Treatment of Patients With Newly Diagnosed Standard Risk B-Lymphoblastic Leukemia (B-ALL) or Localized B-Lineage Lymphoblastic Lymphoma (B-LLy)
Phase: PHASE3
Conditions: Acute Lymphoblastic Leukemia, Adult B Lymphoblastic Lymphoma, Ann Arbor Stage I B Lymphoblastic Lymphoma, Ann Arbor Stage II B Lymphoblastic Lymphoma, Childhood B Acute Lymphoblastic Leukemia, Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Childhood B Lymphoblastic Lymphoma, Down Syndrome, Hypodiploid B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive
Sponsor: Children's Oncology Group

AALL0932 
Version Date: 10/26/17 
1 
Version Date: 
10/26/17 
Activated: 
August 9, 2010 
Closed:        March 21, 2018
Amendment 
#5A 
CHILDREN’S ONCOLOGY GROUP 
AALL0932 
Treatment of Patients with Newly Diagnosed Standard Risk B-Lymphoblastic Leukemia (B-ALL) or 
Localized B-lineage Lymphoblastic Lymphoma (B-LLy) 
A Groupwide Phase III Study 
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 
 
 
 
 
 
 
 
 
 
 
 

 
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2 
TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA (B-ALL PATIENTS): FOR PATIENTS ENROLLED 
BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET 
10 
EXPERIMENTAL DESIGN SCHEMA (B-ALL PATIENTS): FOR PATIENTS ENROLLED 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET 
11 
EXPERIMENTAL DESIGN SCHEMA (B-LLY AND DS B-LLY PATIENTS) 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
1.1 
Primary Objectives 
13 
1.2 
Secondary Objectives 
13 
1.3 
Exploratory Objectives 
14 
2.0 
BACKGROUND 
14 
2.1 
Rationale for Selected Approach and Trial Design for B-ALL 
14 
2.2 Rationale for Selected Approach and Trial Design for Patients with B-LLy 
21 
2.3 
Development Plans 
23 
2.4 
Patient Enrollment After AR B-ALL Accrual Goals Have Been Met 
24 
2.5 
Rationale for additional IT therapy for Non-Down Syndrome (Non-DS) B-Acute 
Lymphoblastic Leukemia (B-ALL) Patients with Central Nervous System 2 (CNS2) 
Disease (Amendment # 4) 
24 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
26 
3.1 
Study Enrollment 
26 
3.2 
Patient Eligibility Criteria 
30 
3.3 
Definitions 
32 
4.0 
TREATMENT PLAN 
37 
4.1 
Overview of Treatment Plan 
37 
4.2 
Induction (35 days) – B-ALL and B-LLy Patients 
42 
4.3 
Consolidation (28 days) – AR B-ALL Patients, LR B-ALL Patients Randomized to     
Arm LR-C and B-LLy Patients 
48 
4.4 
Interim Maintenance I (56 days) – AR B-ALL Patients, LR Patients Randomized to    
Arm LR-C, and B-LLy Patients 
52 
4.5 
Delayed Intensification (56 days) - AR B-ALL Patients, LR B-ALL Patients   
Randomized to  Arm LR-C, and B-LLy Patients 
55 
4.6 
Interim Maintenance II (56 days) – AR B-ALL Patients, LR B-ALL Patients  
Randomized to Arm LR-C, and B-LLy Patients 
60 
4.7 
Maintenance Arm A (AR B-ALL Patients) 
64 
4.8 
Maintenance Arm B (AR B-ALL Patients) 
68 
4.9 
Maintenance Arm C (AR B-ALL Patients and LR B-ALL Patients Randomized to       
Arm LR-C) 
72 
4.10 
Maintenance Arm D (AR B-ALL Patients) 
76 
4.11 
Maintenance Arm LLy (B-LLy Patients) 
80 
4.12 
Consolidation (19 Weeks) – LR B-ALL Patients Randomized to Arm LR-M 
83 
4.13 
Maintenance Arm LR-M – Cycle 1 (LR B-ALL Patients Randomized to Arm LR-M) 90 
4.14 
Maintenance Arm LR-M – Cycle 2 (LR B-ALL Patients Randomized to Arm LR-M) 93 
4.15 
Maintenance Arm LR-M – Cycle 3 (LR B-ALL Patients Randomized to Arm LR-M) 96 

 
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4.16 
Maintenance Arm LR-M – Cycle 4 (LR B-ALL Patients Randomized to Arm LR-M) 99 
4.17 
Maintenance Arm LR-M – Cycle 5 (LR B-ALL Patients Randomized to Arm LR-M) 102 
4.18 
Maintenance Arm LR-M – Cycle 6 (LR B-ALL Patients Randomized to Arm LR-M) 105 
4.19 
Maintenance Arm LR-M – Cycle 7 (LR B-ALL Patients Randomized to Arm LR-M) 108 
4.20 
Induction (35 Days) – DS SR B-ALL and DS B-LLy Patients 
111 
4.21 
Consolidation (28 days) –DS SR B-ALL and DS B-LLy Patients 
115 
4.22 
Interim Maintenance I (56 days) - DS SR B-ALL and DS B-LLy Patients 
118 
4.23 
Delayed Intensification (56 days) - DS SR B-ALL and DS B-LLy Patients 
121 
4.24 
Interim Maintenance II (56 days) - DS SR B-ALL and DS B-LLy Patients 
126 
4.25 
Maintenance Arm DS - DS SR B-ALL and DS B-LLy Patients 
129 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
132 
5.1 
Asparaginase [E.coli, Pegaspargase (PEG-Asparaginase) or Erwinia] 
132 
5.2 
Cyclophosphamide 
133 
5.3 
Cytarabine (ARAC) IV 
134 
5.4 
Intrathecal Cytarabine 
134 
5.5 
Doxorubicin (Anthracyclines) 
134 
5.6 
Intrathecal Methotrexate 
135 
5.7 
IV Methotrexate 
137 
5.8 
PO 6-Mercaptopurine (6-MP) - Consolidation 
141 
5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (6-MP) – Maintenance for all Arms 143 
5.10 
Steroid (Dexamethasone) 
147 
5.11 
PO 6-Thioguanine (6-TG) - Delayed Intensification: 
147 
5.12 
Vincristine 
148 
5.13 
Drug Interactions 
149 
6.0 
DRUG INFORMATION 
150 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
151 
7.1a 
Required and Optional Clinical, Laboratory and Disease Evaluations – AR B-ALL       
and LR  B-ALL Randomized to Arm LR-C 
151 
7.1b 
Required and Optional Clinical, Laboratory and Disease Evaluations – LR B-ALL 
Randomized to Arm LR-M 
152 
7.1c 
Required and Optional Clinical, Laboratory and Disease Evaluations – DS SR B-ALL 153 
7.1d 
Required and Optional Clinical, Laboratory and Disease Evaluations – B-LLy and       
DS-B-LLy 
154 
7.2 
Studies Suggested to be Obtained After Stopping Therapy (B-ALL Patients) 
155 
7.3 
Studies Suggested to be Obtained After Stopping Therapy (B-LLy Patients) 
155 
7.4 
At Relapse 
155 
7.5 
  GEOGRAPHICAL SAMPLE DISTRIBUTION 
156 
8.0 
SUPPORTIVE CARE GUIDELINES 
157 
8.1 
General Guidelines 
157 
8.2 
Guidelines for Induction 
159 
8.3 
Patients with Down syndrome 
160 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
161 
9.1 
Criteria for Removal from Protocol Therapy for B-ALL and B-LLy Patients 
161 
9.2 
Off Study Criteria (B-ALL and B-LLy Patients) 
162 
10.0 
STATISTICAL CONSIDERATIONS 
162 
10.1 
Statistical Design 
162 
10.2 
Patient Accrual and Expected Duration of Trial 
162 

 
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10.3 
Statistical Analysis Methods 
164 
10.4 
Gender and Minority Accrual Estimates 
167 
11.0 
EVALUATION CRITERIA 
168 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
168 
11.2 
Response Criteria for Patients with Leukemia (B-ALL) 
168 
11.3 
Response Criteria for Patients with B-LLy95,96 
168 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
169 
12.1 
Purpose 
169 
12.2 
Determination of Reporting Requirements 
169 
12.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
170 
12.4 
Routine Adverse Event Reporting 
170 
13.0 
RECORDS AND REPORTING 
171 
13.1 
CDUS 
171 
14.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES FOR B-LLY PATIENTS 
171 
14.1 
Pathology Goals 
171 
14.2  
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
172 
14.3 
Immunophenotyping Recommendations for Primary Institutions 
172 
14.4 
Pathology Staging Criteria 
173 
14.5 
Retrospective Central Pathology Review 
173 
14.6 
Optional Minimal Marrow Disease (MMD) Biology Studies 
175 
14.7 
Optional Tissue Banking and Subsequent Biologic Studies 
177 
14.8 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse 
177 
14.9 
Optional Studies of Genomic Variation 
179 
15.0 
THE PATIENT LEUKEMIA EXPERIENCE ANCILLARY STUDY: 
179 
15.1 
Correlative Study Design: 
180 
15.2 
Specific Hypotheses 
182 
15.3 
Specific Aims 
183 
15.4 
Statistical Design 
184 
15.5 
Significance 
185 
16.0 
THE LEUKEMIA PHYSICAL FUNCTIONING STUDY: 
186 
16.1 
Correlative Study Design: 
186 
16.2 
Background and Specific Hypotheses 
190 
16.3 
Statistical Design 
194 
16.4 
Significance 
195 
APPENDIX I: MERCAPTOPURINE DOSING GUIDELINES 
197 
APPENDIX II: THIOGUANINE DOSING GUIDELINES 
199 
APPENDIX III: MERCAPTOPURINE DOSING GUIDELINES 
201 
APPENDIX IV: YOUTH INFORMATION SHEETS 
203 
APPENDIX V: STAGING CLASSIFICATION OF CHILDHOOD NON-HODGKIN 
LYMPHOMA 
207 
APPENDIX VI:  CTEP REGISTRATION PROCEDURES 
210 
APPENDIX VII:  POSSIBLE DRUG INTERACTIONS 
211 
REFERENCES: 
215 

 
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AGENT 
NSC# 
IND# 
 
 
 
6-Mercaptopurine 
755 
Exempt 
 
Cytarabine 
63878 
Exempt 
 
Cyclophosphamide 
26271 
Exempt 
 
Doxorubicin 
123127 
Exempt 
 
Dexamethasone 
34521 
Exempt 
 
Erwinia Asparaginase 
106977 
Exempt 
 
Methotrexate 
740 
Exempt 
 
PEG L-Asparaginase 
624239 
Exempt 
 
Vincristine Sulfate 
67574 
Exempt 
 
Leucovorin Calcium 
003590 
Exempt 
 
6-Thioguanine 
000752 
Exempt 
 
 
 
 
 
 

 
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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 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 
The survival of children with newly diagnosed B-lymphoblastic leukemia (B-ALL) and B-lymphoblastic 
lymphoma (B-LLy) has markedly improved over the past 4 decades with cure rates now 80% - 85%. This 
has been achieved through the identification of effective combination chemotherapy, central nervous 
system (CNS) prophylaxis, and intensified post-Induction therapy that is very similar for B-ALL and B-
LLy patients. For B-ALL the introduction of risk stratification, based on the risk of treatment failure, is 
used to modulate treatment intensity. The previous classification protocol AALL03B1 used by COG 
identified 4 distinct groups of standard risk B-ALL with different outcomes. The National Cancer Institute 
(NCI) Standard Risk group (> 365 days and < 10 years of age with an initial white blood cell count < 
50 000/μL) was divided into Standard Risk low (SR-Low), Standard Risk Average (SR-Avg), Standard Risk 
High (SR-High) and Very High Risk (VHR) subgroups. A revised risk stratification system was 
implemented in 2010 when the second generation of frontline COG ALL trials opened to accrual, including 
this trial. The new classification study, AALL08B1, will continue to stratify B-ALL patients based on the 
combination of NCI risk group, sentinel cytogenetic lesions, clinical variables (CNS and testicular disease 
status) and early treatment response. Day 8 and 15 bone marrow (BM) morphology will no longer be used 
to assess early response and will be replaced by minimal residual disease (MRD) in peripheral blood (PB) 
at Day 8 and BM at Day 29 of Induction therapy. Based on these findings, B-ALL patients will be stratified 
into 1 of 4 risk groups for post-Induction therapy: Low Risk (LR), Average Risk (AR), High Risk (HR), 
and Very High Risk (VHR) with projected 5 year EFS rates of greater than 95%, 90% - 95%, 88% - 90% 
and less than 80%, respectively. All NCI SR B-ALL patients without central nervous system or testicular 
disease will be eligible to receive Induction on AALL0932. The LR and AR risk groups which are a subset 
of the NCI SR group, represent the patient population eligible to receive post-Induction therapy on 
AALL0932. Standard risk patients with Down syndrome (DS) and Day 29 BM MRD < 0.01% will also be 
eligible to receive post-Induction therapy on AALL0932 on a special stratum that will not include 
randomized questions. In addition, patients with localized (Murphy Stage I and II) B-LLy (without Down 
syndrome, CNS or testicular disease) from 1 - 30 years of age will be enrolled on a separate stratum and 
receive the same common Induction therapy given to B-ALL patients, followed by post-Induction therapy 
similar to the standard arm of the AR B-ALL group without any randomized questions in order to provide 
standardized treatment for children with B-LLy. Down syndrome B-LLy (DS B-LLy) patients will receive 
a modified Induction and post-Induction therapy same as for patients with DS SR B-ALL. 
 
AALL0932 will explore the delivery of Maintenance therapy for children with AR B-ALL. This study will 
compare 2 different doses of methotrexate during Maintenance administered with and without a reduced 
frequency of vincristine/dexamethasone (VCR/DEX) pulses, every 12 weeks compared to every 4 weeks, 
respectively, in a 2 x 2 design. Average Risk B-ALL patients will be randomized to 1 of 4 Maintenance 
regimens: (A): VCR/DEX pulses at 4 week intervals and oral methotrexate at 20 mg/m²/week (standard 
arm); (B): VCR/DEX pulses at 4 week intervals and oral methotrexate at 40 mg/m²/week; (C): VCR/DEX 
pulses at 12 week intervals and oral methotrexate at 20 mg/m²/week; and (D): VCR/DEX pulses at 12 week 
intervals and oral methotrexate at 40 mg/m²/week. Patients on all arms will receive intrathecal methotrexate 

 
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9 
every 12 weeks during Maintenance and the duration of therapy will continue to be gender-based. During 
the first quarter of 2017, the Data and Safety Monitoring Committee (DSMC) released data that a 
futility boundary was crossed and that the study would not be able to demonstrate that 40 
mg/m²/week of methotrexate is superior to 20 mg/m²/week of methotrexate. With Amendment #5, 
and effective January 13, 2017, the study committee recommended that all patients randomized to 
receive 40 mg/m²/week of methotrexate (Arms B and D) during maintenance have their dose lowered 
to 20 mg/m²/week, the standard of care therapy, even if they are tolerating higher doses. 
Subsequently, patients should have their doses of 6 mercaptopurine and methotrexate adjusted based 
on tolerability following normal dose escalation procedures, as outlined in the protocol Section 5.9. 
 
AALL0932 also seeks to confirm that children with LR B-ALL can obtain outstanding outcomes using 
either a P9904 based regimen that includes 6 courses of intermediate dose (1 g/m2 over 24 hours) 
methotrexate without alkylating agents or anthracyclines (Arm LR-M), or one identical to that of AR 
patients receiving regimen C Maintenance as above (Arm LR-C). Low-risk patients will be randomized 
between these 2 treatments arms. The goal will not be to prove superiority of 1 regimen, but rather to 
determine if excellent outcomes (at least 95% five-year disease-free survival) are obtained. If both regimens 
meet this benchmark, then physicians and families can select the treatment that they prefer for low risk 
patients in the future. Another important goal of this study is to provide safe and standardized therapy to 
DS patients with SR B-ALL and DS B-LLy, and to facilitate further study of this biologically and clinically 
unique subgroup.  
 
This trial will also incorporate prospective, standardized assessments of health related quality of life 
(HRQOL) among children with AR B-ALL using performance-based and parent-reported measurements. 
These data will serve as the basis for future screening and intervention strategies to minimize the morbidity 
of ALL and its therapy in the growing proportion of children with ALL that are cured. UPDATE: 
Enrollment to both ancillary QOL studies is closed because accrual goals have been met. 
 
For patients with B-LLy, minimal marrow disease (MMD) and recurrent cytogenetic abnormalities by FISH 
at diagnosis will be studied to improve the understanding of the biology of localized B-LLy. Closed 
effective Amendent #5. 
 
As of Amendment 3A, accrual goals for the Average Risk (AR) B-ALL cohorts have been met, therefore 
AR and Low Risk (LR) B-ALL patients will no longer receive post-Induction treatment on AALL0932. 
These patients will still be able to receive Induction treatment and risk stratification on AALL0932. Upon 
completion of Induction, AR and LR patients will come off protocol therapy. HR patients may be eligible 
for enrollment onto AALL1131 after Induction. There are no changes to enrollment for DS, B-LLy, or DS 
B-LLy patients. AR and LR B-ALL patients enrolled before accrual goals for AR patients have been met 
will continue to receive Post-Induction treatment on AALL0932. 
 
Given the significantly inferior EFS reported for non-DS B-ALL patients with CNS2 disease treated on 
AALL0331 and AALL0232 and the available safety data on the use of more frequent IT therapy during 
Induction, with Amendment 4, we are modifying Induction on AALL0932 for patients with CNS2 disease 
such that they will receive twice weekly intrathecal therapy during Induction until 3 consecutive CSF 
samples after diagnosis are clear of blasts. 
 
In addition to the change in maintenance methotrexate dosing for AR patients, Amendment #5 includes 
details regarding the planned transition from AALL08B1, Classification of Newly Diagnosed Acute 
Lymphoblastic Leukemia (ALL) to APEC14B1 (Project:EveryChild, A Registry, Eligibility Screening, 
Biology and Outcome Study) for B-ALL patients, and the discontinuation of MMD testing for B-LLy 
patients. 
 

 
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 Version Date: 04/11/2016 
10 
 
EXPERIMENTAL DESIGN SCHEMA (B-ALL Patients): FOR PATIENTS ENROLLED BEFORE ACCRUAL GOALS FOR AR PATIENTS 
HAVE BEEN MET  
 
ARM A  
VCR/ DEX pulses 
every 4 weeks  
 
PO MTX 
20mg/m2/week 
ARM D 
VCR/ DEX pulses 
every 12 weeks  
 
PO MTX 
@20mg/m2/week 
ARM B 
VCR/ DEX pulses 
every 4 weeks  
 
PO MTX 
@20mg/m2/week 
ARM C 
VCR/ DEX pulses 
every 12 weeks  
 
PO MTX 
20mg/m2/week 
ARM LR-C  
VCR/ DEX pulses 
every 12 weeks  
 
PO MTX 
20mg/m2/week 
ARM DS 
VCR/DEX pulses 
every 12 weeks  
 
PO MTX 
20mg/m2/week 
Delayed Intensification  
(8 weeks) 
Interim Maintenance II  
(8 weeks) 
Maintenance  
(12 week cycles) & 
Randomization 
Delayed Intensification  
(8 weeks) 
Interim Maintenance II  
(8 weeks) 
Maintenance  
(12 week cycles) % 
Maintenance  
(16 week cycles)^ 
Interim Maintenance I  
(8 weeks) 
Delayed Intensification  
(8 weeks) 
Interim Maintenance II  
(8 weeks) 
Maintenance  
(12 week cycles) & 
ARM LR-M 
VCR/ DEX pulses 
every 16 weeks  
 
PO MTX 
20mg/m2/week 
AR B-ALL# 
Interim Maintenance I  
(8 weeks) 
Consolidation  
(4 weeks) 
DS SR B-
Consolidation  
(4 weeks) 
Interim Maintenance I  
(8 weeks) 
LR B-ALL# 
Consolidation 
(19 Weeks) 
Randomization 
Consolidation  
(4 weeks) 
 
ARM LR-M 
 
ARM LR-C 
* NCI/Rome Criteria 
** Induction Therapy – 4 weeks/ 3 drugs.  
Note: Leucovorin rescue will be given after each 
IT MTX for patients with Down syndrome during 
all applicable phases of therapy EXCEPT 
Maintenance. 
# Classification study AALL08B1 criteria (see 
Section 3.3 for further details) 
 
DS SR B-ALL: Day 29 BM MRD < 0.01% 
AR B-ALL: (a) No favorable cytogenetics, CNS1 
or 2, Day 8 PB MRD < 1% & Day 29 BM MRD 
< 0.01%; (b) favorable cytogenetics, Day 29 BM 
MRD < 0.01%; and either Day 8 PB MRD ≥ 
0.01% or CNS2. 
LR B-ALL: Favorable cytogenetics, CNS1, Day 
8 PB & Day 29 BM MRD < 0.01%  
 
Favorable cytogenetics: ETV6/RUNX1 
(TEL/AML1) fusion or double trisomy of 
chromosomes 4 and 10 
 
%Timed from the start of Interim Maintenance I 
for a total of 2 years for both girls and boys. 
 
&Timed from the start of Interim Maintenance I 
for a total of 2 years for girls, and 3 years for 
boys. 
 
^Timed from the date of diagnosis for a total of 
2½ years 
 
@Effective 01/13/17, reduce oral methotrexate 
from 40 mg/m2/week to 20 mg/m2/week 
 
DS SR B-ALL-Standard risk with Down 
syndrome 
LR B-ALL –Low Risk 
AR B-ALL –Average Risk 
HR B-ALL – High Risk 
VHR B-ALL – Very High Risk 
VCR-vincristine 
DEX-dexamethasone 
PO MTX-oral methotrexate 
DS SR B-ALL with 
Day 29 BM MRD 
≥ 0.01% are eligible for 
transfer to the DS 
stratum of the HR trial 
INDUCTION ** 
SR B-ALL * 
CNS1/2 with no testicular leukemia. 
AALL0932 
(On Study) 
AALL08B1 or APEC14B1 
(if open for classification of ALL)
Ph+ patients are eligible 
for transfer to 
AALL1122 or successor 
study by Day 15 of 
Induction. 
HR B-ALL# or VHR B-
ALL# patients are eligible 
for transfer to COG HR or 
VHR trial at the end of 
Induction. 

 
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EXPERIMENTAL DESIGN SCHEMA (B-ALL Patients): FOR PATIENTS ENROLLED AFTER 
ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* NCI/Rome Criteria 
** Induction Therapy – 4 weeks/ 3 drugs.  
Note: Leucovorin rescue will be given after each IT MTX for 
patients with Down syndrome during all applicable phases of 
therapy EXCEPT Maintenance. 
# Classification study AALL08B1 criteria (see Section 3.3 for 
further details) 
 
DS SR B-ALL: Day 29 BM MRD < 0.01% 
AR B-ALL: (a) No favorable cytogenetics, CNS1 or 2, Day 
8 PB MRD < 1% & Day 29 BM MRD < 0.01%; (b) favorable 
cytogenetics, Day 29 BM MRD < 0.01%; and either Day 8 PB 
MRD ≥ 0.01% or CNS2. 
LR B-ALL: Favorable cytogenetics, CNS1, Day 8 PB & Day 
29 BM MRD < 0.01%  
 
Favorable cytogenetics: ETV6/RUNX1 (TEL/AML1) fusion or 
double trisomy of chromosomes 4 and 10 
 
%Timed from the start of Interim Maintenance I for a total of 2 
years for both girls and boys. 
 
