the bone marrow of patients that respond to blinatumomab (i.e., achieve 
complete continuous remission after treatment with blinatumomab) will be characterized by a relative 
predominance of cytotoxic memory/effector T-cells over T regs and MDSCs, , and ex-vivo induction of 
apoptosis and cytokine production, while the opposite pattern will be characteristic of the bone marrow of 
non-responders (i.e., those that relapse after treatment with blinatumomab).  
 

 
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• 
Specific Aim 1: To determine if the balance of enhancing vs. suppressive components of the 
cytotoxic T-cell effector response in the bone marrow microenvironment at baseline correlates with 
disease free survival (DFS) in relapsed ALL patients treated with blinatumomab. 
 
We further hypothesize that lymphocyte populations and cytokine profiles in the peripheral blood at 
baseline and at post-treatment time points (hours 6 and 12 on day 1, and once on days 2, 7, 14 and 21) may 
also provide insight into adverse effects and clinical response, and so we will collect peripheral blood for 
flow cytometric characterization of lymphocyte subsets (including T-cell subsets as above, as well as 
circulating normal B-cells) and isolate plasma for multiplex cytokine profiling (including IL-6, IL-2R, IL-
8, IL-10, MCP-1, MIP-1B, and INF-γ). 
 
• 
Specific aim 2: To determine if peripheral blood patterns of lymphocyte subsets and cytokines, 
both at baseline and at post-treatment time points, correlates with incidence of blinatumomab-
related reportable adverse events (see Section 5.2), and DFS in relapsed ALL patients treated with 
blinatumomab. 
 
c) Methods 
• 
Processing, cryopreservation and quality control 
 
Refer to Section 13.5 for specimen collection and shipment. All blood and marrow samples will first 
be centrifuged to allow isolation of plasma. Plasma will be stored in 250 uL aliquots and stored at -80 
C for subsequent batched assays. Cell pellets will be diluted in HBSS and centrifuged over Lymphocyte 
Separation Medium (LSM) to isolate mononuclear cells, then suspended in cryoprotectant solution and 
viably cryopreserved in liquid nitrogen in aliquots of 10e6 cells for subsequent batched assays. Assays 
will be performed as cohorts of five patients have provided a complete set of samples.  
 
The Brown laboratory routinely processes blood and marrow specimens from cooperative group 
clinical trials and performs a wide variety of assays using plasma and viably cryopreserved cells. 
Samples are generally received in the laboratory within 48 hours of collection and processed 
immediately. Plasma and cells are sufficiently stable in transport under these conditions for the 
proposed assays. The flow cytometric assays are routinely performed in the Pardoll laboratory, which 
is collaborating on this project and has provided the processing protocol described above. 
 
• 
Multiparameter flow cytometric measurement of lymphocyte subsets and MDSCs  
 
Vials of viably cryopreserved marrow and blood cells will be thawed and washed and viable cells 
counted by trypan blue exclusion. Cells will then be stained with isotype controls and the following 
antibody panels, and analyzed in triplicate by flow cytometry 
o For lymphocyte subsets: CD3, CD4, CD8, CD19, CD20, CD45RO, CD45RA, HLADR, CD27, 
CD62L, CD25, CD28 and CD127. 
o For MDSCs (marrow only): Lin, HLA-DR, CD33, CD11b, CD14, CD15 
 
The endpoint for this assay will be the relative percentage and absolute number (in cells/uL) and of 
each of the following: 
o T regs 
o Naïve T-cells 
o Memory T-cells (central vs. effector) 
o Activated T-cells 
o B-cells 
o Monocytic MDSC (marrow only) 
o Granulocytic MDSC (marrow only) 

 
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• 
Cytokine profiling in marrow and blood plasma 
 
Vials of frozen plasma will be thawed and a panel of cytokines will be quantitated in triplicate using a 
custom cytometric bead array kit (custom BD CBA) designed to measure the following: IL-6, IL-2R, 
IL-8, IL-10, MCP-1, MIP-1B, and INF-γ. Isotype controls will serve as negative controls, and standard 
curves will be generated using control cytokine solutions. 
 
The endpoint for this assay will be levels of each cytokine in pg/mL. 
 
• 
Single cell RNA-seq 
 
We will use the 10X Genomics scRNASeq platform, which allows mRNA expression profiling of up 
to ~12,000 individual cells per sample, as an unbiased approach to decompose the cellular 
composition of the BM microenvironment. 
 
The endpoint for this assay will be the relative percentage of each of the following: 
o T regs 
o Naïve T-cells 
o Memory T-cells (central vs. effector) 
o Activated T-cells 
o B-cells 
o Monocytic MDSC (marrow only) 
o Granulocytic MDSC (marrow only) 
 
• 
Functional ex vivo cytotoxic response assays to mimic in vivo response 
 
We will co-incubate: 
o Thawed cryopreserved patient BM samples, initially enriched for mononuclear cells by 
centrifugation over lymphocyte separation medium (with healthy donor BM, available 
through institutional banking protocols, as control); 
o Human B-ALL CD19+ cell lines (REH, NALM6) as leukemia stimulation (with CD19- 
AML cellline HL60 as control); and 
o Blinatumomab (AMG 103) (with control BiTE MEC14 as control)  
 
Co-culture for up to 24 hrs to allow for optimal T-cell activation and blinatumomab-mediated B-ALL 
killing. Harvest cells and measure cytotoxic effect of blinatumomab on the leukemia cell line using 
Annexin V staining in conjunction with CD19 staining to isolate B-ALL cells. The endpoint for this 
assay will be proportion of apoptotic (Annexin V positive) B-ALL cells (relative to normal controls). 
 
Also, harvest cell culture supernatant to measure soluble cytokine protein expression using bead-
based custom assays as above. The endpoint for this assay will be levels of each cytokine in pg/mL 
(relative to negative controls). 
 
• 
Dynamic T-cell clonal repertoire (ImmunoSEQ) 
 
Genomic DNA will be isolated from a small amount of each PB sample. We will send DNA for 
sequencing using the ImmunoSeq platform developed by Adaptive Biotechnologies, which uses 
genomic DNA to generate an absolute count of every TcR sequence present. 
 
 

 
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• 
Rationale for selection of methods and laboratories 
 
The methods described above are performed routinely in the Brown laboratory, and are likely to 
optimize the chances that the proposed studies will be successful. 
 
d) Analysis and Statistical Considerations 
 
• 
Specific Aim 1: 
 
For the flow and scRNASeq assays, we will calculate ratio (R) of enhancing to suppressive components 
in bone marrow microenvironment for each patient as follows: 
 
R = (# Memory T-cells + # Activated T-cells)/(# T regs + # MDSC) 
 
For the ex-vivo assays, we will calculate an apoptosis index (AI) as follows: 
 
AI = (% apoptosis with blina)/(% apoptosis with control BiTE) 
 
We will use logistic regression to model outcome (no relapse vs. relapse) as a function of R. The 
Benjamin-Hochberg procedure will be used to control for multiple comparisons. 
 
The anticipated result is that R and AI are negatively correlated with risk of relapse (i.e., a higher ratio 
of enhancing to suppressive components, and higher ex-vivo apoptosis induction, will reduce risk of 
relapse). If this anticipated result is seen, multivariate analysis that includes known associations with 
relapse (duration of first remission, MRD, etc.) will be performed to determine whether the marrow 
microenvironment ratio adds anything independent to known predictors of relapse in blinatumomab-
treated patients. 
 
This analysis will be performed on the entire cohort of patients treated with blinatumomab, and also 
separately on the HR/IR cohort and on the LR cohort. 
 