DS SR B-ALL-Standard risk with Down syndrome 
LR B-ALL –Low Risk 
AR B-ALL –Average Risk 
HR B-ALL – High Risk 
VHR B-ALL – Very High Risk 
VCR-vincristine 
DEX-dexamethasone 
PO MTX-oral methotrexate 
AALL08B1 or APEC14B1 
(if open for classification of ALL) 
DS SR B-ALL with 
Day 29 BM MRD 
≥ 0.01% are eligible for 
transfer to the DS 
stratum of the HR trial 
SR B-ALL * 
CNS1/2 with no 
testicular leukemia. 
Ph+ patients are eligible 
for transfer to 
AALL1122 or successor 
study by Day 15 of 
Induction. 
HR B-ALL# or VHR B-
ALL# patients are eligible 
for transfer to COG HR or 
VHR trial at the end of 
Induction. 
ARM DS 
VCR/DEX pulses 
every 12 weeks  
 
PO MTX 
20mg/m2/week 
Consolidation  
(4 weeks) 
Delayed Intensification  
(8 weeks) 
Maintenance  
(12 week cycles) % 
Interim Maintenance I  
(8 weeks) 
DS SR B-ALL# 
Interim Maintenance II  
(8 weeks) 
AR B-ALL# 
LR B-ALL# 
OFF PROTOCOL THERAPY 
INDUCTION ** 
AALL0932 
(On Study) 

 
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EXPERIMENTAL DESIGN SCHEMA (B-LLy and DS B-LLy Patients) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AALL0932 
(On Study) 
INDUCTION  
Consolidation  
(4 weeks) 
Interim Maintenance I  
(8 weeks) 
Delayed Intensification  
(8 weeks) 
Interim Maintenance II  
(8 weeks) 
Localized B-LLy and DS B-LLy * 
(CNS1/2 with no testicular lymphoma) 
Maintenance  
(12 week cycles) & 
ARM LLy 
VCR/DEX pulses  
every 4 weeks  
 
PO MTX  
20mg/m2/week 
* Murphy Stages I and II (See Appendix V 
for classification criteria) 
Note:  
 Patients with testicular disease or CNS3 
disease are NOT eligible for this study. 
 Patients with Down syndrome and B-
LLy are eligible for this study.  
 
Note:  
Leucovorin rescue will be given after each 
IT MTX for patients with Down syndrome 
during all applicable phases of therapy 
EXCEPT Maintenance. 
 
End-Induction imaging: Computed 
tomography (CT) ± PET scan (see 7.1d for 
details) 
 
# See Section 11.3 for definitions of 
response criteria. 
 
& Timed from the start of Interim 
Maintenance I for a total of 2 years for both 
girls and boys. 
 
B-LLy: B lineage lymphoblastic lymphoma 
DS B-LLy: B lineage lymphoblastic 
lymphoma with Down syndrome 
PD: Progressive disease 
CR: Complete response 
PR: Partial response 
SD: Stable disease 
VCR: Vincristine 
DEX: Dexamethasone 
PO MTX: Oral methotrexate 
Evaluation 
(CR, PR, SD)#  
Patients with PD# 
are off protocol 
therapy. Further 
therapy is at the 
discretion of the 
treating physician. 
ARM DS 
VCR/DEX pulses  
every 12 weeks  
 
PO MTX  
20mg/m2/week  
Interim Maintenance I  
(8 weeks) 
Delayed Intensification  
(8 weeks) 
Interim Maintenance II  
(8 weeks) 
Maintenance  
(12 week cycles) & 
DS B-LLy 
B-LLy 
Consolidation  
(4 weeks) 
Evaluation 
Patients++, who fail to achieve 
CR are off protocol therapy. 
 
++Except patients with bone 
primaries who are considered 
CR if there is resolution of all 
surrounding soft tissue 
components. 
 
Further therapy is at the 
discretion of the treating 
physician. 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
As current target accrual goals for AR patients have been met, there will be a sufficient number of patients 
enrolled and anticipated to be randomized in order to meet the following protocol objectives: 
 
Primary Objectives: 1.1.1, 1.1.2, 1.1.3 
Secondary Objectives: 1.2.1, 1.2.2 
 
1.1 
Primary Objectives 
 
1.1.1 
To determine if a Maintenance regimen containing weekly oral methotrexate at 40 mg/m²/week will result 
in an improved disease free survival (DFS) compared to that containing weekly oral methotrexate at 
20 mg/m²/week in the AR subset of patients with Standard Risk B-ALL. Complete effective January 13, 
2017. 
 
1.1.2 
To determine whether a reduced-pulses Maintenance regimen with vincristine/dexamethasone pulses 
delivered every 12 weeks can be used without adversely impacting DFS as compared to pulses given every 
4 weeks in the AR subset of patients with Standard Risk B-ALL. 
 
1.1.3 
To confirm that patients in the LR subset of Standard Risk B-ALL, based on clinical and cytogenetic 
features and minimal residual disease (MRD) criteria, can attain a 5 year DFS of at least 95% with either a 
P9904 based regimen that includes 6 courses of intermediate dose (1 g/m2 over 24 hours) methotrexate 
without alkylating agents or anthracyclines (Arm LR-M), or an outpatient based regimen identical to that 
of AR patients with reduced vincristine/dexamethasone pulses at 12 week intervals during Maintenance 
(Arm LR-C) 
 
1.1.4 
To provide standardized treatment and enhanced supportive care to children with SR DS B-ALL in order 
to improve outcomes and facilitate further study of this biologically and clinically unique patient subgroup. 
 
1.1.5  
To improve understanding of the biology of localized B-LLy and DS B-LLy by obtaining biologic data, 
including FISH for recurrent cytogenetic lesions on paraffin specimen, and banking tissue for future 
research. 
 
1.1.6 
To describe the 5-year EFS and overall survival (OS) of patients with Murphy Stage I and II B-LLy receiving 
modified AR B-ALL therapy. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To assess the burden of AR B-ALL therapy as measured by surveys of the child’s quality of life, missed 
days of school/daycare/work by children and parents, family functioning, parental perception of the child’s 
health vulnerability, physical functioning, and emotional distress, 1) overall at different time points during 
and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. every 12 week 
dexamethasone/vincristine pulses during Maintenance. Closed to accrual as of April 19, 2013. 

 
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1.2.2 
To characterize the onset, severity, and natural history of vincristine associated neuropathy by physical 
therapists (or occupational therapists) in children undergoing therapy for AR B-ALL, 1) overall at different 
time points during and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. 
every 12 week dexamethasone/vincristine pulses during Maintenance. Closed to accrual as of March 15, 
2013. 
 
1.3 
Exploratory Objectives 
 
1.3.1 
To explore the correlation of minimal marrow disease (MMD) at diagnosis and outcome for patients with 
B-LLy. Closed effective Amendment #5. 
 
 
2.0 
BACKGROUND 
 
2.1 
Rationale for Selected Approach and Trial Design for B-ALL  
 
After announcement/posting that accrual goals for the Average Risk (AR) B-ALL cohorts have been 
met, AR and Low Risk (LR) B-ALL patients will no longer receive post-Induction treatment on 
AALL0932. These patients will still be able to receive Induction treatment and risk stratification on 
AALL0932. Upon completion of Induction, AR and LR patients will come off protocol therapy. HR 
patients may be eligible for enrollment onto AALL1131 after Induction. There are no changes to 
enrollment for DS, B-LLy, or DS B-LLy patients. 
 
AR and LR B-ALL patients enrolled before accrual goals for AR patients have been met will continue 
to receive Post-Induction treatment on AALL0932. 
 
The merger of the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG) into the 
Children’s Oncology Group (COG) provided a unique opportunity to develop a new classification system 
that built upon the experience of both groups.1 The outcome of over 8,000 patients was assessed with regard 
to clinical and biological variables tracked by both groups (NCI risk group, favorable or unfavorable 
cytogenetic features and early response to therapy). The goal was to define groups with different risks of 
relapse for which different post-Induction therapeutic questions could be asked. These analyses provided 
the rationale for the AALL03B1classification. 
 
With data now mature from the P9900 series of acute lymphoblastic leukemia (ALL) studies, a revised risk 
stratification system has been developed and implemented in the second generations of COG trials for 
newly diagnosed ALL. The new classification study, AALL08B1, will continue to use a combination of 
NCI risk group, sentinel cytogenetic lesions, clinical variables (CNS and testicular status) and early 
treatment response. Day 8 and Day 15 bone marrow (BM) morphology will no longer be used to assess 
early response and will be replaced by minimal residual disease (MRD) in peripheral blood (PB) at Day 8 
and BM at Day 29 of Induction therapy. Based on these findings, patients with B-lymphoblastic leukemia 
(2008 WHO classification), also termed B-precursor ALL will be stratified into 1 of 4 risk groups for post-
Induction therapy: Low Risk (LR), Average Risk (AR), High Risk (HR), and Very High Risk (VHR) with 
projected 5 year EFS rates of greater than 95%, 90% to 95%, 75% to 90% and less than 75%, respectively.  
 
This trial provides 3 drug Induction therapy to children with NCI SR B-lymphoblastic leukemia (B-ALL). 
At the end of Induction, children with SR B-ALL (without Down syndrome [DS]) will be further classified 
as LR or AR. Children with SR B-ALL and Down syndrome (DS SR B-ALL) will receive Induction and 
post-Induction therapy on a separate stratum of this protocol. The LR group consists of a selected group of 

 
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NCI SR patients with favorable cytogenetic features (ETV6/RUNX1 formerly known as TEL-AML1 fusion 
or simultaneous trisomies of chromosomes 4 and 10), CNS 1 status, PB MRD < 0.01% at Day 8 of 
Induction, and BM MRD < 0.01% at Day 29 of Induction and an estimated 5 year EFS of greater than 95%.2 
AALL0932 seeks to confirm that children with LR B-ALL can obtain outstanding outcomes using either a 
P9904-based regimen that includes 6 courses of intermediate dose (1 g/m2 over 24 hours) methotrexate 
without alkylating agents or anthracyclines (Arm LR-M), or one identical to that of AR patients receiving 
regimen C Maintenance (see below) (Arm LR-C). Low-risk patients will be randomized between these 2 
treatments arms. The goal will not be to prove superiority of 1 regimen, but rather to determine if excellent 
outcomes (at least 95% 5 year disease free survival) are obtained. The AR group consists of a selected 
group of NCI SR patients with favorable or neutral cytogenetic features who have Day 8 PB MRD < 1%, 
Day 29 BM MRD < 0.01% and an estimated 5 year EFS of approximately 92% - 94%. The estimated 2% - 
3% of DS SR B-ALL patients will receive modified Induction and post-Induction therapy as part of this 
protocol, but will not be included in the randomized questions addressed in post-Induction therapy for SR 
children without DS because of their higher risk of treatment-related morbidity and mortality. 
 
The most recent trial for NCI SR patients, AALL0331, asked one randomized question regarding the value 
of intensified vs. standard Consolidation following a 3 drug Induction for SR-Avg patients. The AALL0331 
SR-Avg study previously asked a second question regarding the relative merit of augmented therapy during 
the Interim Maintenance (IM) and Delayed Intensification (DI) phases. AALL0331 was amended in Spring 
2008, when maturation of data demonstrated a superior outcome associated with the use of escalating IV 
methotrexate/vincristine during IM on CCG-1991.3 All rapid early responder (RER) patients on AALL0331 
subsequently received this schedule of IV methotrexate and vincristine during a single IM phase, such that 
only the Consolidation question was studied in this population. 
 
While data from AALL0331 regarding an optimal Consolidation regimen for these patients are maturing, 
AALL0932 explores the delivery of Maintenance therapy for children with the AR subset of SR B-ALL. 
This study compares 2 different doses of methotrexate during Maintenance administered with and without 
a reduced frequency of vincristine/dexamethasone (VCR/DEX) pulses, every 12 weeks compared to every 
4 weeks, respectively, in a 2 x 2 design. Patients are randomized to 1 of 4 Maintenance regimens: (A): 
VCR/DEX pulses at 4 week intervals and oral methotrexate at 20 mg/m²/week (standard arm); (B): 
VCR/DEX pulses at 4 week intervals and oral methotrexate at 40 mg/m²/week; (C): VCR/DEX pulses at 
12 week intervals and oral methotrexate at 20 mg/m²/week; and (D): VCR/DEX pulses at 12 week intervals 
and oral methotrexate at 40 mg/m²/week. Patients on all arms receive intrathecal methotrexate every 12 
weeks during Maintenance and the duration of therapy will continue to be gender-based; namely 2 years 
from the start of IM I for girls and 3 years from the start of IM I for boys, consistent with recent COG ALL 
trials. The Data and Safety Monitoring Committee (DSMC) regularly monitors trial progress and released 
data that a futility boundary was crossed and that the study would not be able to demonstrate that 40 
mg/m²/week of methotrexate is superior to 20 mg/m²/week of methotrexate. Effective January 13, 2017, a 
recommendation was made to reduce weekly methotrexate dose to 20mg/m2/week, for all patients receiving 
40 mg/m²/week of methotrexate during Maintenance. Subsequently, patients should have their doses of 6 
mercaptopurine and methotrexate adjusted based on tolerability following normal dose escalation 
procedures, as outlined in the protocol Section 5.9. 
 
2.1.1 
Rationale for 2 Interim Maintenance Phases 
CCG-1991 was a study for children with SR B-ALL, regardless of blast cytogenetic features. Patients with 
SR B-ALL with rapid early response to Induction therapy (Day 15 BM M1 or M2; M1 required if Day 8 
BM was M3; Day 29 BM M1) and no unfavorable cytogenetic features (no t(9;22), balanced t(1;19), t(4;11), 
or hypodiploidy < 45 chromosomes were randomized in a 2 x 2 design to receive one or two DI phases and 
were also randomized to receive 2 different IM phases, one with oral MTX and one with IV escalating 
MTX without leucovorin rescue. There was no benefit to adding a second DI phase3; recent updates show 
5 year EFS of 90.9 ± 1.3% for the single DI regimens, and 90.5 ± 1.3% for the double DI regimens (p = 

 
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0.71). The IV escalating methotrexate IM regimen was superior to oral methotrexate regimen, with 5 year 
EFS of 92.6 ± 1.2% vs. 88.7 ± 1.4% (log rank p = 0.009, RHR = 1.48).3 Based on these results, children 
with AR B-ALL enrolled in AALL0932 will receive 2 IV methotrexate-based IM phases as given in CCG-
1991 with a single DI phase (CCG 1991 regimen IS). 
 
2.1.2 
Rationale for a Randomized Comparison of Oral Methotrexate Doses During Maintenance 
AALL0932 explores optimal oral methotrexate (MTX) dosing during Maintenance as this agent is a key 
component of Maintenance, or Continuation therapy. The poor bioavailability of oral MTX and inter-patient 
variability in plasma MTX levels following oral doses has been well documented.4-7 Though incomplete 
absorption has been documented at all dose levels, saturation of absorption appears to occur at oral doses 
of approximately 40 mg/m2,6,7 suggesting that at doses of only 20 mg/m2 absorption is not saturated for 
many patients. Higher oral doses may deliver more MTX and may enhance efficacy, either directly, or 
through inhibition of xanthine oxidase, which may decrease the first pass effect on the oral 6-
mercaptopurine (6-MP) and increase its bioavailability4,5,8,9.  
 
Recent trials from both St. Jude Children’s Research Hospital (SJCRH) and University of Texas 
Southwestern Medical Center/Dallas Fort Worth (DFW) have used weekly 40 mg/m2 doses of MTX without 
excessive toxicity.10,11 This higher weekly MTX dose of 40 mg/m2 was administered orally in the DFW 
protocol and has been administered intravenously (IV) in SJCRH regimens, beginning in the mid-1980s. 
This dose of MTX has been well tolerated, in combination with daily doses of 6-mercaptopurine (6-MP) of 
75 mg/m2, during Continuation therapy. Specifically, on the Total XII protocol, among children who have 
the thiopurine S-methyltransferase (TPMT) wild-type phenotype, 84% of the oral 6-MP and parenteral 
methotrexate doses were delivered12,13. Although MTX has been administered IV or intramuscularly (IM) 
on SJCRH studies, differences in tolerability and outcomes were not observed on a United Kingdom (UK) 
ALL study which compared identical 20 mg/m2 doses of MTX, administered IV/IM vs. orally 14. In addition, 
nightly oral 6-MP at 75 mg/m2 was well tolerated in combination with 40 mg/m2 weekly oral methotrexate 
during Continuation therapy in a study of 243 children with ALL enrolled in the DFW protocol. This 
combination did not result in excessive toxicity and an overall EFS of 73% was observed among patients 
of all risk groups 11. Notably, increased exposure to IV MTX in two 8-week IM phases also led to significant 
EFS improvements in CCG-1991 3 
 
2.1.3 
Rationale for the Recommendations of Dose Modifications for 6-MP and Methotrexate 
For more than 10 years, dose modifications in the SJCRH ALL protocols have been based on a combination 
of measurements of thioguanine metabolites, TPMT status and clinical tolerance. This approach to 6-MP 
dose modification has enhanced the specificity of 6-MP dosing and optimized dosing of other agents during 
continuation therapy. Efforts have also been made to ensure the continuous delivery of MTX and 6-MP 
during Continuation as prior studies have demonstrated that interruptions in therapy due to profound 
neutropenia have correlated with inferior outcomes12. To this end, the threshold dose modification on 
SJCRH protocols has been lower than on recent COG studies. Specifically, full doses of MTX and 6-MP 
have been administered unless WBC falls below 1,500/μL, the ANC falls below 300/μL, or platelets fall 
below 50 000/μL or toxicity arises12,15. The dose modification section for AALL0932 has uniform 
modification guidelines for the arms of the study and is designed to facilitate continuous delivery of optimal 
doses of 6-MP and methotrexate, to ensure that the dose of methotrexate will differ between the treatment 
arms. For patients who do not tolerate their assigned MTX dose, TPMT testing and specific dose 
adjustments are recommended because there are compelling data demonstrating an inverse relationship 
between TPMT activity and thioguanine nucleotide (TGN) concentrations; with low TPMT activity and 
high TGN correlating with severe bone marrow suppression16,17. Guidelines for dose adjustments for 
patients who experience either significant myelosuppression or prolonged periods of high blood counts 
despite increased doses of 6-MP and MTX are included in protocol Section 5.9. 
 

 
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2.1.4 
Rationale for a Randomized Comparison of Vincristine/Dexamethasone Pulse Frequency During 
Maintenance in Average Risk Subset of SR B-ALL 
Given the excellent outcomes predicted for the SR patient population, another primary objective of this 
study will be to determine if these excellent outcomes can be maintained with every 12 week as opposed to 
every 4 week VCR/DEX pulses during Maintenance therapy. Reduced-pulses Maintenance will lessen the 
burden of therapy by decreasing cumulative exposure to dexamethasone and vincristine in Maintenance by 
two-thirds, with the aim of improving aspects of quality of life during therapy known to be affected by ALL 
treatment. These include vincristine-associated declines in fine motor and sensory-perceptual 
performance.18 Dexamethasone is associated with myopathy-associated pain,19 emotional lability, and 
disruptive behaviors.20 The efficacy of vincristine/prednisone (VCR/PRED) pulses was first established in 
CCG-161 with lower risk patients randomized to receive or not receive monthly vincristine/prednisone 
pulses. There was a statistically significant improvement in EFS associated with the delivery of the pulses.21 
However, this therapy included a prednisone-based Induction, and no Delayed Intensification. Similarly, a 
meta-analysis of randomized ALL trials22 showed a statistically significant advantage of 
vincristine/prednisone pulses on EFS, but there was no effect on overall survival (OS). The strongest effect 
on Maintenance therapy was seen in the 2 to 9 year old age group. However, this analysis was limited to 
trials that began before 1987, which are not reflective of contemporary therapy. None of the regimens used 
a dexamethasone-based Induction; none included a Delayed Intensification phase and overall EFS, was less 
than 70%. More recently, CCG-189123 administered a 3 drug prednisone Induction, and randomized 
intermediate risk B-ALL patients to receive one vs. two DI phases and every 3 week vs. every 4 week 
VCR/PRED Maintenance pulses in the context of a single DI phase. This study showed no advantage to 
more frequent Maintenance pulses. 
 
The Berlin-Frankfurt-Münster (BFM) group has not typically used any vincristine/steroid pulses during 
Maintenance therapy and attains cure rates very similar to those obtained in COG trials. Recently, the I-
BFM-SG ALL IR-95 trial randomized 2,935 intermediate risk patients to Maintenance regimens with and 
without six pulses that consisted of 7 days of DEX with VCR given on Days 1 and 8 of each pulse. The 
outcomes of the 2 groups were virtually identical with 7 year disease free survival rates of 77.5% with 
pulses and 78.4% without pulses, showing no benefit to pulses in the context of their treatment regimen24. 
Though this result is encouraging, it is not directly applicable to COG trials for SR patients since BFM 
therapy includes anthracycline therapy during Induction for all patients as well a more intensive 
Consolidation phase and 4 high dose MTX courses. Nevertheless, as summarized above, efficacy of 
vincristine/steroid pulses was only firmly established in regimens used during the 1970s and 1980s that did 
not use dexamethasone during Induction, did not administer a DI phase, and attained overall cure rates 
substantially below the 90% - 95% cure rate seen with modern SR B-ALL regimens. 
 
In contrast, the European Organization for Research and Treatment of Cancer (EORTC) presented data in 
abstract form recently from their randomized Phase III 58951 study comparing 6 pulses of vincristine and 
corticosteroid every 10 weeks vs. no pulses during Continuation therapy in 411 children with average risk 
B-ALL (n = 384) and non-Hodgkin lymphoma (n = 27).25 Superior outcomes were reported in those 
randomized to receive pulses with 6 year disease-free survival rates of 90.6% ± 2.1% vs. 82.2% ± 2.8%, (p 
= 0.027 ). Note, however, that given the overall duration of Maintenance therapy, the reduced pulses on 
AALL0932 still provides more vincristine and corticosteroid exposure than the “plus pulses” arm of that 
study. Some of the EORTC patients were included in the I-BFM-SG ALL IR-95 trial discussed above, 
which showed no benefit to VCR/DEX pulses in a much larger patient cohort. 
 
It is also important to note that the COG P9904/5 trials administered VCR/DEX pulses every 12 – 16 weeks 
during Maintenance. While outcome for SR B-ALL patients enrolled in 9904/5 was modestly inferior to 
that obtained on CCG-1991 conducted at the same time, this difference is likely accounted for by the fact 
that more than half of patients enrolled in 9904/5 did not receive a DI phase, and therapy was not intensified 
for patients with a poor early response on 9904/5. Accordingly, there is precedent for using less frequent 

 
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VCR/DEX Maintenance pulses in recent COG trials and there are no compelling data to indicate that 
monthly pulses are needed in the context of more effective contemporary chemotherapy regimens. 
AALL0932 will definitely establish the role of monthly Maintenance VCR/DEX pulses in SR B-ALL. 
 
A further potential benefit of reducing the number of VCR/DEX pulses during Maintenance is a reduction 
in the burden of therapy related to corticosteroids and vincristine. We specifically are interested in 
measuring if the less frequent Maintenance pulse schedule will improve altered self- and parent-reported 
quality of life in patients as documented in the ongoing AALL0331 study26, parent perception of the child’s 
health vulnerability27, physical28 and emotional functioning,29 missed days of school/daycare by patients 
and work by parents30,31, and vincristine-associated declines in fine motor and sensory-perceptual 
performance18,32. As discussed in detail later in this protocol document, we propose to directly assess these 
key outcomes in 2 integrated Health Related Quality of Life (HRQOL) ancillary studies (see protocol 
Sections 15.0 and 16.0). UPDATE: Enrollment to both ancillary QOL studies is closed because accrual 
goals have been met. 
 
Patients with SR B-ALL without Down syndrome or LR features will be randomized immediately prior to 
the start of Maintenance therapy using a 2x2 design to 20 mg/m2/week vs. 40 mg/m2/week of methotrexate 
and every 4 week vs. every 12 week VCR/DEX pulses during Maintenance therapy. The baseline EFS 
expected for this SR group is uncertain, as this exact patient group has not been treated with this therapy in 
past studies. Patients that meet this SR definition had a projected 5 year EFS rate of 91% - 93% on P9900. 
The entire group of NCI SR B-ALL patients with a RER based on Day 15 BM status and no unfavorable 
cytogenetic features randomized to the IV MTX IM regimens had a 92.6% 5 year EFS on CCG-1991. This 
included many excellent risk patients with favorable genetic features that will not be included in this trial, 
but also included patients that were MRD positive at end-Induction. Thus we estimate that the baseline 5 
year EFS for AR patients in AALL0932 will be 92% - 94% and have used 93% in the statistical design. 
 
2.1.5 
Inclusion of CNS 2 Patients in Average Risk Subset of SR B-ALL 
Average Risk therapy is appropriate for AR patients with CNS2 status as CCG 1991, upon which this study 
is based, included 67 rapid responding CNS2 patients that participated in the 2x2 randomization. Their 5 
year EFS and OS were 77% (SE = 8.3%) and 92.5% (SE = 5.2%) respectively, as compared to 90.7% ± 
1.0%, and 96.0% ± 1.0% for the entire population of RER patients. Relapses in the CNS were double those 
in the BM in this subset of patients: 9 vs 4. However, the IV methotrexate based IM regimens used in CCG 
1991 provided significant overall benefit that was entirely due to protection from extramedullary relapse. 
Overall on CCG 1991, the patients randomized to the IV methotrexate arms experienced 11 CNS, 5 BM + 
CNS, and 0 testicular relapses. In comparison, patients randomized to the oral MTX based IM regimens 
experienced 26 CNS, 10 BM + CNS, and 7 testicular relapses. While numbers are small for the CNS2 
patients, the incidence of isolated CNS relapses in patients with CNS2 status randomized to the IV MTX 
regimens was less than a third that for those randomized to the PO MTX containing regimens (2/35 vs. 
7/32).3 The combination of dexamethasone in Induction and IV methotrexate during two IM phases appears 
to provide excellent CNS protection for this group. CNS2 patients are explicitly excluded from the low risk 
group. 
 
2.1.6 
Low Risk Subset of SR B-ALL 
Low risk patients will be randomized to 1 of 2 post-Induction therapies on AALL0932. The first regimen 
(Arm LR-M) is based on the excellent outcomes with P9904 therapy (Figure 1). Patients who were NCI SR 
with favorable genetics who lacked CNS or testicular disease, and who had MRD < 0.01% at Day 8 (PB) 
and Day 29 (BM) achieved a 5 year EFS of 97 ± 2% (SE 0.01%) and OS of 98.8 ± 0.8% on P9904.2 P9904 
randomized NCI SR patients with the ETV6/RUNX1 fusion to 1 of 2 methotrexate infusion schedules (1 
g/m2 over 24 hours vs. 2 g/m2 over 4 hours) and ± DI. Patients with trisomies 4 & 10 were included in the 
methotrexate randomization only. Accordingly, approximately 25% of these patients were randomized to 
receive a DI phase, while the other 75% were randomized or assigned to no DI. There is no suggestion of 

 
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benefit to DI among these patients with favorable cytogenetics and no differences in outcome have been 
observed with the different methotrexate schedules. Among 261 patients there have been only 8 events, 
including 6 relapses and 2 second malignant neoplasms. It is unlikely that this outcome will deteriorate 
significantly; to date there has been only 1 event among the 179 patients that are more than 5 years from 
study entry. We anticipate this will translate into long-term EFS of greater than 95%. In addition, patients 
from this group that relapse still have a significant chance of cure. A total of 6 patients have relapsed in this 
group treated on P9904 (2 DI arm, 4 No DI arm). Three were early relapses (< 36 months from diagnosis), 
and 3 were late relapses (≥ 36 months from diagnosis). Three remain alive as of 06/01/2009 (1 early and 2 
late relapses). 
 
 
 
Figure 1. EFS among variably defined groups of good-prognosis patients. NCI SR patients with favorable genetic 
features who were MRD-negative at both Day 8 and Day 29 were the best group, with a 97% ± 1% 5 year EFS. They 
had statistically better outcomes than either patients without the genetic features who had the same MRD 
characteristics (92% ± 3%; P = .020) or end-Induction MRD negative, favorable genetic patients who were Day 8 
MRD positive (93% ± 2%; P = .024)2 
 
Although the evidence on late effects of anthracyclines33,34 and alkylating agents at doses used in CCG-
1991 is inconclusive, it seems prudent to investigate the P9904 regimen that has no exposure to these agents 
given their toxicity and the outstanding EFS attained for LR patients treated without these agents on P9904. 
Note that in a study of 40 pediatric patients with B-ALL who had received only 90 mg/m2 of anthracycline, 
more than 20% had an abnormal left ventricular fractional shortening or afterload.35 
 
The second regimen (Arm LR-C) is based on the outstanding results from CCG-1991 that form the 
backbone for the AR subset. As described in Section 2.2 above, the superior outcome for patients receiving 
Interim Maintenance with intravenous methotrexate compared to oral methotrexate has been reported.3 
Narrowing our focus to outcome for patients with genetic abnormalities eligible for the LR arm, but without 
regard to whether or not they received the more effective intravenous methotrexate regimen or MRD status, 
6 year EFS for randomized patients with trisomy 4 & 10 and ETV6/RUNX1 was 94.5 ± 2.2% and 92.9 ± 
2.6% and 6 year overall survival was 98.6 ± 1.1% and 98.1 ± 1.1%, respectively.36 Thus, even without using 
a filter to remove patients with Day 8 peripheral blood MRD or Day 29 bone marrow MRD > 0.01%, the 6 
year EFS for patients receiving 2 intravenous methotrexate-based IM phases as given in CCG-1991 will 
likely approach or exceed 95% for each of these groups. While intermediate dose methotrexate had been 

 
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administered as a 20 minute bolus followed by a 23.67 hour infusion on P9904, PK modeling demonstrates 
no difference in MTX plasma concentration when given as a 30 minute bolus followed by a 23.5 hour 
infusion (Frank Balis, personal communication). Administration with either of these schemas will be 
allowed based on institutional preference. One modification to the CCG-1991 therapy that will be 
implemented in this regimen is a reduction in the frequency of VCR/DEX pulses to q12 week from q4 
weeks (as in Arm C of the AR subset). Given this outstanding expected outcome, the LR patients 
randomized to this treatment strategy will be non-randomly assigned to receive VCR/DEX pulses every 12 
weeks. This important modification is likely to benefit patients by reducing the burden of therapy.  
 
Thus, there is strong evidence indicating that LR patients can attain a 5 year DFS of > 95% and OS of 98% 
- 99% with either the COG P9904 or CCG-1991 based regimens. This study seeks to validate a very 
important finding, namely that the specific low risk criteria we now define prospectively can identify a 
subset of patients almost certain to be cured. We believe that this is an important goal that has major 
implications for treatment of childhood ALL, and will indeed provide new information. Each regimen has 
relative advantages and disadvantages compared to the other regimen. The COG P9904 therapy includes 
no anthracyclines or alkylating agents, but requires 6 hospitalizations to deliver 24 hour methotrexate 
infusions with accompanying blood draws to monitor methotrexate clearance and additional clinic visits 
during Maintenance. In contrast, the CCG-1991 based regimen includes no inpatient therapy following 
Induction, but during Delayed Intensification may lead to hospitalizations for fever and neutropenia, 
transfusions of blood products and includes 75 mg/m2 of anthracyclines and 1 g/m2 of alkylating agents. 
Given these factors, LR patients will be randomized at the conclusion of Induction therapy to 1 of these 2 
regimens. The goal will not be to prove superiority of 1 regimen, but rather to determine if excellent 
outcomes (at least 95% 5 year DFS) are obtained. If both regimens meet this benchmark, then physicians 
can select the optimal treatment approach based on the needs of the patients and families. 
 
2.1.7 
Children with SR B-ALL and Down syndrome 
Approximately 2% - 3% of children with ALL have Down syndrome, and these DS B-ALL patients have 
an increased risk of treatment related mortality.37 Recently, COG suspended accrual of DS B-ALL children 
to trials for SR (AALL0331) and HR (AALL0232) B-ALL because of excess mortality.38 The trials were 
subsequently reopened after treatment modifications for DS B-ALL patients were introduced. Following 
this safety amendment, there have not been excess deaths among DS SR B-ALL patients enrolled in 
AALL0331; but continued excess mortality among HR B-ALL patients led to permanent closure of 
AALL0232 to patients with DS in January 2008.38 The goal of the DS stratum on this protocol is to improve 
outcomes in children with DS and B-ALL by providing effective therapy, while reducing early deaths from 
toxicity. DS children have therefore been assigned to a DS-specific single-arm, risk based therapeutic 
regimen for Induction and post-Induction therapy, designed in consideration of their increased incidence of 
treatment-related morbidity and mortality. Parents of patients enrolled on this therapeutic trial will have the 
opportunity to consent to optional banking of leukemia and germline specimens on AALL08B1, which will 
facilitate ongoing research to better understand this small but biologically distinct and clinically challenging 
group of patients. Enhanced supportive care guidelines and toxicity monitoring for DS patients are included 
(see Section 8.3) with the goals of prospectively studying treatment related toxicities, and minimizing their 
occurrence. Collection of targeted data on IgG levels, infectious toxicities and febrile neutropenia on 
AALL0932 will identify the relevant types of infectious organisms, sites of infection, timing during ALL 
therapy, and the role of risk factors such as neutropenia and IgG in a large, uniformly treated DS B-ALL 
cohort. The resulting data will provide much-needed evidence for the development of improved supportive 
care recommendations for this subset of B-ALL patients with increased susceptibility to life threatening 
infections. 
 
For DS SR B-ALL patients, the therapeutic changes instituted by the AALL0331 safety amendment 
consisted of leucovorin rescue after intrathecal methotrexate in an attempt to mitigate the known enhanced 
sensitivity to methotrexate toxicity associated with DS39,40, along with elimination of a second DI phase, 

 
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use of interrupted dose dexamethasone during DI phases, and enhanced supportive care recommendations 
As there has been no excessive treatment related mortality among 93 NCI SR DS patients (as of 9/29/2009) 
enrolled since modifications to AALL0331 were instituted, this study will administer Induction therapy 
identical to that given in AALL0331 for NCI SR DS patients except pegaspargase will be administered IV. 
All NCI SR DS patients will be eligible for the DS Induction stratum on this protocol with the exception of 
patients with CNS involvement, testicular disease, or steroid pretreatment. 
 
Following Induction therapy, DS patients with Induction failures or the Philadelphia chromosome will not 
be eligible to continue on a COG ALL trial. Standard risk DS patients that have Day 29 BM MRD ≥ 0.01%, 
KMT2A (MLL) rearrangement, or hypodiploidy are not eligible to receive post-Induction therapy on this 
trial, but will be eligible for post-Induction therapy on the HR protocol. Post-Induction therapy for the 
remainder of NCI SR DS patients is similar to the 1991 IS arm with AALL0331 modifications (including 
leucovorin rescue following intrathecal MTX in all phases prior to Maintenance therapy) for DS patients 
with the exception of reduced frequency VCR/DEX pulses during Maintenance. Two IM phases with IV 
methotrexate were well tolerated among the DS patients on CCG-1991. With the exception of Grade 3 or 
higher stomatitis, which occurred in 28.1% of DS patients who received IV methotrexate during IM#1 and 
26.7% of DS patients during IM #2, all other Grade 3 or higher toxicities observed with escalating IV 
methotrexate during IM were infrequent in children with DS B-ALL. The 5 year EFS for the 77 eligible 
RER DS SR B-ALL patients enrolled on CCG-1991 was 90.1 ± 4.9% overall; with the randomized RER 
DS B-ALL patients attaining 5 year EFS of 83.3 ± 7.6% with oral methotrexate (n = 45) and 100% with IV 
methotrexate (n = 32, p = 0.022). Therefore, the IV MTX based IM regimen is safe and highly effective for 
children with SR DS B-ALL and the CCG-1991 Regimen IS will be used for these patients on AALL0932 
with AALL0331 modifications (including leucovorin rescue following intrathecal MTX in all phases prior 
to Maintenance therapy). Two other differences will be that DS B-ALL patients will be non-randomly 
assigned to every 12 week VCR/DEX pulses during Maintenance, and treatment duration will be 2 years 
from the start of IM#1 for both boys and girls with DS. These changes were made because of the increased 
risk of fatal infectious complications in children with DS B-ALL, which may be heightened by the 
immunosuppressive effects of steroids. Deaths during Maintenance therapy occurred in two HR DS B-ALL 
patients on AALL0232 prior to study closure (E. Larsen, M.D personal communication), and 4 DS patients 
enrolled on the UK ALL 2003 study (A. Vora, M.D, personal communication). 
 
2.1.8 
Exclusion of Patients with Intrachromosomal Amplification of Chromosome 21 (iAMP21) from 
Post-Induction Therapy on AALL0932 
The outcome of patients with intrachromosomal amplification of chromosome 21 (iAMP21) has been 
monitored during the conduct of COG AALL0232 and AALL0331. This monitoring was based on reports 
from other groups of inferior outcomes associated with iAMP21.41-43 COG ALL trials detect iAMP21 due 
to FISH screening for the ETV6-RUNX1 fusion. While earlier analyses suggested that iAMP21 patients had 
outcomes similar to those of non-iAMP21 patients on COG AALL0232 and AALL0331, new analyses with 
larger patient numbers and longer follow-up have shown that the outcome of children with iAMP21 is 
significantly worse than the outcome of those without iAMP21 (Meenakshi Devidas, PhD, unpublished 
data, June 2011). Among NCI SR patients treated on AALL0331 the outcomes for iAMP21 patients (n = 
75) were inferior to non-iAMP21 patients (n = 4,985) overall (4 year EFS 70.4% SE 9.3% vs. 91.8% SE 
0.7%; p < 0.0001) and among those with Day 29 MRD < 0.01% (4 year EFS 81.1% SE 11.1% vs. 94.1% 
SE 0.7%) and those with Day 29 MRD ≥ 0.01% (55.6% SE 15.1% vs. 84.2% SE 2.2%). Therefore with 
Amendment #1, patients enrolled in AALL0932 that are identified to have iAMP21 will be classified as 
Very High Risk and will not be eligible to continue on AALL0932 after Induction therapy, but will be 
eligible to enroll in AALL1131 for post-Induction therapy. 
 
2.2 
Rationale for Selected Approach and Trial Design for Patients with B-LLy 
Children and adolescents with lymphoblastic lymphoma (LLy) are currently treated with therapy derived 
from ALL protocols with disease free survival approaching 80% - 90%. There is a precedent to expand 

 
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ALL trials to include LLy patients, including enrollment of T-NHL patients on AALL0434, and enrollment 
of relapsed T-NHL patients on AALL07P1. Accrual of NHL patients to both of these trials has been more 
robust than anticipated, suggesting overcoming regulatory burdens by enrolling NHL patients to ALL trials 
can increase enrollment and capture of important biological and outcome data. 
 
COG A5971 enrolled patients with B- and T-LLy with modified BFM type ALL therapy. A5971 stratified 
patients by stage (localized [Murphy Stage I and II] versus disseminated [Murphy Stage III and IV]) and 
not by immunophenotype. Out of 380 total accruals, only 11% of patients (n = 42) had precursor B 
phenotype. However, 75% of all patients with localized disease had precursor B phenotype. Those patients 
were enrolled an Arm A0 and received a 4 drug Induction followed by intensified Consolidation with 
cyclophosphamide, cytarabine and mercaptopurine, Interim Maintenance with mercaptopurine and PO 
methotrexate, and standard Delayed Intensification and Maintenance for a total therapy length of 2 years 
from the start of Induction. The outcome of patients with localized B-LLy was a 5 year EFS of 90% (95% 
CI: 74% - 96%) and a 5 year OS of 94% (95% CI: 79% - 99%). 
 
The NHL-BFM study group reported a 5 year-EFS of 86% (SE = 4%) in 73 patient with B-LLy treated on 
NHL-BFM 90 and 95. Among the B-LLy, 27 patients had Murphy Stage I and II, 3 of whom relapsed. 
Therapy consisted of intensive ALL type therapy that included intensified Consolidation (part of Induction 
I in NHL-BFM) and high dose methotrexate in Interim Maintenance (protocol M). Patients with localized 
disease (Murphy Stage I and II) did not receive a Delayed Intensification phase (Re-induction I) which 
reduced the total anthracycline exposure to 120 mg/m2.44 
 
The French reported on 53 children with B-LLy treated on 2 consecutive protocols (LMT 96, EORTC 
58881 and 58951) using BFM derived ALL therapy. LMT96 included cyclophosphamide and high dose 
methotrexate (3 g/m2) in Induction and high dose methotrexate (3 g/m2) in Consolidation but the 
2 consecutive protocols had a standard 4 drug Induction followed by intensified Consolidation as used in 
high risk ALL. All protocols used HD MTX in Interim Maintenance (3 g/m2 x2 in LMT96, 5 g/m2 x 4 in 
EORTC 5881 and 58951). Nineteen of 53 patients had localized disease (Murphy Stage I and II). Patients 
with localized disease received only 2 doses of daunorubicin in Induction and Delayed Intensification, 
respectively, reducing total anthracycline exposure to 120 mg/m2 and did not receive any 
cyclophosphamide either in Consolidation or Delayed Intensification44 in EORTC 58881 and 58951. There 
were no relapses reported in the localized group.45  
 
These data from 3 cooperative groups confirm the excellent outcome patients with B-LLy have with ALL 
derived therapy. Furthermore, A5971 demonstrated that the excellent outcome was preserved without the 
use of HD MTX in Interim Maintenance. Starting with Amendment #2A, patients with localized B-LLy 
(Murphy Stage I and II) will be non-randomly assigned to the standard arm for AR B-ALL with 
Maintenance “Arm LLy”. Patients with localized B-LLy (Murphy Stage I and II) and DS will be non-
randomly assigned to DS SR B-ALL with Maintenance “Arm DS”.  
 
2.2.1 The Rationale for a 3 Drug Induction and Standard Consolidation in B-LLy patients 
The use of a 3 drug Induction instead of a 4 drug Induction reduces the total anthracycline dose to 75 mg/m2 
compared to 175 mg/m2 and the use of standard Consolidation instead of intensified Consolidation reduces 
cyclophosphamide exposure from 3 g/m2 to1 g/m2. The BFM and EORTC groups have shown that dose 
reductions in anthracyclines and cyclophosphamide are feasible. Both the BFM-NHL and EORTC 
protocols used an anthracycline dose of 120 mg/m2 and EORTC did not give any cyclophosphamide to B-
LLy patients with Murphy Stage I and II without jeopardizing outcome. It is hypothesized that these dose 
reductions will not affect outcome and may reduce late effects.  
 

 
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2.2.2 The Rationale for Dexamethasone in Induction 
B-LLy patients regardless of age on AALL0932 will receive dexamethasone as the sole corticosteroid 
during therapy (versus prednisone in A5971). Dexamethasone has been shown in several studies to be 
superior to prednisone in reducing CNS relapses.46-48 A recent meta-analysis of dexamethasone versus 
prednisone included 8 cooperative group studies confirmed the reduction in CNS relapses and showed no 
increased risk of osteonecrosis with dexamethasone versus prednisone. The only study showing an 
increased risk of osteonecrosis in children > 10 years of age was AALL0232; but the dose of dexamethasone 
was higher at 10 mg/m2. EORTC58951 which enrolled patients up to 18 years of age and randomized 
between prednisone (60 mg/m2 x 28 day) and dexamethasone (6 mg/m2 x 28 days) did not show an increased 
risk of osteonecrosis in the dexamethasone arm. 
 
2.2.3 Rationale for 2 Interim Maintenance Phases with Capizzi Methotrexate in B-LLy 
In A5971, patients with localized B-LLy enrolled on Arm A received a single Interim Maintenance phase 
with oral methotrexate and mercaptopurine. Both EORTC and BFM use HD MTX in Interim Maintenance. 
In patients with SR B-ALL enrolled on CCG-1991, the IV escalating methotrexate IM regimen was superior 
to oral methotrexate regimen, with 5 year EFS of 92.6 ± 1.2% vs. 88.7 ± 1.4% (log rank p = 0.009, RHR = 
1.48). Based on these results, children with B-LLy enrolled in AALL0932 will receive 2 IV methotrexate-
based IM phases as given in CCG-1991 with a single DI phase (CCG 1991 regimen IS). 
 
2.2.4 
Rationale for Tissue Collection and Banking in B-LLy patients 
A5971 had very limited specimen collection, particularly in the low stage patients. Only 60% of patients 
had central review of their pathology. There are currently no well defined biological prognostic markers for 
B-LLy.  
 
2.2.5 Rationale for Minimal Marrow Disease Testing at Diagnosis 
Minimal marrow disease (MMD) has been shown to be present in 80% of Stage III T-LLy at diagnosis.49 
On COG AALL0434, MMD is measured at diagnosis in all T-LLy patients enrolled. The importance of 
MMD in B-LLy is currently not known. AALL0932 asks for a single bone marrow at diagnosis to be sent 
for MMD testing and will explore whether it correlates with outcome. Due to changes in funding 
mechanisms and the move to fee per service decentralized MMD testing, effective Amendment #5 
diagnostic MMD for B-LLy patients is closed. 
 
2.2.6 Rationale for Tissue Banking on Subsequent Biologic Studies 
The prognostic significance of recurrent cytogenetic abnormalities in B-ALL has been well described and 
patients with B-ALL are currently risk stratified based on the cytogenetic profile of their blasts. There is a 
paucity of data on cytogenetic abnormalities in B-LLy because in prior studies both obtaining and 
successfully performing cytogenetic analyses on fresh tissue has been difficult. Biology studies will include 
a limited cytogenetic analysis by fluorescence in-situ hybridization (FISH) combined with single nucleotide 
polymorphism (SNP) analysis. The advantage of these methods is that they can be performed on formalin 
fixed paraffin embedded (FFPE) tissue. If they prove feasible they will be the tool for a better classification 
of B-LLy.  
 