We anticipate that a total of 156 evaluable patients will be treated with blinatumomab on this study 
(Section 9.2), of which 72 will be HR/IR and 84 will be LR. We assume that we will have 90% 
compliance with submission of the marrow sample. We assume that about 10% of submitted samples 
will fail analysis for technical reasons. Thus, we expect that our sample size for R will be 127 (59 HR/IR 
and 68 LR).  
 
Since we are proposing to use standard assays (flow cytometric and scRNASeq quantification of 
marrow cell subsets, and ex-vivo apopotosis) in a novel way (calculation of enhancing vs. suppressive 
components), we do not have a priori knowledge of the expected range of observed ratios. As such, 
these studies are exploratory and definitive power calculations are not possible. However, if we assume 
the log(R) and log(AI) follows a Gaussian distribution with a mean of 0 and standard deviation of 1 
(i.e., a standard normal distribution), and assuming an overall relapse rate of 50% for the trial, a sample 
size of 127 will have 80% power to detect an effect size of 0.5, using a 2-sided significance level of 
0.05. For example, if we assume patients who eventually relapse have a mean R/AI of 1 (log(R/AI) = 
0), then we would be able to detect that patients who do not eventually relapse have a mean R/AI of 
>3.16 (log(R/AI) = 0.5) or a mean R/AI of < 0.316 (log(R/AI) = - 0.5). This effect size is not 
unreasonable to expect. These calculations are based on methods from Hsieh, et al. Statist. Med. 17, 
1623-1634 (1998). 
 

 
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The relationships between the ratios and rates of relapse will be described, and subsequent studies will 
be designed to validate these findings prospectively in the context of future clinical trials.  
 
• 
Specific Aim 2: 
 
There are 12 variables to be determined for each blood sample (7 samples per patient): 
1) Total T-cell number 
2) CD4 count 
3) CD8 count 
4) Memory T-cell count 
5) Activated T-cell count 
6-12) Level of each of 7 individual cytokines 
 
For each of the 12 variables, we will determine the baseline value (BV; hour 0) and the maximal change 
value (MCV; value at the post-treatment timepoint for which the variable has increased or decreased to 
the greatest degree). For the MCV, a landmark approach will be used in which all cases are followed 
for  21 days, and the maximal change observed up to that point will be used to predict outcome from 
that point forward for all patients who are still observable up to that landmark time point. 
 
There are 2 outcomes of interest: 
1) Presence or absence of blinatumomab-related reportable adverse event 
2) No relapse vs. relapse 
 
As a first level analysis, we will use logistic regression to model each of the 2 outcomes as a function 
of each of the 12 variable’s BV, and each of the 12 variable’s MCV. The Benjamin-Hochberg procedure 
will be used to control for multiple comparisons. 
 
The anticipated results are: 
 
1) BV of some subsets of T-cell counts (memory T-cells, e.g.) are positively correlated with the risk 
of blinatumomab-related reportable adverse events, and negatively correlated with risk of relapse. 
2) MCV of a subset of cytokines (IL-6 and INF-γ, e.g.) is positively correlated with the risk of 
blinatumomab-related reportable adverse events, and negatively correlated with risk of relapse. 
 
Subsequent levels of analysis will attempt to characterize combinations of T-cell subset counts and 
cytokine levels that may perform better than individual variables in modeling the outcomes of interest. 
 
If any of the anticipated results are seen with respect to the relapse outcomes, multivariate analysis that 
includes known associations with relapse (duration of first remission, MRD, etc.) will be performed to 
determine whether any of the T-cell subset/cytokine variables adds anything independent to known 
predictors of relapse in blinatumomab-treated patients. 
 
This analysis will be performed on the entire cohort of patients treated with blinatumomab, and also 
separately on the HR/IR cohort and on the LR cohort. 
 
We anticipate that a total of 156 evaluable patients will be treated with blinatumomab on this study 
(Section 9.2), of which 72 will be HR/IR and 84 will be LR. We assume that we will have at least 
90% compliance with submission of the blood samples, and that about 10% of submitted samples will 
fail analysis for technical reasons. Thus, we expect that our sample size will be 127 (59 HR/IR and 68 
LR).  
 

 
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Since we are proposing to use standard assays (flow cytometric quantification of blood T-cell subsets 
and cytokines) in a novel way (combining variables to model risks of adverse events and relapse after 
treatment with blinatumomab), we do not have a priori knowledge of the expected ranges of values for 
most variables. As such, these studies are exploratory and definitive power calculations are not possible.  
 
However, some estimates based on specific assumptions are possible. If we assume that the baseline 
value for memory T-cell count for the entire study population follows a Gaussian distribution with a 
mean of 500/uL and a standard deviation of 100/uL, and we assume an overall relapse rate of 50% for 
the trial, a sample size of 127 will have 80% power to detect an effect size of 50/uL, using a 2-sided 
significance level of 0.05. For example, if we assume patients who eventually relapse have a mean BV 
memory T-cell count of 500, then we would be able to detect that patients who do not eventually relapse 
have a mean BV T-cell count of > 550/uL, or a mean BV T-cell count of < 450/uL. This effect size is 
not unreasonable to expect. These calculations are based on methods from Hsieh, et al. Statist. Med. 
17, 1623-1634 (1998). 
 
The relationships between the variable(s) and rates of adverse events/relapse will be described, and 
subsequent studies will be designed to validate these finding prospectively in the context of future 
clinical trials.  
 
For the ImmunoSEQ experiments, we will assay n=72 samples (pre- vs. day 14, n=36 patients, n=18 
relapse, n=18 no relapse). We hypothesize that “no relapse” samples will selectively demonstrate 
oligoclonal expansion of specific TcR clones. We will analyze patterns of T-cell clonal repertoire at 
baseline and changes after therapy, and look for associations of identified patterns and relapse/no 
relapse outcome. For significant associations, baseline/post-treatment patterns will be assessed for 
diagnostic value (e.g., correlation of baseline TcR repertoire with response) to be subsequently tested 
as a predictive biomarker of response. These assays will be descriptive and hypothesis-generating. 

 
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APPENDIX XI: ADDITIONAL INFORMATION FOR PROTEIN CELL STRESS PATHWAYS 
CORRELATIVE BIOLOGY STUDY 
 
a) Rationale 
Many excellent studies have focused on gene expression profiles in ALL.51,52 However, changes in 
protein cell stress pathways and deregulated signal transduction pathways, have been much less well 
studied in ALL. There is an unmet need to learn more about chemotherapy-induced proteins expression 
changes in order to determine if specific proteins or protein clusters can help predict response to 
therapy.  Specific protein expression patterns are likely to correlate with disease-free survival (DFS) 
and will enable us to identify specific populations at risk for relapse.  Since it is very difficult to salvage 
patients after second relapse, one of the goals of this study is to determine which patients classified as 
low risk based on timing and site of relapse (Section 9.2) would benefit from being risk stratified instead 
into the high risk group. This would improve DFS in all patients with relapsed ALL. Relevant protein 
expression profiles will be validated in future COG trial for patients with relapsed ALL and (if the 
increase in correct risk assignment increases to meets statistical specifications) will be used, in 
conjunction with molecular classification systems, as an adjunct for risk assignment.  
 
b) Hypotheses and specific aims   
We hypothesize that activation of cell stress pathways and signal transduction pathways deregulated 
in ALL will correlate with DFS, and that the expression of specific proteins or proteins clusters will 
identify patients classified as low risk patients that would benefit from more intensive therapy.  We 
have two specific aims to address these hypotheses: 
1. To determine if specific protein expression profiles, as determined by reverse-phase protein lysate 
array (RPPA) and phosphoflow cytometry, correlate with clinical outcome (DFS) 
2. To determine if alterations in specific groups of cell stress proteins can be used to generate a “high-
risk” protein expression signature that identifies patients stratified to the low-risk group (based on 
time and site of relapse) that would benefit from stratification into the high-risk group.   
 
c) The contributions that the proposed study will make to the current knowledge base 
Little is known about the changes in cell stress proteins during chemotherapy. This analysis will 
contribute greatly to our current knowledge base by 1) determining if specific proteins or protein 
clusters correlate with response therapy, 2) increasing our knowledge about lymphoblast response to 
standard relapse chemotherapy, 3) allowing a better understanding of the biology-defined ALL 
subgroups, aiding the development of targeted therapies, and 4) allowing for the development of protein 
expression risk-classifiers that could be validated and utilized, along with gene expression profiling, to 
aid in risk stratification in subsequent relapsed clinical trials. 
 
d) Relevant preclinical data 
1. RPPA The Kornblau lab has analyzed two cohorts of adult AML using RPPA. The first, with 539 
samples from 258 patients, was probed with 51 antibodies. the second, with 747 samples from 539 
patients, was probed with 194 antibodies 91,92 These samples demonstrated that there were recurrent 
patterns of protein expression that correlated with outcome. Recent studies have shown that the 
analysis of RPPA and single cell network profiling by phosphoflow to can be analyzed using 
recently developed computational methods to provide a combined protein expression predictor.93  
2. Phosphoflow cytometry: Studies have demonstrated that phosphoflow analyses can be predictive 
of outcome in pediatric acute leukemia. As an example, Redell et al. identified that responsiveness 
to IL-6 in pediatric AML was associated with superior survival.94  
 
e) Relevant data from previous clinical studies 
1. RPPA: Our preliminary data shows that we can reliably assess post-chemotherapy protein 
activation. Using a test set of 32 validated RPPA antibodies, we assessed changes in protein 

 
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expression in 27 COG pediatric leukemia patients following induction chemotherapy.  We have 
determined that 1) CellSave tubes preserve protein expression profiles post-treatment, as shown by 
the relative stability of actin expression, but a decrease in p-AKT; and 2) that we can detect the 
heterogeneous patterns of changes in protein expression over time, including changes in AKT, m-
TOR, MAPkinase and the FOXO3 pathway following treatment (Horton, Kornblau, personal 
communication). 
2. Phosphoflow: Based upon phosphoflow studies from phase 1 COG and adult trials using these 
assays,81,95 we anticipate that we can reliably identify signaling upregulation at baseline and during 
therapy using shipped specimens. In an institutional study of adults with AML treated with 
sirolimus and chemotherapy, inhibition of phosphorylated S6 correlated with clinical responses 
(Perl 2012).  
 
f) The comparability of the methods proposed to those previously used, and the likelihood that the 
resulting data will be able to be compared with existing data. Analysis of RPPA is currently being 
performed using the same methods in AAML1031, and so these results should be directly comparable. 
Analysis of signal transduction networks will use identical methods to those piloted in ADVL1011 and 
ADVL1114, and so these should be comparable as well. 
 
g) The reason for selection of the assay methodology.  
1. RPPA is a technique which can quantitate protein expression from over 1000 patient samples on a 
single slide using validated antibodies.96 The sample requirements are quite small; analysis of 
protein panels can be accomplished with as little as 200,000 cells per patient. This is the only assay 
able to provide detailed analysis of protein expression with this number of cells. This technique is 
also relatively resistant to protein degradation during shipping time. Blood is collected into 
CellSave preservation tubes, which we have shown can stabilize protein expression for up to 72 
hours (Horton et al manuscript in review).  
2. Similarly, phosphoflow cytometry is a very sensitive and reproducible technique, analyzing signal 
transduction abnormalities and the level of the single cell. Phosphoflow can also be used to analyze 
samples both at baseline and following chemotherapy treatment.95  
 
h) The stability of the samples used for analysis:  
Although no formal studies have been performed to determine stability, samples collected locally over 
the past 15 years from the Horton laboratory were examined by RPPA.  There were no statistically 
significant differences in expression patterns or protein intensity based on the age of the sample 
(Kornblau, personal communication).  
 
i) Technical performance characteristics   
1. Antibody validation: RPPA antibodies have gone through extensive testing prior to inclusion on 
the array,88 including both analytic validation, and assay validation with clinically relevant 
samples.94 Antibodies validated for RPPA demonstrate specificity of signal and, in the case of 
phosphorylation or cleavage sensitive antibodies, context-specific validation performed in baseline 
and stimulated samples.87 Validation steps have included: 1) antibody specificity as determined by 
immunoblot, 2) appropriate induction of phosphorylation/cleavage in response to known inducing 
agents, 3) correlation of RPPA signal with immunoblot expression (R>0.5), 4) acceptable 
sigmoidal curve fit of signal with sample dilution (analyzed using Super-Curve), 5) variable slope 
normalization97 and, in cases of high background, 6) topographical normalization. Slides with 
unacceptable variances will be redone. RPPA has acceptable intra-assay and inter-assay variability, 
with intra-assay coefficients of variation (COV) of 6-15% and established inter-assay 
reproducibility. We have established standard operating procedures (SOPs) for sample processing, 
cell sorting and RPPA, and laboratory staff in both the Horton and Kornblau labs are experienced 
with the procedure.  

 
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b. Minimizing sample variability: based on prior testing samples received within 72h of collection 
from the patient have very similar protein expression patterns. (Horton, manuscript in preparation).  
Samples for RPPA will be collected in CellSave preservation tubes and mailed by FedEx courier 
to maintain protein integrity.  
 
j) A description of the positive and negative controls 
Controls will include normal adult and pediatric bone marrow, ALL cell lines, and ALL cells stimulated 
with chemotherapy as described .91,92,98 
 
k) The experience that the investigators have with the assay  
1. The Horton Laboratory will be collaborating with Dr. Steve Kornblau who has extensive 
experience with RPPA analysis of leukemia samples.91,92,98  
2. The Tasian laboratory has extensive experience with phosphoflow cytometry analyses of primary 
patient leukemia specimens and of xenografted pediatric ALL and AML specimens.99-102 
 
l) The methods of scoring and plan for analysis 
a. Overview: Statistical analyses will be performed in a stepwise manner. First, we will analyze 
dynamic changes in protein activations following chemotherapy in all patients. The purpose is to 
discover natural groupings based on proteomic data only and to analyze the response of different 
biologically relevant signal transduction pathways during treatment. Second, we will examine 
protein clustering stratified by risk group and genetic subtype using supervised clustering analysis. 
Third, once clinical outcome data become available, we will analyze differences between treatment 
groups as they relate to DFS. This analysis will include unsupervised clustering methods.91,92,98 
Finally, we will generate a classifier(s) that best correlates with clinical outcome for the group as 
whole. While the primary objective of the study is DFS, we will also examine classifiers stratified 
by CR and relapse after study completion.  
 
b. Statistical analysis: Supercurve algorithms were used to generate a single value from the 5 serial 
dilutions.1  Loading controls2 and topographical normalization3 procedures will account for protein 
concentration and background staining variations.  Analysis using unbiased clustering, perturbation 
bootstrap clustering and principle component analysis was then performed as previously 
described.4  We (SM Kornblau, KR Coombes (MDACC) and A. Qutub (Rice University) have 
developed a novel modification of the Gap statistic, named “stability Gap” for selecting the optimal 
number of patient clusters from the range of possible clusters103 This will be utilized to select the 
optimal number of clusters for comparison in outcomes analysis. Analysis typically places samples 
into 3-7 clusters for further analysis. 
 