2.3 
Development Plans 
AALL0932 seeks to refine Maintenance therapy for patients with SR B-ALL by defining an optimal MTX 
dose and reducing the burden of therapy by reducing the frequency of VCR/DEX pulses. HRQOL measures, 
parent’s perception of child’s health vulnerability, fewer missed days of school/daycare by patients and 
work by parents and peripheral neurological functioning will be compared in children receiving different 
VCR/DEX pulses frequencies to systematically assess the impact of treatment. These proposed changes 
will occur exclusively during the Maintenance phase of therapy while data from AALL0331 are maturing. 
AALL0331 seeks to define the optimal Consolidation therapy for a very similar patient population. We 
anticipate that the best arm of AALL0932, paired with the optimal Consolidation schedule determined in 

 
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AALL0331, will become the standard regimen for patients with SR B-ALL in future studies. The results of 
AALL0932 will have important implications for other ALL risk groups. For example, if excellent outcomes 
are preserved with a reduction in VCR/DEX exposure in these SR patients, a similar reduction could be 
considered for NCI high risk patients, where osteonecrosis is a much more significant concern. Further, if 
a higher dose of methotrexate improves outcomes and is not associated with excess toxicity, this dosage 
could be adopted in Maintenance regimens for other risk groups. Finally, the success of this study will 
depend on strict adherence to dosing modification guidelines for oral methotrexate and 6-MP and the 
guidelines used in this study could similarly be incorporated into trials for other risk groups with the 
potential for individualization of dosing using TPMT status, among other parameters, in the future. Another 
important goal of this trial is to confirm that children with LR B-ALL can attain > 95% 5 year DFS with 
either a P9904-based regimen that includes no alkylating agents or anthracyclines (Arm LR-M) or a CCG 
1991-based regimen with vincristine/dexamethasone pulses at 12 week intervals during Maintenance (Arm 
LR-C). If both regimens meet this benchmark, then physicians and families can select the treatment that 
they prefer for LR B-ALL patients in the future. Finally, another important goal of this study to provide 
safe and standardized therapy to DS patients with SR B-ALL, and to facilitate further study of this 
biologically and clinically unique subgroup. 
 
By including patients with localized B-LLy, this protocol will offer a unified approach to the treatment of 
all patients with standard risk B lymphoblastic lymphoma/leukemia and may lead to a reduction of late 
effects by reducing the dose of cyclophosphamide and anthracycline exposure in B-LLy patients. The 
exploration of MMD and cytogenetic abnormality by FISH may lead to better risk stratification of B-LLy 
patients in the future. 
 
2.4 
Patient Enrollment After AR B-ALL Accrual Goals Have Been Met 
 
After announcement/posting that accrual goals for the Average Risk (AR) B-ALL cohorts have been met, 
AR and Low Risk (LR) B-ALL patients will no longer receive post-Induction treatment on AALL0932. 
These patients will still be able to receive Induction treatment and risk stratification on AALL0932. Upon 
completion of Induction, AR and LR patients will come off protocol therapy. HR and VHR patients may 
be eligible for enrollment onto AALL1131 after Induction. There are no changes to enrollment for DS, B-
LLy, or DS B-LLy patients. 
 
AR and LR B-ALL patients enrolled before accrual goals for AR patients have been met will continue to 
receive Post-Induction treatment on AALL0932. 
 
2.5 
Rationale for additional IT therapy for Non-Down Syndrome (Non-DS) B-Acute 
Lymphoblastic Leukemia (B-ALL) Patients with Central Nervous System 2 (CNS2) Disease 
(Amendment # 4) 
Results of COG AALL0232 and AALL0331 for patients with non-DS B-ALL demonstrate significantly 
inferior outcomes for patients with CNS2 and CNS3 disease compared to those with CNS1 status. The 
5 year event free survival (EFS) for patients with CNS2 versus CNS3 and CNS1 treated on 
AALL0232/0331 were 76 +2%, 76 +5.2% and 85 +0.6%, respectively (p < 0.001). [Personal 
communication, M. Devidas] These differences in EFS are largely the result of CNS relapse rather than 
bone marrow relapse. The incidence of isolated and combined CNS relapse for patients with CNS1 status 
on AALL0232/AALL0331 was 2.9 +0.2% versus 7.8 +0.98% for CNS2 and 5.9 +2.2% for 
CNS3 (p < 0.001). Additionally, there was no significant difference in the rate of bone marrow relapse 
based on CNS status (CNS1 versus CNS2/3; p = 0.1815). No difference in EFS was seen between patients 
with CNS2 due to a traumatic lumbar puncture (TLP) versus CNS2 without a TLP (p = 0.333). In 
multivariate analysis comparing CNS1 to CNS2/CNS3, CNS status remained significant (HR 1.501, 95% 
CI 1.21 – 1.86; p = 0.0002). When analyzing the NCI standard risk (SR) and high risk (HR) patients 
separately, CNS2/3 disease continued to predict worse outcome for both risk groups. SR patients with CNS1 

 
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status on AALL0331 had a 5 year EFS of 90 +0.6% compared to 85 +2% for CNS2 and 82 +7% for CNS3 
(p = 0.0003) and HR patients on AALL0232 with CNS1 status had 5-year EFS of 77 +1% compared to 
67 +3% for CNS2 and 71 +7% for CNS3 (p < 0.0001).  
 
Systemic and intrathecal therapy for HR non-DS B-ALL patients with CNS1 or CNS2 on COG study 
AALL0232 was identical. Only patients with CNS3 disease received more intensive CNS-directed therapy 
during Induction with weekly intrathecal (IT) methotrexate on Days 8, 15, 22 and 29 compared to patients 
with CNS1/2 who received IT methotrexate only on Days 8 and 29. Patients with CNS3 disease did not 
receive IT therapy on Days 15 and 22 of Consolidation but did receive cranial radiation (1,800 cGy) during 
Delayed Intensification. The legacy POG protocols gave additional IT therapy to patients with CNS2 
disease, legacy CCG protocols did not, with both demonstrating a modest increase in risk associated with 
CNS2 disease. The Dana Farber Cancer Institute ALL study DFCI 00-01 gives twice weekly IT cytarabine 
until the cerebral spinal fluid (CSF) clears for three consecutive lumbar punctures during Induction and the 
Berlin-Frankfurt-Munster (BFM) group includes two additional doses of IT methotrexate during Induction 
for CNS2/3 patients. It should be noted, however, that the BFM protocols use less overall IT therapy than 
the COG protocols. St. Jude Children’s Research Hospital gives IT cytarabine Day 1 (as does COG for all 
patients) followed by twice weekly Intrathecal Triple Therapy (ITT) (cytarabine, hydrocortisone, 
methotrexate) in patients with CNS2/3 disease until the CSF is clear of blasts. 
 
Given the significantly inferior EFS reported for non-DS B-ALL patients with CNS2 disease treated on 
AALL0331 and AALL0232 and the available safety data on the use of more frequent IT therapy during 
Induction, we are modifying Induction on AALL0932 for patients with CNS2 disease such that they will 
receive twice weekly intrathecal therapy during Induction until 3 consecutive CSF samples after diagnosis 
are clear of blasts. Patients should receive additional IT Cytarabine on Days 4, 5 or 6 during Induction 
(depending on treatment schedule), IT Methotrexate on Day 8, and then IT Cytarabine on Days 11 or 12. If 
the CSF at all three of these time points is negative for blasts, patients will receive their next IT therapy 
with methotrexate on Day 29. If the CSF remains positive after the initial LP, patients will continue IT 
Cytarabine twice weekly during Induction until the CSF is clear for three consecutive LPs. All patients will 
receive IT therapy with methotrexate on Day 29 at the end of Induction regardless of CSF evaluations. 
 
 
 

 
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3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
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 eRDE system 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.  
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient with a 
known or suspected neoplasm needs to be offered participation in ACCRN07, Protocol for the Enrollment on 
the Official COG Registry, The Childhood Cancer Research Network (CCRN) or 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 VI for detailed CTEP Registration Procedures for Investigators and Associates. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB approval and supporting 
documentation to the Cancer Trials Support Unit (CTSU) Regulatory Office before they can be approved 
to enroll patients. Allow 3 business days for processing. The submission must include a fax coversheet (or 
optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification 
Form may be submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the 
CTSU web page (https://www.ctsu.org). Any other regulatory documents needed for access to the study 
enrollment screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.  
 
IRB/REB approval documents may be submitted via the online portal via www.ctsu.org in the member’s 
section, under the Regulatory Submission Portal where they will be entered and tracked in the CTSU RSS. 
 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab  Regulatory 
Submission 
 
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. 
 
Study centers can check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ web site by entering credentials at 
https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have problems 
with enrollment or the Callback process, email a request for assistance to the COG Help Desk and copy the 
AALL0932 Research Coordinator. See Section 3.1.7 below for full details regarding randomization and 
treatment assignment for patients with LR B-ALL, AR B-ALL, DS SR B-ALL, B-LLy and DS B-LLy. 
 

 
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3.1.4 
Timing 
PATIENTS 
WITH 
B-ALL 
MUST 
BE 
ENROLLED 
ON 
COG 
AALL08B1 
OR 
PROJECT:EVERYCHILD (APEC14B1, IF OPEN FOR CLASSIFICATION OF NEWLY 
DIAGNOSED ALL PATIENTS) BEFORE PROTOCOL THERAPY BEGINS (For the purposes of this 
study, ‘protocol therapy’ does not include the first dose of intrathecal chemotherapy or selected cases of 
steroid pretreatment). PATIENTS THAT BEGIN PROTOCOL THERAPY ON THIS STUDY PRIOR 
TO ENROLLMENT ON AALL08B1 (OR APEC14B1) ARE INELIGIBLE FOR AALL0932. 
 
PATIENTS WITH B-LLy ARE NOT ELIGIBLE FOR ENROLLMENT ON AALL08B1 AND CAN 
ENROLL DIRECTLY ON AALL0932. EVERY EFFORT SHOULD BE MADE TO ACQUIRE AS 
MUCH TISSUE AS POSSIBLE. SPECIFIC INSTRUCTIONS REGARDING TISSUE 
SUBMISSION ARE OUTLINED IN SECTION 14.0. 
 
All Patients:  
 
Informed consent: Except for administration of intrathecal cytarabine or allowable steroid pretreatment 
(defined below), informed consent/parental permission MUST be signed before protocol therapy begins. 
 
Study enrollment: Study enrollment (completion of forms in RDE) 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 protocol therapy is projected to start must be no later than five (5) calendar days after 
enrollment.  
 
Eligibility studies: 
B-ALL: 
Patients must meet all eligibility criteria prior to the start of protocol therapy or enrollment, whichever 
occurs first. Unless otherwise indicated in the eligibility section below, all clinical and laboratory studies 
to determine eligibility must be performed within 7 days prior to the start of protocol therapy or enrollment 
whichever occurs first.  
 
B-LLY: 
Patients must meet all eligibility criteria prior to the start of protocol therapy or enrollment, whichever 
occurs first. Unless otherwise indicated in the eligibility section below, all staging studies to determine 
eligibility must be performed within 7 days prior to the start of protocol therapy or enrollment whichever 
occurs first. The diagnostic biopsy however, does not have to be done within this 7 day time period. 
 
Initiation of systemic protocol therapy: Systemic Induction chemotherapy, with the exception of steroid 
pretreatment as outlined below, must begin within 72 hours of the first dose of intrathecal chemotherapy. 
 
3.1.5 
Staged Consent 
Informed consents will be obtained at critical stages of treatment for the different groups of patients on this 
study. The required consents are different for patients enrolled prior to accrual goals being met than for 
those enrolled after accrual goals have been met (see summary tables below). 
 
Informed consent that describes the first 4 weeks of Induction therapy will be obtained for all patients before 
starting treatment. All patients will receive a common Induction regimen with the exception of children 
with DS SR B-ALL or DS B-LLy, who will also receive 2 doses of oral leucovorin following each dose of 
intrathecal methotrexate during Induction. Patients with B-LLy and DS B-LLy will be approached with a 
single consent prior to starting Induction therapy, which describes all therapy to be received on study. 
 

 
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For patients enrolled before accrual goals for AR patients has been met and all DS B-ALL patients: 
At the end of Induction, after B-ALL patients have been stratified into risk subgroups, a second informed 
consent that describes the next phase of their therapy will be discussed with patients and their families. 
There are separate post-Induction consents for children with LR B-ALL, AR B-ALL, and DS SR B-ALL. 
Patients with AR-subset of SR B-ALL will be approached with a third consent prior to beginning 
Maintenance therapy that describes the 2x2 randomization to 1 of 4 different Maintenance regimens. 
 
For AR and LR B-ALL patients enrolled after accrual goals for AR patients have been met: 
AR and LR B-ALL patients enrolled after accrual goals for AR patients have been met will not receive 
post-Induction treatment on AALL0932. However, upon completion of Induction therapy and risk group 
assignment, AR and LR patients will come off protocol therapy but those patients who are classified at end 
Induction to meet HR-DS, HR and VHR criteria may be eligible for enrollment onto AALL1131 after 
Induction. 
 
Summary of Required Consents for AALL0932: Before Accrual Goals for AR Patients Have Been 
Met 
 
Time Point for Obtaining Consent 
Population for Consent* 
Induction Consent 
Prior to the start of Induction 
 
All SR B-ALL non-Down syndrome 
patients or Down syndrome patients 
(non-randomized) 
Post-Induction 
Consent 
Prior to the start of Consolidation 
 
LR B-ALL (randomized) 
 
AR B-ALL (non-randomized) 
 
DS SR B-ALL (non-randomized) 
Maintenance 
Consent 
Prior to the start of Maintenance 
 
AR B-ALL (randomized) 
Induction and post-
Induction Consent 
Prior to the start of Induction 
 
B-LLy and DS B-LLy (non-
randomized) 
* Each of these groups will sign a separate consent at the designated time points 
 
Summary of Required Consents for AALL0932: After Accrual Goals for AR Patients Have Been 
Met 
 
Time Point for Obtaining Consent 
Population for Consent* 
Induction Consent 
Prior to the start of Induction 
 
All SR B-ALL non-Down syndrome 
patients or Down syndrome patients 
(non-randomized) 
Post-Induction 
Consent 
Prior to the start of Consolidation 
 
DS SR B-ALL (non-randomized) 
Induction and post-
Induction Consent 
Prior to the start of Induction 
 
B-LLy and DS B-LLy (non-
randomized) 
* Each of these groups will sign a separate consent at the designated time points 
 
3.1.6 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.1.7 
Callback for Treatment Assignment/Randomization 
After sufficient AR patients have completed Callback 1 such that accrual goals for AR patients have 
been met, these patients will not receive post-Induction therapy on this study. 
 

 
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For patients enrolled before accrual goals for AR patients have been met: 
There will be 2 Callback procedures performed during this study. The first Callback (Callback #1 – post-
Induction/pre-Consolidation for all patients) is performed for all patients after completion of Induction 
therapy (and subsequent Risk Assignment for the B-ALL patients), and prior to beginning Consolidation 
therapy. Callback #1 will: (1) treatment assign remaining therapy for the DS SR B-ALL patients to Arm 
DS; (2) treatment assign post-Induction therapy through Interim Maintenance II for the AR B-ALL patients; 
and (3) randomly assign the LR B-ALL patients to either Arm LR-M or Arm LR-C; (4) treatment assign 
remaining therapy with Maintenance Arm LLy for the B-LLy patients; and (5) treatment assign remaining 
therapy with Maintenance Arm DS for the DS B-LLy patients. See experimental design schema. 
 
The second Callback (Callback #2 – Maintenance therapy for AR B-ALL patients) is to be performed only 
for the AR B-ALL patients post-Interim Maintenance II therapy within 72 hours prior to the planned start 
of Maintenance therapy. Callback #2 will randomly assign these patients to either treatment Arm A, B, C, 
or D (see experimental design schema.) 
 
For patients enrolled after accrual goals for AR patients have been met: 
There will be no call back for LR, AR, HR and VHR B-ALL patients. 
 
There will be 1 Callback procedure performed during this study. The Callback (Callback #1 – post-
Induction/pre-Consolidation for DS SR B-ALL, DS B-LLy, and B-LLy patients) is performed after 
completion of Induction therapy, and prior to beginning Consolidation therapy. Callback #1 will assign 
remaining post-Induction therapy for the DS SR B-ALL and DS B-LLy patients to Arm DS; as well as non-
DS B-LLy patients. See experimental design schema. 
 
If you have problems with either Callback process, email a request for assistance to the COG Help Desk 
and copy the AALL0932 Research Coordinator. 
 
B-ALL patients classified as AR or LR at the end of Induction will not be eligible for post-Induction therapy 
on this trial. Further treatment for these patients will be up to the discretion of the treating physician. 
 
B-ALL patients classified as HR or VHR at the end of Induction will not be eligible for post-Induction 
therapy on this trial, but may be eligible for enrollment on the COG HR/VHR trial, AALL1131. 
 
B-LLy or DS B-LLy patients with progressive disease (PD) at the end of Induction will not be eligible for 
post-Induction therapy on this trial. 
 
3.1.7.1 LR B-ALL 
LR B-ALL patients enrolled after accrual goals for AR patients have been met will not receive post-
Induction treatment on AALL0932. Further treatment for these patients will be up to the discretion 
of the treating physician. 
 
For patients enrolled before accrual goals for AR patients have been met, randomization for post-Induction 
therapy for patients with LR subset of SR B-ALL is accomplished by completing the Callback in the RDE 
system, after the risk assignment has been completed and consent signed, and prior to the planned start of 
Consolidation therapy. Patients will be randomly assigned to either the Arm LR-M or Arm LR-C; see 
experimental design schema. 
 
3.1.7.2 AR B-ALL 
AR B-ALL patients enrolled after accrual goals have been met will not receive post-Induction 
treatment on AALL0932. Further treatment for these patients will be up to the discretion of the 
treating physician. 

 
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Patients enrolled before accrual goals for AR patients have been met, who are risk-assigned to the AR 
subset of SR B-ALL will sign consent to 7 months of post-Induction/pre-Maintenance therapy prior to 
starting Consolidation. At this time, they will be treatment assigned to this pre-Maintenance therapy via the 
Callback application in the RDE system. They will then sign a third consent and be randomized to 1 of 4 
Maintenance therapy regimens [Treatment Arm A, B, C or D (see experimental design schema)] at the end 
of Interim Maintenance II. Randomization for the AR B-ALL patients is accomplished by going to the 
Callback application in the RDE system for a second time within 72 hours prior to the planned start of 
Maintenance therapy. Effective 01/13/2017 all patients on Arms B or D are recommended to have their oral 
methotrexate dose lowered to 20 mg/m2/week, the standard of care therapy. Subsequently, patients should 
have their doses of 6 mercaptopurine and methotrexate adjusted based on tolerability following normal dose 
escalation procedures, as outlined in the protocol Section 5.9. 
 
3.1.7.3 DS SR B-ALL 
Patients with DS SR B-ALL may consent to non-randomized post-Induction treatment, after risk 
assignment and prior to the beginning of Consolidation therapy. Treatment assignment for these patients is 
accomplished by going to the Callback application in the RDE system at the end of Induction but prior to 
the start of Consolidation. 
 
3.1.7.4 B-LLy or DS B-LLy 
Patients with B-LLy will be non-randomly assigned to post-Induction therapy similar to AR B-ALL with 
Maintenance “Arm LLy”. Patients with DS B-LLy will be non-randomly assigned to post-Induction therapy 
same as for patients with DS SR B-ALL. Treatment assignment for these patients is accomplished by going 
to the Callback application in the RDE system at the end of Induction but prior to the start of Consolidation. 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy 7.2). 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.  
 
INCLUSION CRITERIA 
 
3.2.1 
Classification study 
B-ALL patients must be enrolled on AALL08B1 or APEC14B1 (if open for the classification of newly 
diagnosed ALL patients) prior to treatment and enrollment on AALL0932. 
 
Please note: B-LLy patients are not eligible for AALL08B1, and can enroll directly onto AALL0932. 
 
3.2.2 
Age and WBC Criteria 
 
3.2.2.1 
Patients must be > 365 days and < 10 years of age (for B-ALL patients) 
Patients must be > 365 days and ≤ 30.99 years of age (for B-LLy patients) 
 
3.2.2.2 
B-ALL patients must have an initial white blood cell count < 50,000/μL. 
 
3.2.3 
Diagnosis  
Patients must have newly diagnosed NCI Standard Risk B-ALL or B-LLy Murphy Stages I or II (See 
Appendix V for staging). Patients with Down syndrome are also eligible. 

 
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Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be 
analogous to B-ALL. For tissue processed by other means (i.e. paraffin blocks), the methodology and 
criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting 
institution will be accepted. 
 
EXCLUSION CRITERIA 
 
3.2.4 
Prior Therapy 
With the exception of steroid pretreatment (defined below) or the administration of intrathecal cytarabine, 
patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL 
or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL0932. 
 
Patients receiving prior steroid therapy may be eligible for AALL0932 as defined below (Section 3.3). 
 
3.2.5 
Patients with CNS3 leukemia (see definition in Section 3.3 below). 
CNS status must be known prior to enrollment because NCI SR patients with CNS disease (CNS3) are not 
eligible for AALL0932 (but are eligible for the COG HR ALL protocol). (Note: The CNS status must be 
determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, 
except for steroid pretreatment as discussed in Section 3.3.). B-LLy patients with CNS3 disease are not 
eligible for this protocol or the COG HR ALL protocol. It is recommended that intrathecal cytarabine be 
administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic 
bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to 
registration. Systemic chemotherapy must begin within 72 hours of the first dose of intrathecal 
therapy. 
 
3.2.6 
B-ALL patients with testicular leukemia are not eligible for AALL0932. 
 
3.2.7 
For B-LLy patients the following additional exclusion criteria apply: 
 
T-Lymphoblastic Lymphoma. 
 
Morphologically unclassifiable lymphoma. 
 
Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic 
lymphoma. 
 
CNS3-positive disease (see Section 3.3 for details) or testicular involvement. 
 
M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow. 
 
Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have 
been noted for several of the study drugs. 
 
Lactating females are not eligible unless they have agreed not to breastfeed their infants. 
 
Female patients of childbearing potential are not eligible unless a negative pregnancy test result 
has been obtained. 
 
Sexually active patients of reproductive potential are not eligible unless they have agreed to use 
an effective contraceptive method for the duration of their study participation. 
 
3.2.8 
Eligibility Criteria for the Patient Leukemia Experience Study (see Section 15.1.1) 
Closed to accrual as of April 19, 2013. 
 
3.2.9 
Eligibility Criteria for the Leukemia Physical Functioning Study (see Section 16.1.1) 
Closed to accrual as of March 15, 2013. 
 

 
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REGULATORY  
 
3.2.10 All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.11 All institutional, FDA, and NCI requirements for human studies must be met. 
 
3.3 
Definitions 
 
INITIAL WBC: The first WBC at the treating COG institution, or the WBC prior to intravenous fluids, 
whichever occurred first. If prior therapy (i.e. steroids) has been administered and a CBC is available that 
was obtained within 72 hours prior to steroid therapy, then this pre-steroid WBC should be used. 
 
INITIAL PLATELET COUNT: The first platelet count at the treating COG institution, or the count before 
transfusion of platelets if transfused prior to arrival. 
 
INITIAL HEMOGLOBIN: The first hemoglobin at the treating COG institution, or the hemoglobin prior 
to intravenous fluid or red cell transfusions, whichever occurred first. 
 
STEROID PRETREATMENT FOR B-ALL PATIENTS: 
 
1. For patients older than 10 years of age: the use of steroids prior to diagnosis will not affect their 
Induction therapy. Patients must meet all eligibility criteria (including an M3 bone marrow at 
diagnosis, or peripheral count of at least 1,000/µL leukemic blasts for patients in whom there is a 
medical contraindication to a bone marrow aspirate). Post-Induction risk assignment will be refined 
by leukemia specific genetic features and the level of bone marrow MRD at Day 29. (Note this 
definition applies only to children with NCI HR-ALL). (These patients are not eligible for this trial 
but may be eligible for the COG HR-ALL trial). 
  
2. For patients younger than 10 years of age: If steroids are given for more than 24 hours in the 
2 weeks prior to diagnosis and a CBC is obtained within 3 days prior to initiation of the steroid, the 
patient will be assigned to Induction based on NCI risk group using the pre-steroid WBC. Post-
Induction risk assignment will be refined by leukemia-specific genetic features and the level of 
bone marrow MRD at Day 29, except that SR patients in this group will not be eligible for the LR 
arm of AALL0932. If there is no pre-steroid CBC obtained, the patient will be assigned to receive 
Induction therapy on the COG HR protocol AALL1131. These patients are not eligible for 
AALL0932 but may be eligible for AALL1131. If steroids are given for less than 24 hours in the 
2 weeks prior to diagnosis, Induction risk group will be based on NCI risk group using the initial 
WBC and patients will not be eligible for the LR arm.  
 
3. For patients younger than 10 years of age: Any amount of steroid pretreatment at any time prior to 
2 weeks before diagnosis will not affect initial induction assignment as long as the patient meets 
all other eligibility criteria including the presence of an M3 marrow at diagnosis. The presenting 
WBC at the time of diagnosis will be used to assign the patient to SR or HR Induction therapy. 
Post-Induction risk assignment will be refined by leukemia-specific genetic features and the level 
of bone marrow MRD at Day 29. SR patients in this group may be eligible for the LR arm only if 
they did not receive steroids within the month prior to diagnosis. 
 
4. Inhalational steroids are not considered as pretreatment. 
 
STEROID PRETREATMENT FOR B-LLy PATIENTS: 
Patients receiving steroids within 4 weeks of diagnosis:  

 
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1. Patients who have received ≤ 48 hours of oral or IV steroids will be eligible for AALL0932.  
2. Patients who have received > 48 hours of oral or IV steroids, will not be eligible for AALL0932 
because they cannot reasonably be classified as localized. 
 
CNS LEUKEMIA AT DIAGNOSIS: 
 
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 traumatic LP, > 5/L WBCs, 
cytospin positive for blasts, 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, after traumatic LP presence of ≥ 5/L 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). 
 
B-LLy DEFINITION OF CNS3 POSITIVE DISEASE: 
 
CNS3: Elevated CSF WBC (≥ 5 cells/μL) and a cytocentrifuge preparation demonstrating lymphoblasts. 
CNS lymphoma may also be diagnosed when the CSF WBC is normal but clinical signs of CNS 
involvement are present: 
 Cranial nerve palsy (if not explained by extra cranial tumor) 
 Clinical spinal cord compression 
 Isolated intracerebral mass 
 
B-LLy PATIENTS WHO HAVE CNS3 DISEASE ARE NOT ELIGIBLE FOR THIS STUDY 
 
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 Steinherz/Bleyer algorithm should be used to distinguished between 
CNS2 and CNS3 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 = 1,500/L; blood WBC = 46,000/L; 
blood RBC = 3.0 X 106/L: 
 
60  = 0.04  >  2X   46000   = 0.015 
1500                       3.0 X 106 
 

 
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TESTICULAR LEUKEMIA AT DIAGNOSIS:  
Unilateral or bilateral testiculomegaly. Biopsy is required if clinical findings are equivocal or suggestive of 
hydrocele or a non-leukemic mass. These B-ALL patients are not eligible for this study, but may be eligible to 
enroll on the COG HR B-ALL study.  
 
B-LLy PATIENTS WITH TESTICULAR INVOLVEMENT ARE NOT ELIGIBLE FOR THIS STUDY. 
 
BONE MARROW STATUS: 
M1: < 5% lymphoblasts  
M2: 5%-25% lymphoblasts 
M3: > 25% lymphoblasts. 
 
B-LLy PATIENTS WITH AN M2 OR M3 MARROW AT DIAGNOSIS ARE NOT ELIGIBLE FOR THIS 
STUDY. 
 
BONE MARROW MRD STATUS (Day 29) FOR B-ALL PATIENTS: 
Positive:  ≥ 0.01% detectable leukemia cells 
Negative:  < 0.01% detectable leukemia cells 
 
BONE MARROW MINIMAL MARROW DISEASE (MMD) STATUS FOR B-LLy PATIENTS: 
The MMD status of B-LLy patients will be assessed at diagnosis for research purposes but not used for 
risk stratification. Closed effective Amendment #5. 
 
UNFAVORABLE CHARACTERISTICS FOR B-ALL PATIENTS: 
1. iAMP21 as identified by fluorescence in-situ hybridization (FISH). 
 
2. KMT2A (MLL) rearrangements as identified by cytogenetics, fluorescence in-situ hybridization (FISH), 
or molecular studies.  
 
3. HYPODIPLOIDY: Fewer than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a 
hypodiploid clone. 
 
4. INDUCTION FAILURE:  
a) M3 marrow on Day 29.  
 
Patients entered on AALL0932 who are later found to have 1 of the 4 above UNFAVORABLE 
CHARACTERISTICS will be eligible to enroll into the VHR arms of AALL1131 at end of Induction 
therapy; or otherwise will be off protocol therapy at the end of Induction therapy. 
 
5. PHILADELPHIA CHROMOSOME POSITIVE (Ph+) ALL: 
a) BCR-ABL1 (formerly known as BCR-ABL) fusion transcript determined by FISH or RT-PCR 
b) t(9;22)(q34;q11) determined by cytogenetics 
 
Patients enrolled on AALL0932 who are later found to have Ph+ ALL and meet eligibility criteria for the 
AALL1122 (successor COG Ph+ ALL trial) should be immediately taken off protocol therapy prior to Day 
15 of Induction therapy if eligible to enroll on AALL1122 (or its successor COG Ph+ ALL trial). Otherwise, 
Ph+ ALL patients may continue on AALL0932 until the end of Induction therapy.  
 
RELAPSE (B-ALL PATIENTS):  
Any recurrence of disease whether in marrow or extramedullary. Relapse should be biopsy confirmed. 
 

 
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1) ISOLATED BONE MARROW RELAPSE: 
Patients with an M3 marrow at any point after achieving remission without involvement of the CNS and/or 
testicles. 
 
2) COMBINED RELAPSE: 
M2 or M3 marrow at any point after achieving remission with concomitant CNS and/or testicular relapse.  
 
3) 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. If any CSF evaluation shows positive cytomorphology and 
WBC < 5/µL, a second CSF evaluation is required 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. 
 
4) TESTICULAR RELAPSE: 
Must be documented by testicular biopsy, if not associated with a marrow relapse 
 
RELAPSE/PROGRESSIVE DISEASE (PD): B-LLy PATIENTS: 
Greater than 50% increase in the size of any lesions or appearance of new lesion(s) more than 1.5 cm in 
any axis. 
 
DISEASE EVALUATION DURING FOLLOW-UP: 
A disease evaluation is a procedure ordered with the intent to measure or assess the disease status of a 
patient. The most common evaluations are a bone marrow aspirate and/or biopsy and a lumbar puncture 
(LP). If a CBC has findings that raise suspicion for relapse, a bone marrow aspirate must be performed to 
confirm the relapse. 
 
POST INDUCTION RISK GROUPS FOR B-ALL PATIENTS 
 
LOW RISK B-ALL CRITERIA 
NCI standard risk (age 1.01 - 9.99 years and initial WBC < 50,000/µL) B-ALL and all of the following: 
a. Favorable genetics: the presence of simultaneous trisomies of chromosome 4 and 10 (double 
trisomy; DT) or ETV6/RUNX1 fusion 
b. Day 8 PB MRD less than 0.01% 
c. Day 29 BM MRD less than 0.01% 
d. No CNS2, CNS3 or testicular leukemia  
e. No steroid pretreatment 
f. No Down syndrome 
g. No unfavorable genetic characteristics. 
 
AVERAGE RISK B-ALL CRITERIA: 
NCI standard risk (age 1.01 - 9.99 years and initial WBC < 50,000/μL) B-ALL and: 
a. Favorable genetics: the presence of DT or ETV6/RUNX1 fusion 
b. Day 8 PB MRD ≥ 0.01% or CNS2 status 
c. Day 29 BM MRD less than 0.01% 
d. No CNS3 or testicular leukemia 
e. No Down syndrome 
f. No unfavorable genetic characteristics. 
OR, 
 

 
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NCI standard risk (age 1.01 - 9.99 years and initial WBC < 50,000/μL) B-ALL and: 
a. Neither favorable nor unfavorable cytogenetics 
b. Day 8 PB MRD less than 1% 
c. Day 29 BM MRD less than 0.01% 
d. No CNS3 or testicular leukemia 
e. No Down syndrome 
 
STANDARD RISK DS B-ALL CRITERIA 
NCI standard risk (age 1.01 - 9.99 years and initial WBC < 50,000/μL) DS B-ALL and: 
a. No KMT2A (MLL)-rearrangement, hypodiploidy, or Philadelphia chromosome 
b. Day 29 BM MRD less than 0.01% 
c. No CNS3 or testicular leukemia 
 
Note: DS B-ALL patients who have Day 29 BM MRD ≥ 0.01% will be eligible for post-Induction 
therapy on the DS stratum of the HR trial. 
 
 
For an overview of the classification system for B-ALL, see AALL08B1 or the APEC14B1 (if open 
for classification of newly diagnosed ALL patients) ALL manual of procedures (MOP). 
 
 
 

 
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4.0 
TREATMENT PLAN 
 
 
4.1 
Overview of Treatment Plan 
Informed consent that describes the first 4 weeks of Induction therapy for B-ALL is required. After 
sufficient AR patients have completed Callback 1 such that accrual goals for AR patients have been 
met, AR and LR B-ALL patients will not receive post-Induction treatment on AALL0932 and will 
come off protocol therapy after Induction. Further treatment for these patients will be up to the 
discretion of the treating physician. HR and VHR patients may be eligible for enrollment onto 
AALL1131 after Induction. 
 
At the end of Induction, after patients have been stratified into risk subgroups, a second informed consent 
that describes the next portions of therapy must be signed prior to the start of Consolidation. This second 
consent will include randomized assignment to P9904 regimen A-based (Arm LR-M) or CCG 1991 regimen 
IS-based (with every 12 week vincristine/dexamethasone pulses during Maintenance; Arm LR-C) post-
Induction therapy for LR patients enrolled before accrual goals for AR patients have been met. The second 
consent for DS SR B-ALL patients or AR B-ALL patients (enrolled before accrual goals for AR patients 
have been met) will not include randomized treatment assignment. Patients with AR B-ALL enrolled before 
accrual goals for AR patients have been met, will be approached with a third consent prior to beginning 
Maintenance therapy that describes the randomization to 1 of 4 different Maintenance arms. Effective 
01/13/2017 all patients on Arms B and D were recommended to have their oral methotrexate dose lowered 
to 20 mg/m2/week, the standard of care therapy. Subsequently, patients should have their doses of 6 
mercaptopurine and methotrexate adjusted based on tolerability following normal dose escalation 
procedures, as outlined in the protocol Section 5.9. B-LLy and DS B-LLy patients will sign one consent 
form that describes all therapy to be received on study, prior to beginning Induction therapy.  
 
Revised eligibility includes newly diagnosed patients, ages 1.0 to 30.99 years, with localized B-LLy. 
Patients with testicular involvement or CNS3 disease are not eligible. Down syndrome B-LLy patients are 
eligible and follow the treatment guidelines for Down syndrome B-ALL patients. Patients with Stages I and 
II B-LLy (without Down syndrome) will be non-randomly assigned to post-Induction therapy similar to the 
standard arm for Average Risk B-ALL with Maintenance “Arm LLy” on AALL0932. 
 
CNS status must be known prior to enrollment because patients with CNS3 disease are not eligible for 
AALL0932 but patients with CNS3 B-ALL may be eligible for the COG HR B-ALL protocol. It is 
recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. 
This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second 
lumbar puncture. (Note: The CNS status must be determined based on a sample obtained prior to 
administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment as discussed in 
Section 3.3.) This is allowed prior to registration. Systemic chemotherapy must begin within 72 hours 
of this intrathecal therapy. B-LLy patients with CNS3-positive and/or testicular disease are not eligible 
for this study. 
 
NOTE: FOR NON-DS B-ALL PATIENTS, IF DAY 8 PB AND DAY 29 BM MRD SAMPLES ARE 
NOT OBTAINED AND SHIPPED TO A COG-APPROVED ALL FLOW CYTOMETRY 
LABORATORY, THEN THE PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG 
ALL TRIAL FOLLOWING COMPLETION OF INDUCTION THERAPY. 
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).  

 
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4.1.1 
Induction Therapy for B-ALL Patients 
All patients will receive a common 3 drug dexamethasone based Induction identical to that on CCG 1991 
and COG AALL0331 with the exception of intravenous rather than intramuscular administration of 
pegaspargase. Patients with DS SR B-ALL will also receive leucovorin rescue after IT MTX. At the end of 
Induction, patients will be further classified into risk categories. Those classified as DS SR B-ALL as 
defined by the classification study AALL08B1 or APEC14B1 (see Section 3.3) will be eligible for post-
Induction therapy on AALL0932. Patients classified as LR B-ALL or AR B-ALL as defined by the 
classification study AALL08B1, who enrolled before accrual goals for AR patients have been met will be 
eligible for post-Induction treatment on AALL0932. Patients classified as LR B-ALL or AR B-ALL 
enrolled after accrual goals for AR patients have been met will not be eligible for post-Induction treatment 
on AALL0932. Further treatment for these patients will be up to the discretion of the treating physician. 
 
Those patients classified as HR or VHR based on the Induction MRD responses or adverse cytogenetic 
features are not eligible for post-Induction therapy on AALL0932, but may be eligible to receive post-
Induction therapy on the COG HR- or VHR B-ALL protocols. See Section 7.1 for baseline studies to be 
obtained prior to starting Induction therapy. 
 
Questions regarding Induction therapy should be directed to Dr. Anne Angiolillo and Dr. Reuven 
Schore. 
 
4.1.2 
Post Induction Therapy (Pre-Maintenance) for B-ALL Patients (enrolled before accrual goals for 
AR patients have been met) 
 
Average Risk 
AR B-ALL patients enrolled after accrual goals have been met will not receive post-Induction 
treatment on AALL0932. Further treatment for these patients will be up to the discretion of the 
treating physician. 
 
The AR subset of SR B-ALL patients must consent prior to starting Consolidation therapy to receive 
7 months of therapy identical to the IS-arm of CCG 1991: Consolidation, 2 Interim Maintenance phases 
with vincristine and escalating IV methotrexate, and 1 Delayed Intensification phase. Patients will then be 
approached with a third consent at the end of IM II that describes randomization to 1 of 4 Maintenance 
treatment arms. 
 
Questions regarding the Average Risk patients should first be directed to Dr. Anne Angiolillo. 
 
Low Risk 
LR B-ALL patients enrolled after accrual goals for AR patients have been met will not receive post-
Induction treatment on AALL0932. Further treatment for these patients will be up to the discretion 
of the treating physician. 
 
The LR subset of SR B-ALL group must consent prior to starting Consolidation therapy to be randomized 
to receive either (a) Consolidation therapy identical to that on Regimen A of COG P9904 with the exception 
that oral 6-MP in Consolidation will start 1 week later to allow time for the end-Induction risk assignment 
(Arm LR-M); or (b) therapy identical to that for AR patients with reduced vincristine/dexamethasone pulses 
at 12-week intervals during Maintenance (Arm LR-C). 
 
Questions regarding the Low Risk patients should first be directed to Dr. Reuven Schore. 
 

 
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DS SR B-ALL 
The DS SR B-ALL group will receive modified Induction and post-Induction therapy due to the higher risk 
of treatment-related morbidity and mortality and will not be included in the randomized questions addressed 
in Maintenance therapy for SR B-ALL patients without Down syndrome. At the end of Induction therapy, 
children with DS SR B-ALL must consent prior to starting Consolidation therapy to receive therapy 
identical to the IS-arm of CCG 1991 with the following modifications: (1) Leucovorin rescue will be given 
following intrathecal methotrexate in all phases prior to Maintenance; (2) Maintenance 
vincristine/dexamethasone pulses will be given every 12 weeks; (3) Maintenance duration will be 2 years 
from the start of IM I for both boys and girls. 
 
Questions regarding the Down syndrome patients should first be directed to Dr. Johann Hitzler. 
 
4.1.3 
Post Induction Therapy (Maintenance) for B-ALL Patients (enrolled before accrual goals for AR 
patients have been met) 
 
 
Average Risk- Patients randomized prior to June 15, 2015 
AR B-ALL patients enrolled after accrual goals have been met will not receive post-Induction 
treatment on AALL0932. Further treatment for these patients will be up to the discretion of the 
treating physician. 
 
The AR subset of SR B-ALL patients will be randomized to 1 of 4 Maintenance treatment arms at the end 
of IM II: 
 
i.) 
Arm A- vincristine/dexamethasone pulses at 4 week intervals, intrathecal methotrexate 
every 12 weeks and oral methotrexate at dose 20 mg/m2/week.  
 
ii.) 
Arm B- vincristine/dexamethasone pulses at 4 week intervals, intrathecal methotrexate 
every 12 weeks and oral methotrexate at dose 40 mg/m2/week.  
 
iii.) 
Arm C-vincristine/dexamethasone pulses at 12 week intervals, intrathecal methotrexate 
every 12 weeks and oral methotrexate at dose 20 mg/m2/week.  
 
iv.) 
Arm D-vincristine/dexamethasone pulses at 12 week intervals, intrathecal methotrexate 
every 12 weeks and oral methotrexate at dose 40 mg/m2/week.  
 
Effective the memo dated 01/13/2017 all patients on Arms B and D were recommended to have their 
oral methotrexate dose lowered to 20 mg/m2/week, the standard of care therapy. Subsequently, 
patients should have their doses of 6 mercaptopurine and methotrexate adjusted based on tolerability 
following normal dose escalation procedures, as outlined in the protocol Section 5.9. 
 
Questions regarding the Average Risk patients should first be directed to Dr. Anne Angiolillo. 
 
Low Risk 
LR B-ALL patients enrolled after accrual goals for AR patients have been met will not receive post-
Induction treatment on AALL0932. Further treatment for these patients will be up to the discretion 
of the treating physician. 
 
The LR subset of SR B-ALL patients will have been randomly assigned to either: 
 

 
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i.) 
Arm LR-M - vincristine/dexamethasone pulses at 16-week intervals, intrathecal 
methotrexate every 12 weeks (until completion of 8 doses) and oral methotrexate at dose 
20 mg/m2/week. 
 
Maintenance therapy starts at the end of Consolidation and is based on Regimen A of COG 
P9904. 
 
ii.) 
Arm LR-C - vincristine/dexamethasone pulses at 12-week intervals, intrathecal 
methotrexate every 12 weeks and oral methotrexate at dose 20 mg/m2/week. 
 
Questions regarding the Low Risk patients should first be directed to Dr. Reuven Schore. 
 
DS SR B-ALL 
DS SR B-ALL patients will be non-randomly assigned the Arm DS Maintenance arms. 
 
4.1.4 
Induction and Post-Induction Therapy for B-LLy and DS B-LLy Patients 
All B-LLy patients will receive a common 3-drug dexamethasone-based Induction with intravenous rather 
than intramuscular administration of pegaspargase. B-LLy patients without progressive disease at end-
Induction will be non-randomly assigned to post-Induction therapy similar to AR B-ALL with a modified 
Maintenance (Arm LLy), to receive 7 months of therapy identical to the IS-arm of CCG 1991: 
Consolidation, 2 IM phases with vincristine and escalating IV methotrexate, and 1 DI phase followed by a 
modified standard Maintenance (Arm LLy). Modified Standard Maintenance will comprise 
vincristine/dexamethasone pulses at 4-week intervals and a weekly oral methotrexate dose of 20 mg/m2 and 
the following modification: 
 
 
Total treatment length for girls AND boys will be 2 years from the start of IM I. 
 
DS B-LLy patients will receive a modified Induction and post-Induction therapy same as for patients with 
DS SR B-ALL due to the higher risk of treatment-related morbidity and mortality. Following Induction, 
DS B-LLy patients without progressive disease will be non-randomly assigned to post-Induction therapy 
same as for patients with DS SR B-ALL, to receive 7 months of therapy identical to the IS-arm of CCG 
1991: Consolidation, 2 IM phases with vincristine and escalating IV methotrexate, and 1 DI phase followed 
by Maintenance (Arm DS). The modifications to the therapy for patients with DS B-LLy are: 
 
 
Leucovorin rescue will be given following intrathecal methotrexate in all phases prior to 
Maintenance. 
 
Maintenance vincristine/dexamethasone pulses will be given every 12 weeks. 
 
Maintenance duration will be 2 years from the start of IM I for both boys and girls.  
 
Questions regarding the B-LLy or DS B-LLy patients should first be directed to Dr. Birte 
Wistinghausen. 
 
4.1.5 
Duration of Therapy 
 
Average Risk 
AR B-ALL patients enrolled after accrual goals have been met will not receive post-Induction 
treatment on AALL0932. Further treatment for these patients will be up to the discretion of the 
treating physician. 
 

 
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The duration of Maintenance therapy will continue to be gender based for patients with AR subset of SR 
B-ALL: 2 years from the start of Interim Maintenance I for female patients and 3 years from the start of 
Interim Maintenance I for male patients. 
 
Questions regarding the Average Risk patients should first be directed to Dr. Anne Angiolillo. 
 
Low Risk 
LR B-ALL patients enrolled after accrual goals for AR patients have been met will not receive post-
Induction treatment on AALL0932. Further treatment for these patients will be up to the discretion 
of the treating physician. 
 
For LR subset of SR B-ALL patients assigned to Arm LR-M, the duration of therapy will be 2½ years from 
diagnosis for both female and male patients. For those assigned to Arm LR-C, the duration of therapy will 
continue to be gender based: 2 years from the start of Interim Maintenance I for female patients and 3 years 
from the start of Interim Maintenance I for male patients. 
 
Questions regarding the Low Risk patients should first be directed to Dr. Reuven Schore. 
 
DS B-ALL 
For DS SR B-ALL patients, duration of Maintenance therapy will not be gender based; instead both female 
and male patients will receive 2 years from the start of Interim Maintenance I. 
 
Questions regarding the Down syndrome patients should first be directed to Dr. Johann Hitzler. 
 
B-LLy and DS B-LLy 
The duration of Maintenance therapy will not be gender based and will be 2 years from the start of IM I for 
both boys and girls. 
 
Questions regarding the B-LLy or DS B-LLy patients should first be directed to Dr. Birte 
Wistinghausen. 
 
4.1.6 
HRQOL Ancillary Studies (B-ALL Patients ONLY). 
Both HRQOL ancillary studies are closed to new patient enrollment due to accrual goals being met. 
Closure to accrual occurred on March 3, 2013 for the LPFS study and April 19, 2013 for the PLES 
study.  
 
Institutions are required to continue data collection at remaining evaluation time points for patients 
already enrolled on this study. 
 
These patients will have additional required observations during Consolidation and Maintenance. For 
further instructions on timing and specific tests to be administered see Sections 15.0 & 16.0. 
 
Questions regarding the HRQOL surveys should be directed to Dr. Nina Kadan-Lottick. 
 
 

 
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4.2 
Induction (35 days) – B-ALL and B-LLy Patients 
All patients without DS will receive common Induction therapy. For patients with Down syndrome see 
Section 4.20. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special precautions and 
suggestions for patient monitoring during the infusions. As applicable, also see the CAGs for suggestions 
on hydration, or hydrate according to institutional guidelines. 
 