Comparison of the protein levels between paired samples will be done by performing paired t-
tests.  Association between protein expression levels and categorical clinical variables will be 
assessed in R using standard t tests, linear regression or mixed-effects linear models.  Association 
between continuous variable and protein levels will be assessed by using Pearson and Spearman 
correlation and linear regression.  Bonferroni corrections were performed to account for multiple 
statistical parameters for calculating statistical significance.  The Kaplan-Meier method was used 
to generate the survival curves.  Univariate and multivariate Cox proportional hazard modeling will 
be performed to investigate association with survival with protein levels as categorized variables 
using Statistica version 10 software (StatSoft, Tulsa, OK).   
 
 
Other methods of analysis may include: Hierarchical Clustering, Principal Component Analysis 
(PCA), Self-Organizing Maps (SOM) and other class discovery methods.104 Cluster stability will 
be accessed using reproducibility measures, including GAP,105  and Stability Gap (manuscript in 
preparation), as well as robustness and discrepancy indices.106 Differentially expressed proteins 

 
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will be found using paired t-test as well as repeated measures, mixed effect ANOVA and ANOVA 
with contrasts. To determine if dynamic changes in specific protein pathways predict 
chemoresistance, we will use different regression and classification methods: Self Organizing 
Maps(SOM) (when no outcome is used), class prediction methods such as logistic regression, 
Support Vector Machine,107 Random Forest,108 Binary Tree Prediction, Bayesian Compound 
Covariate Predictor,  and Discriminant analysis (http://linus.nci.nih.gov/techreport/Manual32.pdf).  
 
Correlation of protein data with clinical variables 
For Specific Aim 1, we will determine if there is a protein classifier prognostic for clinical outcome.  
After assignment of each patient to a risk group (based on time and site of relapse, n=403 low-risk, 
n=195 high-risk), samples will be stratified based on risk group and supervised clustering analysis will 
be performed based on clinical outcome variables (DFS).  
 
For Specific Aim 2, we will determine which patients classified as low-risk (based on time and site of 
relapse) that would benefit from the more intensive chemotherapy given to high-risk patients (i.e., 
reassignment to the high risk group).  Following the generation of a risk-based protein expression 
classifier from all low-risk patients, further testing of the putative classifier will be based on 
performance characteristics using predefined cutpoints using ROC curves. Comparisons will be made 
using the AUC of ROC curves between standard risk stratification (time and site of relapse), MRD 
response, and the putative protein expression classifiers. Model overfitting and biased assessment of 
model performance will be minimized using bootstrap clustering as previously described 91ROC curves 
will be generated for each stratification group, as well as for combinations of groups.  Since attainment 
of CR following subsequent relapse is suboptimal,109,110 and DFS is guarded following subsequent 
relapse, protein expression classifiers that maximize specificity with adequate sensitivity will be 
prioritized for further characterization. 
 
m) The sites performing the correlative studies.  
RPPA analysis will be performed in the Kornblau laboratory (MD Anderson Cancer Center, Houston 
TX) in collaboration with Dr. Horton.  Phosphoflow analysis will be performed in the Tasian laboratory 
(Children’s Hospital of Philadelphia).  
 
n) Maintenance of quality control/assurance 
Quality control will be maintained as previously described (Section i).91,92,98 
 
o) Marker prevalence:  
Since the methods will analyze multiple proteins (RPPA) and signal transduction pathways 
(phosphoflow), the prevalence of each marker will vary. 
 
p) Estimate what proportion of patients on a therapeutic trial will have available sample for 
correlative study analysis; discuss possible biases. 
Based on prior samples obtained for RPPA analysis from patients enrolled on the Phase 3 COG AML 
trial AAML1031, we estimate 40% of enrollments will provide an evaluable sample. As the most 
common reasons for sample dropout include technical issues (20% sample dropout due to sample 
quality, 40% due to samples not being drawn at site, 10% due to delays in shipping), lack of consent 
(10-15%), and insufficient lymphoblasts in peripheral blood to qualify for the study (20%).  The latter 
20% will have a bias toward high-risk disease and early marrow relapse. 
 
q) Specify how any cutpoints will be determined 
Specific aim 1: Performance characteristics and cutpoints will be made by comparison of AUC for 
ROC curves of available classifiers including standard risk stratification (time to and site of relapse) 
and MRD status. Since the objective of this study is to improve DFS, and DFS are can be estimated by 

 
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both the hazard ratio and probability of relapse. These numbers will become available from AALL0433, 
AALL01P2, AALL04P2 and AALL07P1 prior to trial completion. In order to identify patients likely 
to relapse, without increasing the risk of overtreating patients that require minimal therapy to achieve 
DFS, we will choose classifiers that maximize the true positive rate (sensitivity) while maintaining 
adequate specificity using statistically meaningful and clinically relevant cutpoints. 
 
Specific aim 2: To determine if alterations in specific cell stress proteins can be used to generate a 
“high-risk” protein expression signature that identifies patients stratified to the low-risk (based on time 
and site of relapse)  group that would have benefited from stratification into the high-risk group. For 
analysis of clinical utility, assumptions are usually made based on prior clinical trials for a similar 
pediatric relapsed ALL cohort. However, previous relapsed ALL COG studies have used different risk 
assessments, making a priori cutpoint determination challenging. Therefore, we will present basic 
principles for determining cutpoints for protein expression classifiers. 
 
To aid in determining specific cutpoints, data from the recently completed AALL0433 clinical trial will 
be used to determine the prevalence of relapse and DFS in a similar LR population. 
 
Since our aim is to improve the detection of true high risk patients misclassified into the low-risk group, 
we are interested in both the sensitivity and specificity of a putative protein classifier. The clinical 
usefulness of a protein expression classifier is dependent the proportion of low-risk patients that relapse 
(which can be estimated from the AALL0433 trial), as well as the proportion of low-risk patients with 
the “high-risk” putative classifier (determined by this study). Depending on the change in DFS for those 
correctly identified as having a “high-risk” protein classifier, the relative risks that can be used to 
identify the clinical usefulness can be estimated. Once these estimates are known, we can estimate both 
absolute risk reduction and decrease in relative risk of a low-risk patient with a “high-risk” classifier. 
Our goal would be to identify a classification signature that outperforms the current method of risk 
stratification (time and site of relapse) and/or allowed for an absolute risk reduction of at least 5% in 
the low-risk group.  
 
r) Specify the statistical power of the correlative study  
 
Sample size for basis of power calculations: 
Based on power size calculations (Section 9.2.2), we anticipate that the study will enroll 598 patients, 
including 195 high-risk and 403 low-risk patients (based on time and site of relapse). Based on sample 
retrieval rate of 36% (see Section p), we will have 215 patients for protein expression analysis. For 
specific aim 1, all evaluable patients with usable sample would be considered for analysis (n=215).  For 
the second aim, patients in the low-risk group (n=403) would be eligible if we receive usable sample. 
Based on sample recruitment in AAML1031 (36%), we expect to collect usable sample for 145 of the 
403 evaluable patients.  Although all sample set are required to have a 0h sample, about 82% of samples 
have the full data set (i.e. sufficient material for RPPA (CellSave preservation tubes) and phospho-flow 
(heparin tubes) at 0h, 6h, and 24h). For measures of changes over time, we anticipate that we will have 
176 patient sets for SA1 and 118 patients for SA2. If the unfolded protein response is of interest, we 
expect that 90% of patients will have sufficient material for transcript analysis (n=193 for SA1, n=130 
for SA2). 
 