Cytarabine: Intrathecal (IT) 
All patients: Given at the time of diagnostic lumbar puncture (LP) OR on Day 1. May be given up to 
72 hours prior to the start of protocol therapy for patient convenience. 
 
Age-based dosing for Day 1 IT Cytarabine: 
Age (yrs) 
Dose 
1 – 1.99 
30 mg 
2 – 2.99 
50 mg 
≥ 3 
 
70 mg 
 
B-ALL CNS2 patients ONLY: In addition to the initial dose (above), patients will receive additional IT 
Cytarabine on either Day 4, 5 or 6 during Induction, IT Methotrexate on Day 8, and then receive IT 
Cytarabine on Days 11 or 12. If the CSF at all three of these time points is negative for blasts, patients will 
receive their next IT therapy with methotrexate on Day 29. If the CSF remains positive after the initial LP, 
patients will continue IT Cytarabine twice weekly during Induction until the CSF is clear for three 
consecutive LPs. All patients will receive IT therapy with methotrexate on Day 8 and 29 at the end of 
Induction regardless of CSF evaluations. 
 
Age-based dosing for additional IT Cytarabine for B-ALL CNS2 patients ONLY (Days 4, 5 or 6 and 
Days 11 or 12) and additional IT Cytarabine until clear: 
Age (yrs) 
Dose 
1 – 1.99 
20 mg 
2 – 2.99 
30 mg 
≥ 3 
 
40 mg 
 
For IT administration use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 8, 15 and 22 
Dose: 1.5 mg/m2/dose (maximum 2 mg) 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 

 
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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. 
 
Dexamethasone: PO (may be given IV) 
Days 1 - 28 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/day, divided BID) may be used temporarily as 
needed. 
 
Pegaspargase: IV over 1 - 2 hours  
Day 4*  
Dose: 2,500 International Units/m2/dose 
 
Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
*PLEASE NOTE: FOR B-ALL PATIENTS, DUE TO THE IMPORTANCE OF DAY 8 EARLY 
RESPONSE 
ASSESSMENT, 
PEGASPARGASE 
SHOULD 
BE 
ADMINISTERED ON DAY 4. Deviation from Day 4 administration may 
adversely impact risk categorization. 
 
Special precautions: 
1. Pegaspargase may affect coagulation factors and predispose to bleeding and/or thrombosis. Caution 
should be used when administering any concurrent anticoagulant therapy. 
2. 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.  
 
Methotrexate: Intrathecal (IT) 
Days 8 and 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 

 
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Disease Evaluations During Induction for B-ALL Patients: 
 
Day 8: 5 mL of peripheral blood will be obtained and shipped to a COG-Approved ALL Flow 
Cytometry Laboratory for MRD determination. Day 8 PB sample must be collected prior to 
administration of Day 8 IV/IT chemotherapy. 
 
Day 29: Bone marrow sample will be obtained for morphology and a 2 mL aliquot will be shipped 
to a COG-Approved ALL Flow Cytometry Laboratory for MRD determination. 
 
Research Studies (for B-ALL patients that consented to studies of genomic variation on AALL08B1 
or APEC14B1 (if available for classification of newly diagnosed ALL patients)) 
 
Day 29: 5 mL of peripheral blood will be obtained and shipped to the COG ALL Molecular 
Reference Laboratory for studies of genomic variation and cell banking. This specimen is very 
important and should be obtained on all patients that have provided consent. 
 
NOTE: FOR NON-DS B-ALL PATIENTS, IF DAY 8 PB AND 29 BM MRD SAMPLES ARE NOT 
OBTAINED 
AND 
SHIPPED 
TO 
A 
COG-APPROVED 
ALL 
FLOW 
CYTOMETRY 
LABORATORY, THEN THE PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG 
ALL TRIAL FOLLOWING COMPLETION OF INDUCTION THERAPY. 
 
Disease Evaluation for B-LLy Patients:  
 
Before starting therapy and on Day 29: patients will have a CT of the neck, chest, abdomen and 
pelvis, CXR, a PET scan, and if indicated a bone scan (please refer to Section 7.1d for details).  
 
Note: A PET scan is highly recommended but not required at diagnosis, at the end of Induction and if there 
are residual masses at the end of Consolidation. 
 
Optional Research Studies for B-LLy Patients (see Section 14.0 for details): 
 
If patient consents, paraffin embedded tissue will be submitted at diagnosis for FISH analysis. 
 
If patient consents, fresh tissue will be submitted at diagnosis for banking. 
 
Day 29: 5 mL of peripheral blood will be obtained and shipped to the COG ALL Molecular 
Reference Laboratory for studies of genomic variation. This specimen is very important and 
should be obtained on all patients that have provided consent. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR 
SUPPORTIVE CARE GUIDELINES. 
 
Following completion of Induction, based upon the patient’s Day 29 MRD results, B-ALL patients will be 
classified as AR B-ALL or LR B-ALL: 
 
For AR B-ALL patients enrolled before accrual goals for AR patients have been met: Consolidation 
(Section 4.3) starts on Day 36 or when blood count parameters are met (whichever occurs later) 
 
For LR B-ALL patients enrolled before accrual goals for AR patients have been met: For LR patients 
randomized to Arm LR-C, Consolidation (Section 4.3) starts on Day 36 or when blood count parameters 
are met (whichever occurs later). For LR patients randomized to Arm LR-M, Consolidation (Section 4.12) 
starts on Day 36 regardless of blood count parameters. 
 
Following completion of Induction, only B-LLy patients without PD (see Section 11.3 for definition) will 
be eligible to continue Consolidation therapy. B-LLy patients with PD at end-Induction will be 

 
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considered off protocol therapy. Consolidation (Section 4.3) starts on Day 36 or when blood count 
parameters are met (whichever occurs later).  
 
The therapy delivery maps (TDMs) for Induction are on the next two (2) pages. For B-ALL patients see 
Section 4.2.1 and for B-LLy patients see Section 4.2.2. 
 
 

 
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4.2.1 
Induction (35 days).- B-ALL Patients 
All patients without DS receive common Induction Therapy. 
For patients with Down syndrome see Section 4.20. 
 
___________________ 
______________________ 
Patient name or initials 
 
DOB 
Induction therapy lasts 5 weeks (35 days). See Section 4.1 for full details regarding assignment to treatment arms and subsequent therapy. This Therapy 
Delivery Map is on one (1) page 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Cytarabine  
(IT ARAC) 
IT 
Age (yrs) Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
≥ 3 
 70 mg 
Given at time of 
diagnostic LP 
OR Day 1* 
See Section 4.2 for administration guidelines 
 
Note age-based dosing 
a. Hx, PE, Wt, Ht 
b. CBC/diff/platelets 
c. BM eval1 
d. PB sample1 
e. CSF cell count, cytospin2 
f. 
Creatinine, Bili, Albumin & ALT 
g. Varicella titer 
h. TPMT and NUDT15 genotype# 
 
 
1See Section 7.1 for details 
2 Obtain with each IT administration 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Intrathecal 
Cytarabine  
(IT ARAC) 
IT 
CNS2 patients ONLY 
 
Age (yrs) 
Dose 
1-1.99 
20 mg 
2-2.99 
30 mg 
≥ 3 
40 mg 
CNS2: twice 
weekly† 
† The initial dose is followed by twice weekly IT 
ARAC except during weeks when Days 8 & 29 
IT MTX is administered 
 
Note: IT therapy is administered until 3 consecutive 
CSF samples are clear of blasts. 
VinCRIStine 
(VCR) 
IV push  
over 1 minute+ 
1.5 mg/m2/dose 
Days 1, 8, 15 
&22 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Dexamethasone 
(DEX) 
PO 
(may give IV) 
3 mg/m2/dose BID 
Days 1-28  
(do not taper) 
Total daily dose: 
6 mg/m2/day, divided BID 
See Section 4.2 for administration guidelines 
Pegaspargase  
(PEG-ASP) 
IV  
over 1-2 hours 
2500 International 
units/m2/dose 
Day 4  
Note: pegaspargase should be administered on 
Day 4. 
 
Administer through the tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
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 
Days 8 and 29 
See Section 4.2 for administration guidelines 
 
Note age-based dosing 
 
Note: All patients receive Day 8 and 29 IT MTX 
regardless of CSF evaluation. 
 
Ht___________cm  
Wt__________kg  
 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
IT ARAC 
______mg 
IT ARAC 
_____mg 
VCR 
_____mg 
DEX (BID dosing) 
__mg __mg 
PEG-ASP 
______IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
_____mg 
 
 
 
 
 
(a%-c, e-g)@ 
 
 
 
-2/-1/0/LP* 
 
 
 
 
 
 
 
 
 
1 
 
_____mg 
__mg __mg 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4♦ 
 
_____mg♦ 
 
______IU  
 
e♦ 
 
--- 
 
 
8 
 
 
_____mg 
 
____mg 
a%, b, d**, e 
 
 
 
9 
 
 
 
 
 
 
 
--- 
 
 
11♦ 
 
_____mg♦ 
 
 
 
e♦ 
 
--- 
 
 
15 
 
 
_____mg 
 
 
a%, b, h 
 
--- 
 
 
22 
 
 
_____mg 
 
 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
____mg 
a%, b, c**, d***, e 
 
--- 
 
 
35 
 
 
 
 
 
 
 
 
 
 
36 
 
Begin Consolidation (Section 4.3) for AR B-ALL (without PD) or LR B-ALL patients randomized to Arm LR-C on Day 
36 or when blood count parameters have been met (whichever occurs later). Begin Consolidation (Section 4.12) for LR B-
ALL patients randomized to Arm LR-M on Day 36 regardless of blood counts. 
* On Day 1 OR at the time of diagnostic lumbar puncture (LP) if < 72 hours from the start of protocol therapy. 
 
 
 
@Baseline 
♦ CNS2 patients only: administer IT therapy twice weekly until 3 consecutive CSF are clear of blasts. Day 8 & 29 IT therapy will remain IT MTX for all patients.  
Note: CNS2 patients receive IT ARAC on Days 4, 5, or 6 and 11 or 12, etc., depending on treatment schedule. Log additional IT-ARAC doses in the comments section.  
** 
Note: For B-ALL patients, if Day 8 PB and 29 BM MRD samples are not obtained and shipped to a COG Approved ALL flow cytometry laboratory, then the patient will not 
be eligible to continue on a COG ALL trial following completion of Induction therapy. Day 8 PB sample must be collected prior to Day 8 IV/IT chemotherapy. 
*** Day 29 PB specimen should be shipped to the COG ALL Molecular Reference Laboratory for all B-ALL patients that consented to studies of genomic variation on AALL08B1 
or APEC14B1 (if open for classification of ALL patients) (see Section 14.0 for specimen shipping and handling). This specimen is very important. 
% Note: Height (Ht) is only required at the beginning of this course. 
 # TPMT and NUDT15 genotype (TPMT highly recommended for all subjects; NUDT15 is highly recommended for subjects of Hispanic/Native American or East Asian ancestry, 
and optional for all other subjects (See Section 5.9) 
DO CALL-BACK PRIOR TO BEGINNING CONSOLIDATION THERAPY FOR ALL B-ALL PATIENTS WHO HAVE SIGNED CONSENT FOR POST-INDUCTION 
THERAPY. 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE GUIDELINES. 
Page 1 of 2 

 
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4.2.2 
Induction (35 days).- B-LLy Patients 
All patients without DS receive common Induction Therapy. 
For patients with Down syndrome see Section 4.20. 
 
___________________ 
______________________ 
Patient name or initials 
 
DOB 
Induction therapy lasts 5 weeks (35 days). See Section 4.1 for full details regarding assignment to treatment arms and subsequent therapy. This Therapy 
Delivery Map is on one (1) page 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Cytarabine  
(IT ARAC) 
IT 
Age (yrs) Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
≥ 3 
70 mg 
Given at time of 
diagnostic LP 
OR Day 1 
See Section 4.2 for administration guidelines 
 
Note age-based dosing. 
a. 
Hx, PE, Wt,Ht 
b. CBC/diff/platelets 
c. BM eval1 
d. PB sample1 
e. CSF cell count, cytospin2 
f. 
Creatinine, Bili, Albumin & ALT 
g. Varicella titer 
h. TPMT and NUDT15 genotype# 
i. 
CT (neck, chest, abdomen & 
pelvis), CXR, PET, bone scan (if 
bone involvement). 3  
j. 
Diagnostic biopsy/cytology 3  
k. Biology/banking (optional) 4 
 
1See Section 7.1 for details 
2 Obtain with each IT administration 
3 See Section 7.1d for details 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine 
(VCR) 
IV push  
over 1 minute+ 
1.5 mg/m2/dose 
Days 1, 8, 15 
&22 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Dexamethasone 
(DEX) 
PO 
(may give IV) 
3 mg/m2/dose BID Days 1-28  
(do not taper) 
Total daily dose: 
6 mg/m2/day, divided BID 
See Section 4.2 for administration guidelines 
Pegaspargase  
(PEG-ASP) 
IV  
over 1-2 hours 
2500 International 
units/m2/dose 
Day 4  
Note: pegaspargase should be administered on 
Day 4. 
 
Administer through the tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
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 
Days 8 and 29 
See Section 4.2 for administration guidelines 
 
Note age-based dosing 
 
 
Ht___________cm  
Wt__________kg  
 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
IT ARAC 
______mg 
VCR 
_____mg 
DEX (BID dosing) 
__mg __mg 
PEG-ASP 
______IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
_____mg 
 
 
 
 
(a%-c, e-g, i-k)@ 
 
 
 
-2/-1/0/LP* 
 
 
 
 
 
 
 
 
1 
_____mg 
__mg __mg 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
______IU  
 
 
 
--- 
 
 
8 
 
_____mg 
 
____mg 
a%, b, e 
 
 
 
9 
 
 
 
 
 
 
--- 
 
 
15 
 
_____mg 
 
 
a%, b, h 
 
--- 
 
 
22 
 
_____mg 
 
 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
29 
 
 
 
 
____mg 
a%, b, d***, e, i 
 
--- 
 
 
35 
 
 
 
 
 
 
 
 
 
36 
Begin Consolidation (Section 4.3) for B-LLy patients (without PD) on Day 36 or when blood count parameters have been met 
(whichever occurs later). Note: B-LLy patients with PD at end-Induction are off protocol therapy. 
 
* On Day 1 OR at the time of diagnostic lumbar puncture (LP) if < 72 hours from the start of protocol therapy. 
@ Baseline 
*** Day 29 PB specimen should be shipped to the COG ALL Molecular Reference Laboratory for all B-LLy patients that consent on AALL0932 (see Section 14.0 for 
specimen shipping and handling). This specimen is very important. 
% Note: Height (Ht) is only required at the beginning of this course. 
Note: PET scans are highly recommended, not required, and CXR is not required if CT chest is done. 
# TPMT and NUDT15 genotype (TPMT highly recommended for all subjects; NUDT15 is highly recommended for subjects of Hispanic/Native American or East Asian 
ancestry, and optional for all other subjects (See Section 5.9) 
 
DO CALL-BACK PRIOR TO BEGINNING CONSOLIDATION THERAPY FOR ALL B-LLY PATIENTS WHO DO NOT GO OFF PROTOCOL THERAPY 
AT END-INDUCTION. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE GUIDELINES. 
  
 
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48 
4.3 
Consolidation (28 days) – AR B-ALL Patients, LR B-ALL Patients Randomized to Arm 
LR-C and B-LLy Patients 
 
 
FOR 
B-ALL 
PATIENTS: 
CONSENT 
TO 
POST-INDUCTION 
THERAPY 
(AND 
RANDOMIZATION FOR LR B-ALL PATIENTS) MUST TAKE PLACE BEFORE STARTING 
CONSOLIDATION THERAPY AFTER THE END-INDUCTION RISK ASSIGNMENT HAS 
BEEN COMPLETED. DO CALL-BACK PRIOR TO BEGINNING CONSOLIDATION THERAPY 
FOR ALL PATIENTS WHO HAVE SIGNED CONSENT FOR POST-INDUCTION THERAPY. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS THERAPY ARE OFF PROTOCOL 
THERAPY. 
 
FOR PATIENTS WITH B-LLy: DO CALL-BACK PRIOR TO BEGINNING CONSOLIDATION 
THERAPY FOR ALL PATIENTS WHO DO NOT GO OFF PROTOCOL THERAPY AT THE END 
OF INDUCTION. 
 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC 
≥ 750/µL and platelets ≥ 75 000/µL (whichever occurs later) after the post-Induction risk assignment has 
been completed. Patients with severe systemic illness, who will not tolerate initiation of Consolidation on 
Day 1 or without count recovery, should begin this phase of therapy when appropriate in the judgment of 
the treating physician. 
 
Therapy should be interrupted for patients with suspected or proven serious infection and resumed when 
the signs of infection have abated. Therapy should not be interrupted for fever, if there are no signs of 
serious infection. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 ONLY 
Dose: 1.5 mg/m2/dose (maximum 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.” 
 
NOTE FOR B-ALL PATIENTS: AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN 
MET, ADDITIONAL PATIENTS CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT 
RECEIVE POST-INDUCTION TREATMENT ON AALL0932. FURTHER TREATMENT FOR 
THESE PATIENTS WILL BE UP TO THE DISCRETION OF THE TREATING PHYSICIAN. AR 
AND LR B-ALL PATIENTS RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR 
PATIENTS HAVE BEEN MET WILL CONTINUE TO RECEIVE POST INDUCTION THERAPY 
ON THIS PROTOCOL. 

 
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49 
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 - 28 
Dose: 75 mg/m2/dose once daily * 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. If using tablets, adjust dose using ½ tablets and different 
doses on alternating days in order to attain a weekly cumulative dose as close to 525 mg/m2/week as 
possible. See Appendix I for details. Do not escalate dose based on blood counts during this cycle (see 
Section 5.8). 
 
Methotrexate: Intrathecal (IT) 
Days 1, 8, and 15Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
HRQOL Studies (B-ALL patients only) 
The LFPS and PLES have met accrual goals and are closed to new patient enrollment as of March 15, 
2013 and April 19, 2013, respectively. However, institutions are required to continue data collection 
at remaining evaluation time points, for patients already enrolled on this study. 
 
Please note:  
For AR B-ALL patients enrolled on the optional Patient Leukemia Experience Study (available at all 
centers) the first evaluation time point can occur anytime after Day 15 of Consolidation and prior to the 
start of Interim Maintenance I. For AR B-ALL patients enrolled on the Leukemia Physical Functioning 
Study (at selected sites only-available on the COG AALL0932 protocol webpage), the first evaluation time 
point can occur anytime after Day 15 of Consolidation and prior to the start of Interim Maintenance I. See 
Sections 15.0 & 16.0 for details of evaluation schedules. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Consolidation is on the next page.  
 

 
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50 
For B-ALL and B-LLy patients: Following completion of Consolidation, the next course (Interim 
Maintenance I, Section 4.4) starts on Day 29 or when blood count parameters are met (whichever occurs 
later). 
 
Note: Following completion of Consolidation, B-LLy patients who fail to achieve CR (see Section 11.3 
for definitions), are off protocol therapy with the exception of B-LLy patients with bone primaries 
who will be considered CR if there is resolution of all surrounding soft tissue component by the end 
of Consolidation. 
 

 
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4.3.1  Consolidation (28 days) – AR B-ALL Patients, LR B-ALL Patients 
 Randomized to Arm LR-C and B-LLy Patients 
 
 
 
_____________________________ 
Patient name or initials 
 
________________________ 
DOB 
Consolidation is 4 weeks (28 days). Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC 
≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). See Section 4.3 for detailed therapy guidelines. 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 
Day 1 ONLY 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. Hx, PE, Wt , Ht 
b. CBC/diff/platelets 
c. CSF cell count, cytospin1 
d. Bilirubin, ALT & Creatinine 
e. Patient Leukemia Experience surveys2 
f. Leukemia Physical Functioning Study 
evaluation2 
 
B-LLy patients only 
g  CT (neck, chest, abdomen & pelvis), 
CXR, PET, bone scan (if bone 
involvement).  
 
1 Obtain with each IT administration 
 
2 For AR B-ALL patients already enrolled 
on these ancillary studies; evaluations can 
be done any time from Day 15-29 (see 
Sections 15.0 & 16.0 for details). Note: B-
LLy patients are not eligible for this study. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose* Days 1-28 
See Section 4.3 & Appendix I for 
administration guidelines. 
* For suggested dose based on 
TPMT and NUDT15 status, see 
Section 5.9  
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 
Days 1, 8 & 15 
 
 
See Section 4.3 for administration 
guidelines 
 
Note age-based dosing 
 
 
Ht__________cm 
        Wt__________kg 
 
         BSA__________m2 
 
Date Due Date Given Day 
VCR 
______mg 
MP 
______mg 
IT 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, c, d 
 
 
 
-- 
 
 
 
 
 
 
8 
 
_____mg 
c 
 
 
 
-- 
 
 
 
 
 
 
15 
 
_____mg 
c, e, f 
 
 
 
-- 
 
 
 
 
 
 
22 
 
 
 
 
 
 
-- 
 
 
 
 
 
 
28 
 
 
g^ 
 
 
 
29 
Begin next course (Interim Maintenance I, Section 4.4) on Day 29 or when blood count parameters are 
met (whichever occurs later) 
Note: B-LLy patients without CR at end-Consolidation are off protocol therapy, except patients with bone 
primaries who are considered CR if there is resolution of all surrounding soft tissue component by the end 
of Consolidation. 
^ For B-LLy patients ONLY. See Section 7.1d for details and exceptions. Note: PET scans for residual masses are highly recommended, not required and 
CXR is not required if CT chest is done. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
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4.4 
Interim Maintenance I (56 days) – AR B-ALL Patients, LR Patients Randomized to Arm LR-
C, and B-LLy Patients 
 
 
Criteria to Start Interim Maintenance I 
Begin IM I on Day 29 of Consolidation or when peripheral counts recover with an ANC ≥ 750/µL and 
platelets ≥ 75,000/µL, whichever occurs later. 
 
Interruption and/or Modification of Therapy 
All therapy should be interrupted for patients with presumed or proven severe infections and resumed when 
the signs of infection have abated. Obtain blood counts prior to each dose of methotrexate. 
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts in 
4 days. 
1. In 4 days, if ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as 
previously. 
2. In 4 days, if ANC is still < 500/µL or platelets < 50,000/µL, give VCR (and IT MTX if Day 
31) (omitting IV MTX) and repeat counts in 7 days to begin next dose of VCR and IV MTX  
if counts are adequate.  
a) If after 7 days, ANC ≥ 500/µL and platelets ≥ 50,000/µL reduce dose of MTX by 20% 
(Do not make up missed dose of MTX). For subsequent doses, resume escalation as 
per A-C.  
b) If after 7 days ANC is still < 500/µL or platelets < 50,000/µL, hold therapy until counts 
recover to ANC > 500/µL and platelets > 50,000/µL. When ANC ≥ 500/µL and 
platelets ≥ 50,000/µL, resume at 80% of last dose of MTX. For subsequent doses, 
resume escalation as per A - C. 
B) If ANC ≥ 500/µL but < 750/µL and/or platelets ≥ 50,000/µL but < 75,000/µL, give same dose of 
MTX as previously (i.e. no escalation). 
C) If ANC ≥ 750/µL and platelets ≥ 75 000/µL escalate MTX by 50 mg/m2/dose. 
D) Do not escalate MTX dose and resume at 80% of last dose if it had been delayed secondary to 
myelosuppression and/or Grade 3 mucositis. For subsequent doses, resume escalation as per A-C. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 11, 21, 31, and 41 
Dose: 1.5 mg/m2/dose (maximum 2 mg)  
 
NOTE FOR B-ALL PATIENTS: AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE 
BEEN MET, ADDITIONAL PATIENTS CLASSIFIED AS AR AND LR B-ALL PATIENTS 
WILL NOT RECEIVE POST-INDUCTION TREATMENT ON AALL0932. FURTHER 
TREATMENT FOR THESE PATIENTS WILL BE UP TO THE DISCRETION OF THE 
TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS RISK ASSIGNED BEFORE 
ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL CONTINUE TO RECEIVE 
POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Version Date: 10/26/2017 
  
53 
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: IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted). 
Days 1, 11, 21, 31 and 41 
Starting dose of 100 mg/m2/dose; thereafter, escalate by 50 mg/m2/dose  
 
Methotrexate: Intrathecal (IT) 
Day 31 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Interim Maintenance I is on the next page.  
 