A summary of sample size data is provided in Table XI-1:  
 
In addition to determining the effect sizes (defined as the difference in the corresponding mean 
outcomes over a common standard deviation) of assays between treatment groups, we will also compare 
protein classifiers with clinical outcome (MRD status and EFS).  For the analysis of data across time 
(0h, 6h and 24h) we do not know a priori the most relevant time points to compare. Short-term 

 
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differences could have returned to baseline by 24h, and may be most accurately estimated by changes 
between 0h and 6h. Long-term differences would be best measured by 0h-24h comparison.  Complex 
changes, such as increase at 6h and decreases by 24h (seen with NF-B after chemotherapy) are best 
measured using all three time points as descriptors. However, for simplicity we have provided the affect 
sizes for changes from 0h to 24h in Table XI-1. 
 
Table XI-1: Effect-size differences based on sample size for protein cell stress pathways 
1. 
RPPA 
and 
phospho-flow 
studies 
Samples size (max) 
Effect size * 
Baseline and change at 24h by 
treatment 
arm 
(blinatumomab 
therapy 
vs 
non-blinatumomab 
therapy; randomized patients only) 
135 (67/tx group)  
 
110 (55/tx group) 
0.488 
 
0.539 
Baseline and change at 24h by 
MRD response (rate of MRD >= 
0.1%: 62% for high-risk, 28% for 
low-risk; 39% overall) 
 
 
 
All patients:  
215 (84 MRD >=0.1%/ 131 MRD 
< 0.1%) for baseline comparisons. 
 
176 (69 MRD >=0.1%/107 MRD < 
0.1%) for changes over time. 
 
Low-risk: 
145 (41 MRD >=0.1%/ 104 MRD 
< 0.1%) for baseline comparisons. 
 
118 (33 MRD >=0.1%/85 MRD < 
0.1%) for changes over time. 
 
 
 
0.393 
 
 
0.435 
 
 
 
 
0.520 
 
 
0.579 
Baseline and change at 24h by 3-
year DFS for randomized patients 
(estimated 3-year DFS 64%) 
135 (86 no event/ 49 with event) for 
baseline changes. 
 
110 (70 no event/ 40 with event) 
For changes over time.  
0.505 
 
 
0.560 
Assumptions: alpha = 0.05, beta = 0.2.Abbreviations: grp= group, tx = treatment 
* 
With this effect size, the study will have at least 80% power at 2-sided significance level of 
0.05 to detect such difference given the corresponding sample size. 
 
 
s) Corrections for multiple comparisons 
We will use the Benjamini-Hochberg correction to account for multiple comparisons.111 
 
t) Discuss how the results will have an impact on future studies. 
This contribution will significantly impact future studies because it will add protein cell stress markers 
to the armamentarium of genetic mutations currently used to assess relapse risk, increasing the power 
of risk stratification, and identifying patients most likely to relapse and those most likely to benefit 
from therapies that target deregulated cell signaling pathways in relapsed ALL. 
 
 

 
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APPENDIX XII: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS 
HOST DISEASE (GVHD)  
 
Reporting Requirements for Acute GVHD in COG Studies 
In an attempt to standardize reporting of acute GVHD, the COG Stem Cell Transplantation Committee has 
adopted a modification of guidelines that were originally developed at the University of Michigan. 
 
Table 1 outlines standard criteria for GVHD organ staging. However, confounding clinical syndromes (such 
as non-GVHD causes of hyperbilirubinemia) may make staging GVHD in a given organ difficult. In 
addition, timing of organ specific symptoms affects whether that symptom is more or less likely to be true 
GVHD. Please refer to Tables 2 and 3 to assist you in deciding whether to attribute these clinical findings 
to GVHD, especially in situations where a biopsy is not possible. For additional help, please see the text 
which follows the tables. Table 4 reviews the approach to assessing GVHD as acute, chronic, or the overlap 
between the two. 
 
Finally, engraftment syndrome will be reported separately from the GVHD scoring presented below. 
Engraftment Syndrome 
A clinical syndrome of fever, rash, respiratory distress, and diarrhea has been described, just prior 
to engraftment in patients undergoing unrelated cord blood and mismatched transplantation. If, in 
the judgment of the local investigator, a patient experiences this syndrome, details of the event 
should be reported when requested in the study CRFs. 
 
Modified Glucksberg Staging Criteria for Acute Graft versus Host Disease 
 
Table 1 Organ Staging (See tables and text below for details) 
Stage 
Skin  
Liver (bilirubin)  
Gut (stool output/day)  
0  
No GVHD rash  
< 2 mg/dL  
Adult: < 500 mL/day  
Child: < 10 mL/kg/day  
1  
Maculopapular rash  
< 25% BSA  
2 - 3 mg/dL  
Adult: 500 – 999 mL/day  
Child: 10 - 19.9 mL/kg/day  
Or persistent nausea, vomiting, or 
anorexia, with a positive upper GI biopsy.  
2  
Maculopapular rash  
25 – 50% BSA  
3.1 - 6 mg/dL  
Adult: 1,000 – 1,500 mL/day Child: 20 – 
30 mL/kg/day  
3  
Maculopapular rash 
> 50% BSA  
6.1 - 15 mg/dL  
Adult: > 1,500 mL/day  
Child: > 30 mL/kg/day  
4  
Generalized erythroderma 
plus bullous formation and 
desquamation > 5% BSA  
> 15 mg/dL  
Severe abdominal pain with or without 
ileus, or grossly bloody stool (regardless of 
stool volume).  

 
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For GI staging: The “adult” stool output values should be used for patients > 50 kg in weight. Use 3 day 
averages for GI staging based on stool output. If stool and urine are mixed, stool output is presumed to be 
50% of total stool/urine mix (see Section 3.2). 
 
For stage 4 GI: the term “severe abdominal pain” will be defined as: 
(a) Pain control requiring institution of opioid use, or an increase in on-going opioid use, PLUS 
(b) Pain that significantly impacts performance status, as determined by the treating MD. 
 
If colon or rectal biopsy is +, but stool output is < 500 mL/day (< 10 mL/kg/day), then consider as GI stage 0.  
 
There is no modification of liver staging for other causes of hyperbilirubinemia 
 
Overall Clinical Grade (based on the highest stage obtained): 
Grade 0: No Stage 1 - 4 of any organ 
Grade I: Stage 1 - 2 skin and no liver or gut involvement 
Grade II: Stage 3 skin, or Stage 1 liver involvement, or Stage 1 GI 
Grade III: Stage 0 - 3 skin, with Stage 2 - 3 liver, or Stage 2 - 3 GI 
Grade IV: Stage 4 skin, liver or GI involvement 
 
Table 2 Evaluating Liver GVHD in the Absence of Biopsy Confirmation (See Table 3.0 below) 
 
Establishing liver GVHD with no skin or GI GVHD 
No Skin/GI GVHD 
Day 0 - 35 
Assume no liver GVHD, unless proven by biopsy  
No Skin/GI GVHD  
Day 36 - 100 
If NO other etiology identified, NO 
improvement with stopping 
hepatotoxic medications/TPN: 
Stage as liver GVHD  
If other etiology identified or 
improves with stopping hepatotoxic 
drugs/TPN: 
Do not stage as liver GVHD  
 
Establishing liver GVHD with skin or GI GVHD and other cause of hyperbilirubinemia 
Skin and/or GI GVHD 
present  
Worsening bilirubin level (includes 
worsening just prior to onset of skin 
or GI tract GVHD) OR stable 
elevated bilirubin despite resolution 
of non-GVHD cause of increased 
bilirubin:  
Stage as liver GVHD  
Stable or improving bilirubin after 
diagnosis of skin or GI GVHD, 
irrespective of treatment:  
Do not stage as liver GVHD 
 
Changing liver GVHD stage with other cause of hyperbilirubinemia 
Skin and GI GVHD 
stable, improving, or 
absent  
Liver GVHD staging is carried forward without increase in stage until other 
disease process resolves (e.g., if TTP is diagnosed in the presence of stage 2 
liver GVHD, the liver GVHD stage 2 is carried forward despite rising 
bilirubin level until TTP is resolved. If there is no liver GVHD – stage 0 – 
and new onset TTP, the stage 0 is carried forward until TTP is resolved).  

 
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Skin and/or GI GVHD 
worsening  
Liver GVHD is staged according to the Glucksberg criteria. The 
elevated bili is attributed to GVHD alone. 
 
Thus, when skin or GI GVHD is worsening, there is no downgrading of 
liver GVHD staging for other causes of hyperbilirubinemia. (e.g., if TTP is 
diagnosed in the presence of stage 2 liver GVHD and worsening skin or GI 
GVHD, the liver is staged according to the actual bilirubin level even if 
some of the rise in bilirubin is attributed to TTP). 
 
Similarly, even if there is no liver GVHD at onset of a new process, (such 
as TPN cholestasis), but skin or GI GVHD worsen during that process, then 
liver GVHD is diagnosed and staged according to the height of the 
bilirubin. 
 
There is one exception to this: the diagnosis of TTP, with high LDH and 
unconjugated bilirubin precludes the diagnosis and staging of new liver 
GVHD in the absence of a confirmatory liver biopsy. 
 
Table 3 Evaluating GI GVHD in the Absence of Biopsy Confirmation (See Table 4.0 below) 
 
Establishing GI GVHD with new onset diarrhea and no skin or liver GVHD 
No Skin/liver GVHD  
Day 0 through 
engraftment 
Assume no GI GVHD, unless proven by biopsy  
 
No Skin/liver GVHD 
Engraftment through 
day 100  
NO other etiology of diarrhea 
identified: 
Stage as GI GVHD  
Any other etiology of diarrhea 
identified: 
Do not stage as GI GVHD  
 
Establishing GI GVHD with pre-existing diarrhea and skin or liver GVHD 
Skin and/or liver GVHD 
present  
Worsening diarrhea (includes 
worsening just prior to onset of skin 
or liver GVHD) OR persistent 
diarrhea despite resolution of non-
GVHD cause: 
Stage as GI GVHD  
Improving diarrhea after the 
diagnosis of skin or liver GVHD 
(irrespective of treatment) OR 
persistent diarrhea without resolution 
of underlying non-GVHD cause: 
Do not stage as GI GVHD  
 
 
Differentiating Acute GVHD, Chronic GVHD, and Overlap Syndrome  
There is often confusion differentiating acute from chronic GVHD, especially in the setting of reduced 
intensity transplants, DLI and new prophylactic treatments. The NIH Working Group recently published 
new classifications for GVHD: 
 
 
 

 
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Table 4 Acute GVHD, Chronic GVHD, and Overlap Syndrome 
Category  
Time of Symptoms 
after HCT or DLI  
Presence of Acute 
GVHD features  
Presence of Chronic 
GVHD features  
Acute GVHD  
 
 
 
Classic acute GVHD  
≤100 d  
Yes  
No  
Persistent, recurrent, or 
late-onset acute GVHD  
>100 d  
Yes  
No  
Chronic GVHD  
 
 
 
Classic chronic GVHD 
No time limit  
No  
Yes  
Overlap syndrome  
No time limit  
Yes  
Yes  
 
• 
Scoring of acute GVHD may need to occur past day 100. In particular, patients should continue to 
be scored for acute GVHD when classic acute GVHD symptoms (maculopapular rash, nausea, 
vomiting, anorexia, profuse diarrhea - particularly if bloody and ileus) persist past day 100 or if 
identical symptoms previously scored as acute GVHD resolve and then recur within 30 days during 
immunosuppression taper but past day 100. 
• 
Those patients being scored as having acute GVHD should NOT have diagnostic or distinctive 
signs of chronic GVHD. 
• 
Patients with both acute and chronic symptoms should be diagnosed as having Overlap 
Syndrome and scored according to their chronic GVHD score.  
 
Further Explanation of Criteria presented in Tables 2 and 3 
 
1.0 Assessment of Skin GVHD  
1.1 Presence or Absence of Skin GVHD: Skin GVHD will be considered present if a rash characteristic 
of acute GVHD develops after allogeneic marrow transplantation involving more than 25% of the 
body surface not clearly attributable to causes such as drug administration or infection. The extent of 
the body surface area involved can be estimated by the “Rule of Nines”. In estimating the extent of 
skin GVHD, the area involved is calculated for individual anatomic areas, such as the arm or leg, and 
then the total is derived from a simple summation. Areas that are non-blanching should not be 
considered involved regardless of the overlying color of the rash (red, brown, etc.). Limited 
distribution erythema (with the exception of palms and soles) in the absence of associated rash 
elsewhere on the body will not be considered GVHD.  
 
2.0 Assessment of Liver GVHD  
2.1 Assessing for the Presence or Absence of Liver GVHD 
A. Hyperbilirubinemia (total bilirubin > 2.0 mg/dL) in the absence of other signs of acute GVHD in 
the skin or GI tract: 
i) Day 0-35: If hyperbilirubinemia alone is present with no other signs of acute GVHD in other 
organ systems, acute GVHD will not be diagnosed based solely on laboratory abnormalities. 
Acute GVHD will be diagnosed if findings on histopathology studies of liver from a biopsy or 
autopsy are confirmatory. 
ii) Day 35-100: If hyperbilirubinemia (must be conjugated bilirubin) is not improving or is 
exacerbated (especially if serum alkaline phosphatase is increased), in the absence of acute 
GVHD in other organ systems, no other etiologies are identified, and does not improve with 
discontinuation of hepatotoxic drugs, acute GVHD will be diagnosed. However, it is 
distinctly unusual to develop ascites or a coagulopathy in the early stages of acute GVHD of 

 
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the liver alone. In the absence of histopathology studies of liver from a biopsy or autopsy 
specimen, ascites or a coagulopathy secondary to liver dysfunction will be considered to 
indicate the presence of another disease process (e.g. veno-occlusive disease). Recommended 
non-invasive studies to define an etiology for hyperbilirubinemia are: 
a. Imaging of liver (CT or ultrasound) 
b. Hepatitis screen (only if ALT is elevated) 
c. PT 
d. Blood cultures 
e. Review of medication list for potentially hepatotoxic drugs 
f. 
Review of risk factors for viral liver infection (HSV, CMV, VZV, adenovirus, EBV, 
HBV, and HCV) 
g. Hemolysis screen 
 
B. Pre-existing hyperbilirubinemia clearly attributed to an etiology other than acute GVHD in the 
presence of signs of acute GVHD in other organ systems. 
i) If pre-existing non-GVHD liver disease (documented clinically, by lab assessment, or by 
imaging studies) is stable or improving at the onset of signs of acute GVHD in other organs, 
then acute GVHD of the liver will not be considered to be present unless proven by liver 
biopsy or autopsy. 
ii) If hyperbilirubinemia worsens several days before or at the time of onset of signs of acute GVHD 
in other organ systems, GVHD will be considered to be present unless histopathology studies 
of liver are available and negative on a biopsy during that time interval or autopsy results 
exclude GVHD. 
iii) If hyperbilirubinemia persists and is not improving after resolution of a pre-existing non-GVHD 
liver disease process (e.g. localized infection of liver, systemic sepsis, biliary tract obstruction) 
when signs of acute GVHD are present in other organ systems or no other intervening cause 
has been diagnosed, then acute GVHD will be considered to be present in the absence of a new, 
clearly identifiable cause of non-GVHD liver disease or unless a liver biopsy or autopsy 
specimen is negative.  
 