For B-ALL and B-LLy patients: Following completion of Interim Maintenance I, the next course (Delayed 
Intensification, Section 4.5) starts on Day 57 or when blood count parameters are met (whichever occurs 
later). 
 
 
 

 
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54 
4.4.1 
Interim Maintenance I (56 days) – AR B-ALL Patients, LR 
B-ALL Patients Randomized to Arm LR-C, and B-LLy 
Patients  
 
 
_____________________________ 
Patient name or initials 
 
________________________ 
DOB 
Interim Maintenance I begins when ANC ≥ 750/µL and platelets ≥ 75,000/µL. This course lasts 8 weeks (56 days) and this 
Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 11, 21, 
31 & 41 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. Hx, PE, Wt., Ht. 
b. CBC/diff/platelets 
c. CSF, cell count, cytospin1 
d. Bilirubin, ALT & 
Creatinine. 
 
B-LLy patients only 
e. CT (neck, chest, abdomen 
& pelvis), CXR, bone 
scan (if bone 
involvement). 
 
1 Obtain with each IT 
administration 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR 
GOOD PATIENT CARE 
Methotrexate 
(MTX) 
IV over  
2-5 min (undiluted) or 
10-15 min (diluted) 
Starting dose 
100 mg/m2 & escalate 
by 50 mg/m2/dose 
Days 1, 11, 21, 
31 & 41 
See Section 4.4 for 
administration 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 
Day 31 ONLY 
See Section 4.4 for 
administration guidelines 
 
Note age-based dosing 
 
 
Ht___________cm 
Wt__________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
____mg 
(escalating dose) 
IT MTX 
____mg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual administered dose 
below 
 
 
 
 
1 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
11 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
21 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
31 
____mg 
____mg 
____mg 
a%, b, c, d 
 
 
 
--- 
 
 
 
 
 
 
 
41 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
56 
 
 
 
e^ 
 
 
 
57 
Begin next course (Delayed Intensification, Section 4.5) on Day 57 or when blood count parameters 
are met (whichever occurs later). 
^ For B-LLy patients ONLY. Note: CXR is not required if CT chest is done .See Section 7.1d for details.  
% Note: Height (Ht) is only required at the beginning of this course. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
Page 1 of 1 

 
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4.5 
Delayed Intensification (56 days) - AR B-ALL Patients, LR B-ALL Patients Randomized to 
 
Arm LR-C, and B-LLy Patients 
 
 
Criteria to Start Delayed Intensification 
Delayed Intensification begins on Day 57 of Interim Maintenance I, or when ANC  750/L and platelets 
 75,000/L, whichever occurs later. 
 
Interruption and/or Modifications of Therapy 
All therapy should be interrupted for presumed or proven serious infection. Myelosuppression alone does 
not delay therapy on Days 1 - 28 or Days 30 - 43, but Day 29 does not begin until ANC  750/L and 
platelets  75,000/L. Therapy interruptions should be made-up. In case of delays of 3 weeks or longer, 
notify the Study Chair.  
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special precautions and 
suggestions for patient monitoring during the infusions. As applicable, also see the CAGs for suggestions 
on hydration, or hydrate according to institutional guidelines. 
 
Dexamethasone: PO (may give IV) 
All patients, receive discontinuous dexamethasone therapy. 
Days 1 - 7 and 15 - 21 
Dose: 5 mg/m2/dose BID (i.e., total daily dose: 10 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (10 mg/m2/day, divided BID) may be used temporarily as 
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.” 
 
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. 
NOTE FOR B-ALL PATIENTS: AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE 
BEEN MET, ADDITIONAL PATIENTS CLASSIFIED AS AR AND LR B-ALL PATIENTS 
WILL NOT RECEIVE POST-INDUCTION TREATMENT ON AALL0932. FURTHER 
TREATMENT FOR THESE PATIENTS WILL BE UP TO THE DISCRETION OF THE 
TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS RISK ASSIGNED BEFORE 
ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL CONTINUE TO RECEIVE 
POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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56 
 
DOXOrubicin: IV push/infusion over 1 - 15 minutes  
Days 1, 8 and 15. 
Dose: 25 mg/m2/dose 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 1-15 minutes. Short 
infusion times may be lengthened slightly (and up to 60 minutes) if institutional policies mandate. It is 
suggested that DOXOrubicin be administered through the tubing of rapidly infusing solution of D5W or 
0.9% NaCl and that it is infused into a large vein or central venous access device. 
 
Pegaspargase: IV over 1 - 2 hours  
Day 4 
Dose: 2,500 International Units/m2/dose 
Administer through the tubing of a freely 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.  
 
Cyclophosphamide: IV over 30 - 60 minutes 
Day 29 
Dose: 1,000 mg/m2/dose  
 
Hydrate according to institutional guidelines. Suggested hydration: Pre-hydrate using fluids containing at 
least 0.45% NaCl. Achieve urine specific gravity of ≤ 1.010 prior to start of cyclophosphamide. Continue 
hydrating at a rate of 125 mL/m2/hour IV/PO for at least 8 hours after cyclophosphamide administration.  
 
Mesna is not required for this dose of cyclophosphamide, but may be administered at institutional 
discretion. 
 
Thioguanine: PO 
Days 29 - 42. 
Dose: 60 mg/m2/dose/once daily* 
 
*See Section 5.11 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that thioguanine be taken at the same time each day. 
 
Tablets are scored and doses can be rounded to half tablet. Adjust dose using ½ tablets and different doses 
on alternating days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. See 
Appendix II for details. 
 
 
 

 
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57 
Cytarabine: IV over 1 - 30 minutes or subcutaneous  
Days 29 - 32 and 36 - 39 
Dose: 75 mg/m2/dose/day  
 
When given subcutaneously, reconstitute to a concentration not to exceed 100 mg/mL. Rotate injection 
sites to thigh, abdomen, and flank regions. Avoid repeated administration to a single site. Aspirate prior to 
injection to avoid injection into a blood vessel. 
 
Methotrexate: Intrathecal (IT) 
Days 1 and 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The Therapy Delivery Maps (TDMs) for Delayed Intensification are on the next two (2) pages. 
 
For B-ALL and B-LLy patients: Following completion of Delayed Intensification, the next course (Interim 
Maintenance II, Section 4.6) starts on Day 57 or when blood count parameters are met (whichever occurs 
later). 
 
 

 
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4.5.1a Delayed Intensification (56 days)– AR B-ALL Patients, LR B-ALL Patients 
 
Randomized to Arm LR-C, and B-LLy Patients 
____________________                                     __________________ 
Patient name or initials                                                   DOB 
Delayed Intensification is 8 weeks (56 days). Begin DI on Day 57 of IM I or when ANC ≥ 750/µL and platelets ≥75,000/µL, whichever occurs later. See Section 4.5 for detailed therapy interruption guidelines. 
This therapy delivery map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, divided BID 
See Section 4.5 for administration guidelines 
a. Hx, PE, Wt., Ht. 
b. CBC/diff/platelets 
c. CSF cell count, cytospin1 
d. Bilirubin, ALT, & 
Creatinine 
e. Echocardiogram2 
 
 
1 Obtain with each IT 
administration 
2 Prior to first dose of 
doxorubicin 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m2/dose  
Days 1, 8 & 15 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
DOXOrubicin (DOXO) 
IV push/infusion  
over 1-15 min 
25 mg/m2/dose 
Days 1, 8 & 15 
See Section 4.5 for administration guidelines. 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4  
Administer through the tubing of a freely infusing solution 
of D5W or 0.9% NaCl 
Cyclophosphamide (CPM) IV over 30-60 min 
1000 mg/m2/dose 
Day 29* 
See Section 4.5 for administration guidelines. 
Thioguanine (TG) 
PO 
60 mg/m2/dose/day Days 29*-42 
See Section 4.5 & Appendix II for administration guidelines 
*for suggested dose based on TPMT and NUDT15 status, 
see Section 5.11 
Cytarabine (ARAC) 
IV over 1-30 min or SubQ 75 mg/m2/dose/day Days 29-32 & 36-39  
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 
Days 1 & 29 
See Section 4.5 for administration guidelines 
 
Note age-based dosing 
 
 
 
 
Ht__________cm   
Wt_________kg 
 
BSA_________m2 
Date 
Due 
Date 
Given 
Day 
DEX 
____mg ____mg 
VCR 
____mg 
DOXO 
____mg 
PEG-ASP 
_____IU 
CPM* 
____mg 
TG* 
_____mg 
ARAC* 
______mg 
IT MTX 
______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, e# 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
_____IU 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
8 
 
____mg 
____mg 
 
 
 
 
 
a%, b 
 
 
 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
15 
____mg ____mg 
____mg 
____mg 
 
 
 
 
 
a%, b 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
This Therapy Delivery Map continues on the next page 
* Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL to begin Day 29 therapy.  
# Prior to first doxorubicin dose 
% Note: Height (Ht) is only required at the beginning of this course. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
Page 1 of 2 

 
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4.5.1b Delayed Intensification (56 days) – AR B-ALL Patients, LR Patients Randomized to 
 
Arm LR-C, and B-LLy Patients (Continued) 
_________________                         _______________ 
Patient name or initials                                     DOB 
Delayed Intensification is 8 weeks (56 days). Begin DI on Day 57 of IM I or when ANC ≥ 750/µL and platelets ≥75,000/µL, whichever occurs later. See Section 4.5 for 
detailed therapy interruption guidelines. This therapy delivery map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, divided BID 
See Section 4.5 for administration guidelines 
a. Hx, PE, Wt., Ht.  
b. CBC/diff/platelets 
c. CSF cell count, cytospin1 
d. Bilirubin, ALT, & 
Creatinine 
e. Echocardiogram2 
 
1 Obtain with each IT 
administration 
2 Prior to first dose of 
doxorubicin 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m2/dose  
Days 1, 8 & 15 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
DOXOrubicin (DOXO) 
IV push/infusion over 1-
15 min 
25 mg/m2/dose 
Days 1, 8 & 15 
See Section 4.5 for administration guidelines. 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4  
Administer through the tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Cyclophosphamide (CPM) 
IV over 30-60 min 
1000 mg/m2/dose 
Day 29* 
See Section 4.5 for administration guidelines 
Thioguanine (TG) 
PO 
60 mg/m2/dose/day Days 29*-42 
See Section 4.5 & Appendix II for administration guidelines 
*for suggested dose based on TPMT and NUDT15 status, see 
Section 5.11 
Cytarabine (ARAC) 
IV over 1-30 min or SubQ 
75 mg/m2/dose/day Days 29-32 & 36-39  
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 
Days 1 & 29 
See Section 4.5 for administration guidelines 
 
Note age-based dosing 
 
 
 
 
Ht__________cm 
  
Wt_________kg  
BSA_________m2 
Date 
Due 
Date 
Given 
Day 
DEX 
____mg ____mg 
VCR 
____mg 
DOXO 
____mg 
PEG-ASP 
_____IU 
CPM* 
____mg 
TG* 
_____mg 
ARAC* 
______mg 
IT MTX 
______mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
29* 
 
 
 
 
____mg 
_____mg 
______mg 
______mg a%, b, c, d 
 
 
 
30 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
36 
 
 
 
 
 
______mg 
 
b 
 
 
 
37 
 
 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
 
 
43 
 
 
 
 
 
 
 
 
 
 
 
 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
 
 
 
 
57 
Begin next course (Interim Maintenance II, Section 4.6) on Day 57, or when blood count parameters are met (whichever occurs later)  
* Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL to begin Day 29 therapy.  
% Note: Height (Ht) is only required at the beginning of this course. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 2 of 2 

 
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4.6 
Interim Maintenance II (56 days) – AR B-ALL Patients, LR B-ALL Patients Randomized to 
Arm LR-C, and B-LLy Patients 
 
 
Criteria to Start Interim Maintenance II 
Begin IM II on Day 57 of DI, or when peripheral counts recover with an ANC ≥ 750/µL and platelets 
≥ 75,000/µL, whichever occurs later. 
 
Interruption and/or Modification of Therapy 
All therapy should be interrupted for patients with presumed or proven severe infections and resumed when 
the signs of infection have abated. Obtain blood counts prior to each dose of methotrexate. 
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts in 
4 days. 
1. In 4 days, if ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as 
previous cycle. 
2. In 4 days, if ANC is still < 500/µL or platelets < 50,000/µL, give VCR (and IT MTX if Day 31) 
(omitting IV MTX) and repeat counts in 7 days to begin next dose of VCR and IV MTX if 
counts are adequate.  
a. If after 7 days, ANC ≥ 500/µL and platelets ≥ 50,000/µL, reduce dose of MTX by 20% 
(Do not make up missed dose of MTX). For subsequent doses, resume escalation as per A-
C.  
b. If after 7 days ANC is still < 500/µL or platelets < 50,000/µL, hold therapy until counts 
recover to ANC > 500/µL and platelets > 50,000/µL. When ANC ≥ 500/µL and platelets 
≥ 50,000/µL, resume at 80% of last dose of MTX. For subsequent doses, resume escalation 
as per A-C. 
B) If ANC ≥ 500/µL but < 750/µL and/or platelets ≥ 50,000/µL but < 75,000/µL, give same dose of 
MTX as previously (i.e. no escalation). 
C) If ANC ≥ 750/µL and platelets ≥ 75,000/µL escalate MTX by 50 mg/m2/dose. 
D) Do not escalate MTX dose and resume at 80% of last dose if it had been delayed secondary to 
myelosuppression and/or Grade 3 mucositis. For subsequent doses, resume escalation as per A - C. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special precautions and 
suggestions for patient monitoring during the infusions. As applicable, also see the CAGs for suggestions 
on hydration, or hydrate according to institutional guidelines. 
 
 
 
NOTE FOR B-ALL PATIENTS: AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE 
BEEN MET, ADDITIONAL PATIENTS CLASSIFIED AS AR AND LR B-ALL PATIENTS 
WILL NOT RECEIVE POST-INDUCTION TREATMENT ON AALL0932. FURTHER 
TREATMENT FOR THESE PATIENTS WILL BE UP TO THE DISCRETION OF THE 
TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS RISK ASSIGNED BEFORE 
ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL CONTINUE TO RECEIVE 
POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
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61 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 11, 21, 31, and 41. 
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: IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted). 
Days 1, 11, 21, 31 and 41 
Starting dose is two-thirds of the maximum tolerated dose attained in Interim Maintenance I. For example, 
if a patient has toxicity at 250 mg/m² on Interim Maintenance I, the starting dose for Interim Maintenance 
II will be two thirds of 200 mg/m2 (or 130 mg/m2) IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes 
(diluted). Subsequent doses will be escalated by 50 mg/m² every 10 days (± 2 days) for 4 doses, to toxicity 
Days 11, 21, 31 and 41. 
 
Methotrexate: Intrathecal (IT) 
Days 1 and 31 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
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. 
 
FOR PATIENTS WITH AR B-ALL: CONSENT TO 1 OF 4 DIFFERENT MAINTENANCE 
REGIMENS MUST TAKE PLACE BEFORE STARTING MAINTENANCE THERAPY. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
For patient convenience, consent for Maintenance therapy can be obtained any time from Day 41 of IM II 
to just prior to the planned start of Maintenance therapy and randomization via the RDE Callback form, can 
be done as early as 72 hours prior to and must be done before start of Maintenance therapy 
 
LR B-ALL PATIENTS RANDOMIZED TO ARM LR-C WILL CONTINUE TO MAINTENANCE 
WHEN COUNT PARAMETERS ARE MET 
 

 
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62 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Interim Maintenance II is on the next page.  
 
For B-ALL Patients: 
Following completion of Interim Maintenance II, the next course (Maintenance Arms A, B, C or D, Sections 
4.7, 4.8, 4.9 or 4.10 - depending on randomization results for AR B-ALL patients; Maintenance Arm C, 
Section 4.9 for LR B-ALL patients on Arm LR-C) starts on Day 57 or when blood count parameters are 
met (whichever occurs later). 
 
For B-LLy Patients: 
Following completion of Interim Maintenance II, the next course (Maintenance Arm LLy, Section 4.11) 
starts on Day 57 or when blood count parameters are met (whichever occurs later). 
 
 
Page 1 of 1 

 
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4.6.1 
Interim Maintenance II – AR B-ALL Patients, LR B-ALL 
 
Patients Randomized to Arm LR-C and B-LLy Patients (56 
days)  
 
 
___________________________ 
Patient name or initials 
 
________________________ 
DOB 
Interim Maintenance II begins on Day 57 of DI or when ANC ≥ 750/µL and platelets ≥ 75,000/µL whichever occurs later. 
This course lasts 8 weeks (56 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
min+ 
1.5 mg/m2/dose 
Days 1, 11, 21, 
31 & 41 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. Bilirubin, ALT, & 
Creatinine. 
 
! Obtain with each IT 
administration. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(MTX) 
IV over 2-5 min 
(undiluted) or 
10-15 min 
(diluted) 
____mg/m2/dose* Days 1, 11, 21, 
31 & 41 
*Starting dose for Interim 
Maintenance II is two-thirds of the 
maximum tolerated dose attained in 
Interim Maintenance I (see Section 
4.6 for details). Thereafter, escalate 
by 50 mg/m2/dose 
See Section 4.6 for administration 
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 
Days 1 and 31  See Section 4.6 for administration 
guidelines 
 
Note age-based dosing 
 
 
 
 
Ht___________cm 
Wt__________kg 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
____mg 
(escalating dose) 
IT MTX 
____mg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual administered dose below. 
 
 
 
 
1 
____mg 
____mg 
____mg 
a%, b, c, d 
 
 
 
--- 
 
 
 
 
 
 
 
11 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
21 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
31 
____mg 
____mg 
____mg 
a%, b, c, d 
 
 
 
--- 
 
 
 
 
 
 
 
41 
____mg 
____mg 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
57 
Begin next course (Maintenance Arms A, B, C or D, Sections 4.7, 4.8, 4.9 or 4.10 - depending on 
randomization results for AR B-ALL patients; Maintenance Arm C, Section 4.9 for LR B-ALL patients 
on Arm LR-C); Maintenance Arm LLy, Section 4.11 for B-LLy patients on Day 57 or when blood count 
parameters are met (whichever occurs later). 
% Note: Height (Ht) is only required at the beginning of this course. 
 
DO CALL-BACK #2 PRIOR TO BEGINNING MAINTENANCE THERAPY FOR AR B-ALL PATIENTS 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
 

 
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4.7 
Maintenance Arm A (AR B-ALL Patients) 
 
 
CONSENT TO 1 OF 4 DIFFERENT MAINTENANCE REGIMENS MUST TAKE PLACE 
BEFORE STARTING MAINTENANCE THERAPY FOR PATIENTS WITH AR B-ALL. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
For patient convenience, consent for Maintenance therapy can be obtained any time from Day 41 of IM II 
to just prior to the planned start of Maintenance therapy and randomization. Randomization via the RDE 
Callback form (Callback #2), must be done within 72 hours PRIOR TO the planned start of Maintenance 
therapy. 
 
Treatment administered to AR B-ALL patients randomized to Maintenance treatment Arm A: 
 
Vincristine/dexamethasone pulses at 4 week intervals,  
 
IT methotrexate every 12 weeks 
 
Oral methotrexate at 20 mg/m2/week.  
 
Criteria to begin Maintenance  
Maintenance begins on Day 57 of IM II, or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
Maintenance consists of 12 week cycles repeated until total duration of therapy is 2 years for female 
patients and 3 years for male patients from the start of Interim Maintenance I. 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for  
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
  
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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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. 
 
Dexamethasone: PO 
Days 1 - 5, 29 - 33 & 57 - 61(do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as 
needed. 
 
Methotrexate: PO 
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration.  
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that thioguanine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.9 for 
dose modifications during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
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 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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66 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
HRQOL Studies  
Both HRQOL ancillary studies are closed to new patient enrollment due to accrual goals being met. 
Closure to accrual occurred on March 3, 2013 for the LPFS study and April 19, 2013 for the PLES 
study. Institutions are required to continue data collection at remaining evaluation time points, for 
patients already enrolled on these studies. 
 
Please note: For AR B-ALL already patients enrolled on the optional Patient Leukemia Experience Study 
(available at all centers), evaluations are due on Day 29 (or within 1 month afterwards) of Cycles 1, 4, 7 
and end of therapy for boys, Day 29 (or within 1 month afterwards) of Cycles 1, 4 and end of therapy for 
girls. See Section 15.0 for details of evaluation schedule.  
 
For AR B-ALL patients already enrolled on the optional Leukemia Physical Functioning Study (at selected 
centers-available on the COG AALL0932 protocol webpage), evaluations for boys are due on Day 29 (or 
within 1 month afterwards) of Cycles 1, 7 and also 1 year post therapy; evaluations for girls are due on 
Day 29 (or within 1 month afterwards) of Cycle 1 and end of therapy, as well as 1 year post therapy. See 
Section 16.0 for details of evaluation schedule. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm A (AR B-ALL patients) is on the following page. 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
67 
 
4.7.1 
Maintenance - Treatment Arm A- Standard Treatment (AR B-ALL Patients) 
__________________                  ________________ 
Patient name or initials                                 DOB 
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later) for Cycle 1. For 
subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.7 and 5.9 for details. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Days 1, 29 & 57 
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht. 
b. 
CBC/diff/platelets 
c. 
CSF cell count, cytospin1 
d. 
Bilirubin, ALT, & Creatinine 
e. 
Patient Leukemia Experience Study 
surveys2 
f. 
Leukemia Physical Functioning Study 
evaluations3 
 
1 Obtain with each IT administration 
2 For the Patient Leukemia Experience study, 
boys’ evaluations is due on Day 29 of Cycles 1, 
4, 7 and also at end of therapy; for girls Cycles 
1, 4 and also end of therapy. See Section 15.0 
for details. 
 
3For the Physical Functioning study, 
evaluations for boys are due on Day 29 of 
Cycles 1, 7 & 1 year post therapy; evaluations 
for girls are due on Day 29 of Cycle 1, at the 
end of therapy and 1 year post therapy. See 
Section 16.0 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5, 29-33 & 
57-61 (do not taper)  
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.7 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-84 
*see Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.7 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week Days 8, 15, 22, 29, 
36, 43, 50, 57, 64, 71 
& 78 
Omit Day 1 dose as it coincides with IT 
MTX  
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 
Day 1 
 
See Section 4.7 for administration guidelines 
 
Note age-based dosing 
Enter Cycle # _______Ht__________cm 
        Wt_________kg  
BSA_________m2 
Date Due 
Date Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
_______mg 
 
a%, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
8 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
- 
 
22 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
______mg 
_____mg _____mg 
 
_______mg 
a%, b, e, f 
 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
36 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
______mg 
_____mg _____mg 
 
_______mg 
a%, b 
 
 
 
58 
 
 
 
 
 
 
 
59 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
- 
 
64 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs (females) or 3 yrs (males) from start of IM I  
% Note: Height (Ht) is only required at the beginning of each course/cycle.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
68 
 
4.8 
Maintenance Arm B (AR B-ALL Patients) 
 
 
CONSENT TO 1 OF 4 DIFFERENT MAINTENANCE REGIMENS MUST TAKE PLACE 
BEFORE STARTING MAINTENANCE THERAPY FOR PATIENTS WITH AR B-ALL. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
For patient convenience, consent for Maintenance therapy can be obtained any time from Day 41 of IM II 
to just prior to the planned start of Maintenance therapy and randomization. Randomization via the RDE 
Callback form (Callback #2), must be done within 72 hours PRIOR TO the planned start of Maintenance 
therapy.  
 