C. Prior acute GVHD in liver with new onset of a disease process that exacerbates pre-existing or 
recently resolved hyperbilirubinemia: 
i) If an etiology other than acute GVHD is clearly identified as causing or exacerbating 
hyperbilirubinemia and acute liver GVHD has been diagnosed and has been stable, improving, 
or resolved, then the liver will not be restaged for acute GVHD until the resolution or stabilizing 
of the concurrent disease process (i.e., the liver stage prior to the onset of the new disease 
process will be carried forward until the new disease process resolves). Example: Acute GVHD 
of the liver and gut is diagnosed on Day 20. Treatment of acute GVHD results in falling 
bilirubin levels to liver Stage 1. Sepsis or TTP develops with transient worsening of the 
hyperbilirubinemia. The liver stage is not increased, despite a higher bilirubin level, because 
the cause of worsening hyperbilirubinemia is attributed to sepsis or TTP. 
ii) If an etiology other than acute GVHD is clearly identified as causing or exacerbating 
hyperbilirubinemia in the presence of already worsening acute liver GVHD or GVHD of the 
skin or GI tract is simultaneously worsening, then the liver GVHD will be staged according to 
the actual bilirubin level, even though another cause of hyperbilirubinemia is present. 
 
3.0 Assessment of GVHD of the Gastrointestinal Tract 
3.1 Assessing for the Presence or Absence of GVHD of the Gastrointestinal Tract 
A. Diarrhea (> 500 mL/day in adults or > 10 mL/kg in pediatric patients) in the absence of other signs 
of acute GVHD in other organ systems 
i) Day 0-engraftment: If diarrhea alone is present without other signs of acute GVHD in other 

 
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organ systems, acute GVHD will not be considered present. Diarrhea will be attributed to acute 
GVHD if histopathology studies of gastrointestinal tract from a biopsy or autopsy are 
diagnostic. 
 
ii) Engraftment-day 100: If diarrhea persists and is not improving, is exacerbated, or develops de 
novo in the absence of acute GVHD in other organ systems, histopathology studies of gut 
biopsies or from autopsy specimens are not available, and no other etiologies are clearly 
identified, acute GVHD will be considered to be the cause. A stool specimen should be 
examined to rule out infectious causes (e.g. rotavirus, adenovirus, and C. difficile toxin). It is 
recommended, if at all possible, that biopsies be obtained for diagnostic purposes. 
B. Pre-existing diarrhea clearly attributed to an etiology other than acute GVHD in the presence of 
signs of acute GVHD in other organ systems: 
i) If pre-existing diarrhea caused by a process other than GVHD has been documented clinically 
or by lab assessment and is stable or improving at the onset of signs of acute GVHD in the skin 
or liver, then acute GVHD of the intestine will not be considered to be present in the absence 
of biopsy confirmation or autopsy report. 
ii) If diarrhea or gastrointestinal symptoms are already present, but worsen significantly at the 
time of onset of signs of acute GVHD in the skin or liver, GVHD will be considered present, 
unless biopsy or autopsy are negative. 
iii) If diarrhea persists after resolution of a pre-existing disease process with signs of acute 
GVHD present in other organ systems, GVHD will be considered present, unless biopsy or 
autopsy are negative. 
C. Prior or present acute GVHD in other organ systems with new onset of diarrhea: 
If diarrhea is clearly attributable to an etiology other than acute GVHD (e.g., infection) and a 
history of acute GVHD exists or acute GVHD is present in other organ systems and is stable, then 
the gastrointestinal tract will not be evaluable for acute GVHD until the resolution or stabilizing of 
the other disease process (e.g., infection) in the absence of biopsy or autopsy confirmation. 
D. Persistent anorexia, nausea or vomiting in the absence of signs of acute GVHD in other organ 
systems:  
Persistent anorexia, nausea or vomiting in the absence of other known causes of these 
symptoms will be considered Stage 1 acute GVHD if confirmed by endoscopic biopsy. 
 
If a biopsy is not possible (e.g. secondary to thrombocytopenia) but the clinical findings 
are compatible with acute GVHD, then the patient will be treated and recorded as having 
acute GVHD. 
3.2 Staging of the Gastrointestinal Tract for the Severity of Acute GVHD 
The severity of gastrointestinal tract GVHD will be staged according to modified Glucksberg criteria. 
To minimize errors caused by large day-to-day variation, diarrhea volume is measured as an average 
over 3 days and reported as the volume in milliliters per day. When urinary mixing is noted the stool 
volume will be considered half of the total volume unless nursing staff is able to give a better estimate 
from direct observation. Abdominal cramps are considered significant for staging if the severity results 
in a clinical intervention (e.g. analgesia, fasting, etc.). Blood in the stools is considered significant if 
the blood is visible or hematochezia/ melena is present and not clearly attributed to a cause other than 
GVHD (e.g. epistaxis/ hemorrhoids). 
 
 
 

 
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APPENDIX XIII: CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually. To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in the table 
below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
 
 
 
 
 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the [insert study number] protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting documents is 
restricted and is based on person and site roster assignment housed in the CTSU RSS. 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Either enter the protocol # in the search field at the top of the protocol tree, or 
▪ 
Click on the By Lead Organization folder to expand 
▪ 
Click on the COG link to expand, then select trial protocol #[insert study number] 
Click on LPO Documents, select the Site Registration documents link, and download and complete the 
forms provided. 
 
Requirements For AALL1331 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must be aligned to 
a RTI provider.  To manage provider associations access the Provider Association tab on the CTSU website 
at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated providers.  Sites must 
be linked to at least one IROC credentialed provider to participate on trials with an RT component.   
• 
 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 
Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: Sites 
will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 

 
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▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional compliance with 
protocol-specific requirements as outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling investigator’s status with 
the NCI or their affiliated networks. 
 
 

 
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APPENDIX XIV: POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Cyclophosphamide 
 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Amiodarone 
• 
Carbamazepine 
• 
Cyclosporine 
• 
Digoxin  
• 
Efavirenz 
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Lumacaftor 
• 
Mifepristone 
• 
Pentostatin 
• 
Rifampin 
• 
Ritonavir  
• 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Cyclosporine 
 
Drugs that may interact with cyclosporine 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Aripiprazole, citalopram, clozapine, escitalopram, fluoxetine, fluvoxamine, lurasidone, 
nefazodone, paliperidone, quetiapine, thioridazine, ziprasidone 
• 
Antifungals  
o Amphotericin, caspofungin, fluconazole, itraconazole, isavuconazole, ketoconazole, 
posaconazole, voriconazole 
• 
Anti-inflammatory, arthritis, or pain medications  
o Aspirin, celecoxib, hydroxychloroquine, ibuprofen, indomethacin, ketorolac, leflunomide, 
naproxen, meloxicam, oxaprozin, sulindac, tofacitinib, tolmetin 
• 
Anti-rejection medications 
o Mycophenolate, sirolimus, tacrolimus 

 
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• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delavirdine, efavirenz, etravirine, fosamprenavir, indinavir, letermovir,  
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• 
Anti-seizure medications  
o Carbamazepine, phenobarbital, phenytoin, primidone 
• 
Cholesterol medications  
o Atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, fenofibrate, 
gemfibrozil, colesevelam, griseofulvin 
• 
Heart medications  
o Aliskiren, amiodarone, dronedarone, carvedilol, digoxin, diltiazem, eplerenone, verapamil, 
captopril, enalapril, lisinopril, ramipril 
• 
Kidney medications  
o Acetazolamide, amiloride, spironolactone, triamterene 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Ambrisentan, bosentan, sitaxentan, aprepitant, allopurinol, colchicine, danazol, 
fluoxymesterone, modafinil, methyltestosterone, omeprazole, oxandrolone, mifepristone, 
natalizumab, pimozide, butabarbital, secobarbital, ivacaftor, octreotide 
 
Food and supplements that may interact with cyclosporine 
• 
Alfalfa 
• 
Black cohosh 
• 
Echinacea 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
• 
Red Yeast Rice 
• 
St. John’s Wort 
 
 
Cytarabine (by vein) 
 
Drugs that may interact with cytarabine 
• Clozapine, flucytosine, leflunomide, natalizumab 
 
Food and supplements that may interact with cytarabine 
• 
Echinacea 
 
 
Dexamethasone 
 
Drugs that may interact with dexamethasone 
• Antibiotics  
o Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin, rifabutin, 
rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, 
nefazodone, quetiapine 
• Antifungals 

 
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o Caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, 
nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, amlodipine, dronedenarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Some oral contraceptives or birth control medications 
• 
Many other drugs, including the following: 
o Aprepitant, artemether/lumefantine, aspirin, deferasirox, ibuprofen, ivacaftor, lomitapide, 
mifepristone, natalizumab, nimodipine, praziquantel, warfarin 
 
Food and supplements that may interact with dexamethasone 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Etoposide 
 
Drugs that may interact with etoposide 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Clozapine, nefazodone 
• 
Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, 
nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, dronedenarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Aprepitant, atovaquone, bosentan, deferasirox, ivacaftor, lomitapide, mifepristone, modafinil, 
natalizumab, pimozide 

 
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Food and supplements that may interact with etoposide 
• 
Echinacea 
• 
Glucosamine 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Fludarabine 
 
Drugs that may interact with fludarabine 
• Clozapine, leflunomide, natalizumab, pentostatin, tofacitinib  
 
Food and supplements that may interact with fludarabine 
• Echinacea 
 
 
Leucovorin 
 
Drugs that may interact with leucovorin 
• 
Glucarpidase 
• 
Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
• 
Trimethoprim 
 
Food and supplements that may interact with leucovorin 
• 
Folic acid 
 
 
Methotrexate (by mouth or by vein) 
 
Drugs that may interact with methotrexate 
• 
Some antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, penicillin, piperacillin, tetracycline, 
trimethoprim/sulfamethoxazole) 
• 
Some anti-inflammatory drugs (aspirin, ibuprofen, naproxen, ketorolac, sulfasalazine, sulindac) 
• 
Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole) 
• 
Several other specific agents, including the following: amiodarone, clozapine, cyclosporine, 
eltrombopag, fosphenytoin, gemfibrozil, leflunomide, phenytoin, pimecrolimus, probenecid, 
pyrimethamine, ranolazine, retinoids, teriflunomide,  theophylline, tolvaptan, warfarin 
 
 
 

 
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Food and supplements that may interact with methotrexate 
• 
Alcohol 
• 
Echinacea 
• 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
 
 
Mercaptopurine 
 
Drugs that may interact with mercaptopurine 
• 
Artiritis medications: leflunomide, tofacitinib 
• 
Other medications, such as adalimumab, allopurinol, azathioprine, certolizumab pegol, clozapine, 
etanercept, febuxostat, golimumab, infliximab, natalizumab, olsalazine, sulfasalazine, warfarin 
 
Food and supplements that may interact with mercaptopurine 
• 
Echinacea 
 
 
Mitoxantrone 
 
Drugs that may interact with mitoxantrone 
• Aripiprazole 
• Clozapine 
• Cyclosporine 
• 
Eltrombopag 
• Leflunomide 
• Natalizumab 
• Tofacitinib 
 
Food and supplements that may interact with mitoxantrone 
• 
Echinacea 
 
 
Mycophenolate mofetil 
 
Drugs that may interact with mycophenolate mofetil 
• 
Antacids such as aluminum hydroxide, magnesium hydroxide 
• 
Arthritis medications such as leflunomide, tofacitinib 
• 
Some antibiotics and antiviral medications (be sure to talk to your doctor about this) 
• 
Some heartburn medications including esomeprazole, lansoprazole, omeprazole, pantoprazole 
• 
Other medications such as cholestyramine, cyclosporine, natalizumab, oral contraceptives (“birth 
control”), probenecid, rifabutin, rifampin, rifapentine, sevelamer, tolvaptan, teriflunomide 
 
Food and supplements that may interact with mycophenolate mofetil 
• 
Echinacea  
• 
Vitamins and supplements containing magnesium 

 
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Pegaspargase 
 
Drugs that may interact with pegaspargase 
• 
Leflunomide, natalizumab, pegloticase, tofacitinib 
 
Food and supplements that may interact with pegaspargase 
• 
Echinacea 
 
 
Tacrolimus 
 
Drugs that may interact with tacrolimus 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Citalopram, clozapine, escitalopram, nefazodone, paliperidone, quetiapine, thioridizine, 
ziprasidone 
• 
Antifungals  
o Caspofungin, fluconazole, isavuconazole,itraconazole, ketoconazole, posaconazole, 
voriconazole 
• 
Anti-inflammatory, arthritis, or pain medications  
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine, sirolimus  
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, 
nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, tipranavir 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, diltiazem,dronedenarone, disopyramide, procainamide, propafenone, quinidine, 
ranolazine,  sotalol, verapamil 
• 
Kidney medications  
o Amiloride, spironolactone, triamterene 
• 
Stomach and reflux medications 
o Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, rabeprazole 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, colchicine, conivaptan, mifepristone, modafinil, natalizumab, 
pimozide  
 
Food and supplements that may interact with tacrolimus 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 

 
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Thioguanine 
 
Drugs that may interact with thioguanine 
• Arthritis medications: leflunomide, tofacitinib 
• Other medications, such as adalimumab, allopurinol, azathioprine, certolizumab pegol, clozapine, 
etanercept, golimumab, infliximab, natalizumab, olsalazine, sulfasalazine 
 
Food and supplements that may interact with thioguanine 
• Echinacea 
 
 
 
Thiotepa 
 
Drugs that may interact with thiotepa 
• Arthritis medications like leflunomide or tofacitinib 
• Other medications like bupropion, clozapine, efavirenz, methadone, promethazine, or natalizumab 
 
Food and supplements that may interact with thiotepa 
• 
Echinacea 
 
 
Vincristine 
 
Drugs that may interact with vincristine 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, tenofovir, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedenarone, propafenone, quinidine, ranolazine,  
verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 

 
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o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, ivacaftor, 
mifepristone, modafinil, natalizumab, nefazodone, netupitant 
 
Food and supplements that may interact with vincristine 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
 

 
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REFERENCES: 
 
1. 
Nguyen K, Devidas M, Cheng SC, et al: Factors influencing survival after relapse from 
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2. 
Handgretinger R, Zugmaier G, Henze G, et al: Complete remission after blinatumomab-
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lymphoblastic leukemia. Leukemia 25:181-4, 2012 
 
3. 
Klinger M, Brandl C, Zugmaier G, et al: Immunopharmacologic response of patients with 
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4. 
Topp MS, Gokbuget N, Zugmaier G, et al: Long-term follow-up of hematologic relapse-
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5. 
Topp MS, Kufer P, Gokbuget N, et al: Targeted therapy with the T-cell-engaging 
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Lia Gore, Gerhard Zugmaier, Rupert Handgretinger, et al: Cytological and molecular 
remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute 
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Raetz EA, Borowitz MJ, Devidas M, et al: Reinduction platform for children with first 
marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]. J Clin 
Oncol 26:3971-8, 2008 
 
8. 
Tallen G, Ratei R, Mann G, et al: Long-term outcome in children with relapsed acute 
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