Treatment administered to AR B-ALL patients randomized to Maintenance treatment Arm B: 
 
Vincristine/dexamethasone pulses at 4 week intervals,  
 
IT methotrexate every 12 weeks  
 
Oral methotrexate at 20 mg/m2/week.  
 
Criteria to begin Maintenance  
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
Maintenance consists of 12 week cycles repeated until total duration of therapy is 2 years for female 
patients and 3 years for male patients from the start of Interim Maintenance I. 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for  
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
  
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
69 
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. 
 
Dexamethasone: PO 
Days 1 - 5, 29 - 33 & 57 - 61 (do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as 
needed. 
 
Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration.  
For ease of swallowing, methotrexate injection can be administered orally (see drug monograph). 
 
Effective the memo dated 01/13/2017 all patients on Arms B and D were recommended to have their oral 
methotrexate dose lowered to 20 mg/m2/week, the standard of care therapy. Subsequently, patients should 
have their doses of 6 mercaptopurine and methotrexate adjusted based on tolerability following normal dose 
escalation procedures, as outlined in the protocol Section 5.9. 
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.8 for 
dose modifications during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
Day 1  
Age-based dosing: 
Age (yrs) 
Dose 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
70 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
HRQOL Studies 
Both HRQOL ancillary studies are closed to new patient enrollment due to accrual goals being met. 
Closure to accrual occurred on March 3, 2013 for the LPFS study and April 19, 2013 for the PLES 
study. Institutions are required to continue data collection at remaining evaluation time points, for 
patients already enrolled on these studies. 
 
Please note: For AR B-ALL patients already enrolled on the optional Patient Leukemia Experience Study 
(available at all centers), evaluations are due on Day 29 (or within 1 month afterwards) of Cycles 1, 4, 7 
and end of therapy for boys; Day 29 (or within 1 month afterwards) of Cycles 1, 4 and end of therapy for 
girls. See Section 15.0 for details of evaluation schedule.  
 
For AR B-ALL patients already enrolled on the optional Leukemia Physical Functioning Study (at selected 
centers available on the COG AALL0932 protocol webpage), evaluations for boys are due on Day 29 (or 
within 1 month afterwards) of Cycles 1, 7 and also 1 year post therapy; evaluations for girls are due on 
Day 29 (or within 1 month afterwards) of Cycle 1 and end of therapy, as well as 1 year post therapy. See 
Section 16.0 for details of evaluation schedule. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm B (AR B-ALL patients) is on the following page. 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
71 
 
4.8.1 
Maintenance - Treatment Arm B (AR B-ALL Patients) ____________________________                        ______________________________________ 
Patient name or initials                                                                               DOB 
Maintenance begins on day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL, (whichever occurs later) for Cycle 1. 
For subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.8 and 5.9 for details. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Days 1, 29 & 57 
 
+ Or infusion via minibag as per 
institutional policy. Maximum dose: 2 mg 
a. Hx, PE, Wt ., Ht. 
b. CBC/diff/platelets 
c. CSF cell count, cytospin1 
d. Bilirubin, ALT, & Creatinine 
e. Patient Leukemia Experience 
Study surveys2 
f. 
Leukemia Physical Functioning 
Study evaluations3 
1 Obtain with each IT administration 
2 For the Patient Leukemia Experience 
study, boys’ evaluations are due on Day 29 
of Cycles 1, 4, 7 and also at end of therapy; 
for girls, Cycles 1, 4 and also end of 
therapy. See Section 15.0 for details. 
 
3For the Physical Functioning study; 
evaluations for boys are due on Day 29 of 
Cycles 1, 7 & 1 year post therapy; 
evaluations for girls are due on Day 29 of 
Cycle 1, at the end of therapy, and 1 year 
post therapy. See Section 16.0 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5, 29-33 & 
57-61 (do not taper) 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.8 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-84 
*See Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.8 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week Days 8, 15, 22, 29, 
36, 43, 50, 57, 64, 
71 & 78 
Omit Day 1 dose as it coincides with IT 
MTX 
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 
Day 1 
 
See Section 4.8 for administration guidelines 
 
Note age-based dosing 
Enter Cycle # _______Ht__________cm 
        Wt_________kg  BSA_________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
_______mg 
 
a%, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
8 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
______mg 
_____mg _____mg 
 
_______mg 
a%, b, e, f 
 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
______mg 
_____mg _____mg 
 
_______mg 
a%, b 
 
 
 
58 
 
 
 
 
 
 
 
59 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs (females) or 3 yrs (males) from start of IM I  
% Note: Height (Ht) is only required at the beginning of each course/cycle.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
72 
4.9 Maintenance Arm C (AR B-ALL Patients and LR B-ALL Patients Randomized to Arm LR-C) 
 
 
CONSENT TO 1 OF 4 DIFFERENT MAINTENANCE REGIMENS MUST TAKE PLACE 
BEFORE STARTING MAINTENANCE THERAPY FOR PATIENTS WITH AR B-ALL ONLY. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
For patient convenience, consent for Maintenance therapy can be obtained any time from Day 41 of IM II 
to just prior to the planned start of Maintenance therapy and randomization. Randomization via the RDE 
Callback form (Callback #2), must be done within 72 hours PRIOR TO the planned start of Maintenance 
therapy. 
 
Treatment administered to AR B-ALL patients randomized to Maintenance treatment Arm C: 
 
Vincristine/dexamethasone pulses at 12 week intervals,  
 
IT methotrexate every 12 weeks 
 
Oral methotrexate at 20 mg/m2/week.  
 
Criteria to begin Maintenance  
Maintenance begins on day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
Maintenance consists of 12 week cycles repeated until total duration of therapy is 2 years for female 
patients and 3 years for male patients from the start of Interim Maintenance I. 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
  
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
73 
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. 
 
Dexamethasone: PO 
Days 1 - 5 (do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as 
needed. 
 
Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. The liquid or tablet 
formulation may be used. Tablets are scored and doses can be rounded to half tablet. If using tablets, adjust 
dose using ½ tablets and different doses on alternating days in order to attain a weekly cumulative dose as 
close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.8 for dose modifications 
during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
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 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
74 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
HRQOL Studies  
Both HRQOL ancillary studies are closed to new patient enrollment due to accrual goals being met. 
Closure to accrual occurred on March 3, 2013 for the LPFS study and April 19, 2013 for the PLES 
study. Institutions are required to continue data collection at remaining evaluation time points, for 
patients already enrolled on these studies. 
 
Please note: For AR B-ALL patients already enrolled on the optional Patient Leukemia Experience Study, 
evaluations are due on Day 29 (or within 1 month afterwards) of Cycles 1, 4, 7 and end of therapy for boys; 
Day 29 (or within 1 month afterwards) of Cycles 1, 4 and end of therapy for girls. See Section 15.0 for 
details of evaluation schedule.  
 
For AR B-ALL patients already enrolled on the optional Leukemia Physical Functioning Study, evaluations 
for boys are due on Day 29 (or within 1 month afterwards) of Cycles 1, 7 and also 1 year post therapy; 
evaluations for girls are due on Day 29 (or within 1 month afterwards) of Cycle 1 and end of therapy, as 
well as 1 year post therapy. See Section 16.0 for details of evaluation schedule. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm C (AR B-ALL patients and LR B-ALL Patients 
Randomized to Arm LR-C) is on the following page. 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
75 
4.9.1 
Maintenance - Treatment Arm C (AR B-ALL Patients and 
 
LR B-ALL Patients Randomized to Arm LR-C) 
 
_____________________                                                  ___________________ 
Patient name or initials                                                                               DOB 
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL, (whichever occurs later) for Cycle 1. 
For subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.9 and 5.9 for details. This Therapy Delivery Map is on one 
(1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Day 1 
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, cytospin1 
d. 
Bilirubin, ALT, & Creatinine 
e. 
Patient Leukemia Experience 
Study surveys2 
f. 
Leukemia Physical Functioning 
Study evaluation3. 
 
1 Obtain with each IT administration 
2 For the Patient Leukemia Experience 
study, boys’ evaluations are due on Day 
29 of Cycles 1, 4, 7 and also at end of 
therapy; for girls Cycles 1, 4 and also 
end of therapy. See Section 15.0. 
 
3For the Physical Functioning study; 
evaluations for boys are due on Day 29 
of Cycles 1, 7 & 1 year post therapy; 
evaluations for girls are due on Day 29 
of Cycle 1, at the end of therapy and 
1 year post therapy. See Section 16.0 for 
details. 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5 (do not taper) Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.9 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-84 
*See Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.9 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 8, 15, 22, 29, 36, 
43, 50, 57, 64, 71 & 78 
Omit Day 1 dose as it coincides with IT 
MTX 
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 
Day 1  
 
See Section 4.9 for administration guidelines 
 
Note age-based dosing 
 
Enter Cycle # _______Ht__________cm 
  Wt_______ kg 
 
BSA_________m2 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______mg 
PO MTX 
_______mg 
Studies 
Comments 
 
 
 
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 
a%, b, e, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
_______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs (females) or 3 yrs (males) from start of IM I  
% Note: Height (Ht) is only required at the beginning of each course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
76 
4.10 
Maintenance Arm D (AR B-ALL Patients) 
 
 
CONSENT TO 1 OF 4 DIFFERENT MAINTENANCE REGIMENS MUST TAKE PLACE 
BEFORE STARTING MAINTENANCE THERAPY FOR PATIENTS WITH AR B-ALL. 
PATIENTS WHO ELECT NOT TO CONSENT TO THIS RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
For patient convenience, consent for Maintenance therapy can be obtained any time from Day 41 of IM II 
to just prior to the planned start of Maintenance therapy and randomization. Randomization via the RDE 
Callback form (Callback #2), must be done within 72 hours PRIOR TO the planned start of Maintenance 
therapy. 
 
Treatment administered to AR B-ALL patients randomized to Maintenance treatment Arm D: 
 
Vincristine/dexamethasone pulses at 12 week intervals,  
 
IT methotrexate every 12 weeks  
 
Oral methotrexate at 20 mg/m2/week.  
 
Criteria to begin Maintenance  
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
Maintenance consists of 12 week cycles repeated until total duration of therapy is 2 years for female 
patients and 3 years for male patients from the start of Interim Maintenance I. 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
  
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST-INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
77 
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. 
 
Dexamethasone: PO 
Days 1 - 5(do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as 
needed. 
 
Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Effective the memo dated 01/13/2017 all patients on Arms B and D were recommended to have their 
oral methotrexate dose lowered to 20 mg/m2/week, the standard of care therapy. Subsequently, 
patients should have their doses of 6 mercaptopurine and methotrexate adjusted based on tolerability 
following normal dose escalation procedures, as outlined in the protocol Section 5.9. 
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.8 for 
dose modifications during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
Day 1  
Age-based dosing: 
Age (yrs) 
Dose 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
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78 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
HRQOL Studies 
Both HRQOL ancillary studies are closed to new patient enrollment due to accrual goals being met. 
Closure to accrual occurred on March 3, 2013 for the LPFS study and April 19, 2013 for the PLES 
study. Institutions are required to continue data collection at remaining evaluation time points, for 
patients already enrolled on these studies. 
 
Please note: For AR B-ALL patients already enrolled on the optional Patient Leukemia Experience Study, 
evaluations are due on Day 29 (or within 1 month afterwards) of Cycles 1, 4, 7 and end of therapy for boys; 
Day 29 (or within 1 month afterwards) of Cycles 1, 4 and end of therapy for girls. See Section 15.0 for 
details of evaluation schedule.  
 
For AR B-ALL patients already enrolled on the optional Leukemia Physical Functioning Study, evaluations 
for boys are due on Day 29 (or within 1 month afterwards) of Cycles 1, 7 and also 1 year post therapy; 
evaluations for girls are due on Day 29 (or within 1 month afterwards) of Cycle 1 and end of therapy, as 
well as 1 year post therapy. See Section 16.0 for details of evaluation schedule. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm D (AR B-ALL patients) is on the following page. 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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79 
G 
4.10.1 Maintenance - Treatment Arm D (AR B-ALL Patients) 
 
 
_____________________                                     ___________________ 
Patient name or initials                                                                         DOB 
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL, (whichever occurs later) for 
Cycle 1. For subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.10 and 5.9 for details This Therapy Delivery Map 
is on one (1) page. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Day 1 
 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, cytospin1 
d. 
Bilirubin, ALT, & Creatinine  
e. 
Patient Leukemia Experience 
Study surveys2 
f. 
Leukemia Physical Functioning 
Study evaluation3 
 
1 Obtain with each IT administration 
2 For the Patient Leukemia Experience 
study, boys’ evaluations are due on Day 29 
of Cycles 1, 4, 7 and also at end of therapy; 
for girls Cycles 1, 4 and also end of 
therapy. See Section 15.0  
 
3For the Physical Functioning study; 
evaluations for boys are due on Day 29 of 
Cycles 1, 7 & 1 year post therapy; 
evaluations for girls are due on Day 29 of 
Cycle 1, at the end of therapy and 1 year 
post therapy. See Section 16.0 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5  
(do not taper)  
Total daily dose: 6 mg/m2/day, divided 
BID 
See Section 4.10 for administration 
guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-84 
*See Section 5.9 for suggested starting 
dose based on TPMT and NUDT15 
status 
See Section 4.10 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 8, 15, 22, 29, 
36, 43, 50, 57, 64, 
71 & 78 
Omit Day 1 dose as it coincides with IT 
MTX 
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 
Day 1  
 
See Section 4.10 for administration 
guidelines 
 
Note age-based dosing 
Enter Cycle # _______Ht__________cm 
  Wt_______ kg 
 
BSA_________m2 
 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______mg 
PO MTX 
_______mg 
Studies 
Comments 
 
 
 
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 
a%, b, e, f 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
_______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs (females) or 3 yrs (males) from start of IM I  
% Note: Height (Ht) is only required at the beginning of each course/cycle.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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80 
4.11 
Maintenance Arm LLy (B-LLy Patients) 
 
PATIENTS ARE NON-RANDOMLY ASSIGNED TO CONTINUE MAINTENANCE ARM LLy 
THERAPY. CALLBACK #2 IS NOT SUBMITTED FOR B-LLy PATIENTS. 
 
Criteria to begin Maintenance  
Maintenance begins on Day 57 of IM II, or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
B-LLy patients will be non-randomly assigned to Maintenance Arm LLy: 
 
Vincristine/dexamethasone pulses at 4 week intervals,  
 
IT methotrexate every 12 weeks 
 
Oral methotrexate at 20 mg/m2/week.  
 
Maintenance consists of 12 week cycles repeated until total duration of therapy is 2 years from the 
start of Interim Maintenance I 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
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. 
 
Dexamethasone: PO 
Days 1 - 5, 29 - 33 & 57 - 61(do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
81 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as 
needed. 
 
Methotrexate: PO 
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration.  
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.9 for 
dose modifications during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LLy (B-LLy patients) is on the following page. 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
82 
4.11.1 Maintenance Arm LLy (B-LLy Patients only) 
_____________________                          ___________________ 
Patient name or initials                                                DOB 
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL whichever occurs later for Cycle 1. For 
subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.11 and 5.9 for details. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Days 1, 29 & 57 
 
+ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg 
a 
Hx, PE, Wt., Ht.  
b 
CBC/diff/platelets 
c 
CSF cell count, cytospin! 
d 
Bilirubin, ALT, & Creatinine 
e. 
CT (neck, chest, abdomen & pelvis),  
CXR, bone scan (if bone 
involvement) ^ 
 
!Obtain with each IT administration 
^Please refer to Section 7.1d for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE  
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5, 29-33 & 57-61 
(do not taper)  
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.11 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-84 
*See Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.11 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week Days 8, 15, 22, 29, 36, 43, 
50, 57, 64, 71 & 78 
Omit Day 1 dose as it coincides with IT MTX 
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 
Day 1 
 
See Section 4.11 for administration guidelines 
 
Note age-based dosing 
Enter Cycle # _______Ht__________cm 
        Wt_________kg  
BSA_________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
______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 
_______mg 
______mg 
 
a%, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
8 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
- 
 
22 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
______mg 
_____mg _____mg 
 
_______mg 
a%, b 
 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
______mg 
_____mg _____mg 
 
_______mg 
a%, b 
 
 
 
58 
 
 
 
 
 
 
 
59 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
- 
 
64 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
_______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
e^ 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs from start of IM I for both males and 
females. 
% Note: Height (Ht) is only required at the beginning of each course/cycle. 
 
^At completion of Maintenance therapy. Note: CXR is not required if CT chest is done (see Section 7.1d for details).  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Version Date: 10/26/2017 
  
83 
4.12 
Consolidation (19 Weeks) – LR B-ALL Patients Randomized to Arm LR-M  
 
 
PATIENTS DETERMINED TO BE LOW RISK MUST CONSENT TO BE RANDOMIZED FOR 
POST-INDUCTION THERAPY BEFORE STARTING CONSOLIDATION. PATIENTS WHO 
ELECT NOT TO CONSENT TO THIS TREATMENT RANDOMIZATION ARE OFF 
PROTOCOL THERAPY. 
 
Day 1 of Consolidation begins one week after the end of Induction regardless of counts.  
 
However, oral 6-MP should not be started until ANC ≥ 500/µL and platelets ≥ 75,000/µL.  
 
If the start of oral 6-MP is delayed, DO NOT “make up” missed doses. It is recommended to repeat a CBC 
every 2 to 3 days and start oral 6-MP when counts meet criteria; deliver initial IV MTX 2 weeks after end 
of Induction (i.e. on Day 8 of Consolidation) if count parameters are met regardless of the length of 6-MP 
administration. If count parameters are not met, patient will begin Day 8 of Consolidation as soon as they 
are met. 
 
Each MTX infusion is to begin when ANC ≥ 500/μL and platelets ≥ 75,000/μL; ALT < 20 x upper 
limit of normal and bilirubin and creatinine normal for age.  
 
After an IV dose of MTX is given, continue with oral 6-MP for the next 3 weeks even in the face of 
uncomplicated myelosuppression. 
 
When a course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, delay IV MTX 
administration and HOLD 6-MP until ANC ≥ 500/μL and platelets ≥ 75,000/μL, then restart 6-MP and IV 
MTX at 100% dosing. IV MTX should continue on an every 3-week schedule. 
 
When a subsequent course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, delay IV 
MTX administration and HOLD 6-MP until count recovery and then restart 6-MP at 75% dose and IV MTX 
at 100% dosing. IV MTX should continue on an every 3 week schedule. 
 
See Section 5.7.2 for additional details of dose modification for this course. 
 
Also consider TMP/SMX as possible cause of neutropenia. Consider discontinuing TMP/SMX in favor of 
an alternative approach to Pneumocystis prophylaxis, as per COG Supportive Care Guidelines (see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
For patients with TPMT and NUDT15 mutations see Section 5.9 for starting doses of 6-MP. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
84 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 15, 22, 78 and 85  
Dose: 1.5 mg/m2/dose (maximum 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: IV over 24 hours 
Days 8, 29, 50, 71, 92 and 113  
Dose: 1000 mg/m2 
 
Given as a 200 mg/m2 bolus over 20 - 30 minutes followed by 800 mg/m2 over 23.5 hours (if initial bolus 
was over 30 minutes) or 23 hours and 40 minutes (if initial bolus was over 20 minutes). 
 
The goal is to complete the intermediate dose methotrexate infusion in 24 hours; however, due to infusion 
pump variability, acceptable total infusion time is 24 ± 2 hours. 
 
Leucovorin rescue begins at 10 mg/m2 every 6 hours beginning 42 hrs after the start of the infusion. 
Continue leucovorin until plasma MTX is < 0.2μM. If the patient has had clinical toxicity (see definition 
below) on a prior cycle, consider giving the 54 hour dose of leucovorin even if the 48 hour MTX is < 0.2 μM. 
Methotrexate levels are drawn at the end of methotrexate infusion and 24 hours after completion of the 
methotrexate infusion and every 12 to 24 hours thereafter until the level is < 0.2 μM. See Section 5.7.2 for 
more detailed recommendations on hydration and leucovorin administration. 
 
Suggested hydration and alkalinization: 
Pre-hydrate with D5 ¼ NS with 30 mEq/L sodium bicarbonate at 100 mL/m2/hour until urine specific gravity 
is ≤ 1.010 and urine pH is ≥ 6.5 and ≤ 8.0. 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 and pH at above parameters. A bicarbonate bolus (25 mEq/m2 over 15 minutes) may be given to 
raise the urine pH relatively quickly; a normal saline bolus may also be helpful in facilitating hydration. 
Continue with hydration until plasma MTX level is < 0.2μM. 
 
Special precautions: IV leucovorin and sodium bicarbonate are incompatible 
 
See Section 5.7.2 for Toxicity Monitoring  
 
Leucovorin: PO (may be given IV if necessary) 
Days 9 - 10, 30 - 31, 51 - 52, 72 - 73, 93 - 94, and 114 - 115 
Dose: 10 mg/m2/dose for at least 2 doses given 42 and 48 hours after the START of MTX infusion, and 
continuing q 6 hours until MTX plasma MTX level is < 0.2μM 

 
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85 
 
Leucovorin rescue will be given after IV MTX during Consolidation therapy. The first dose beginning 
42 hrs after the START of the methotrexate infusion. Continue leucovorin until plasma methotrexate is 
< 0.2µM. In the absence of toxicity, the Hour 54 leucovorin dose should be eliminated if the 48 Hour plasma 
methotrexate concentration is < 0.2 µM. In case of prolonged clearance see Section 5.7.2 
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
Methotrexate: Intrathecal (IT)* 
Days 8, 29, 50, 71, 92 and 113  
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
*Deliver IT therapy within 6 hrs of the beginning of the IV methotrexate infusion. (Hour -6 to +6, with 
hour 0 being the start of the MTX bolus) 
 
For IT administration, use 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). 
 
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 encouraged but not mandated for patients on COG studies. 
 
Dexamethasone: PO (may be given IV) 
Days 15 - 21 and 78 - 84 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/day, divided BID) may be used temporarily as 
needed. 
 
Mercaptopurine: PO 
Days 1 - 133 
Dose: 50 mg/m2/dose once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 350 mg/m2/week as possible. See Appendix III for details. Do not escalate dose 
based on blood counts during this cycle (see Section 5.8). 

 
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SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery maps (TDMs) for Consolidation are on the next three (3) pages. 
 
Following completion of Consolidation, the next course (Maintenance Arm LR-M - Cycle 1, Section 4.13) 
starts on Day 134 or when blood count parameters are met (whichever occurs later). 
 

 
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87 
 
 
 
 
4.12.1a Consolidation (19 weeks) – LR B-ALL Patients Randomized to Arm LR-M 
Leucovorin rescue will be given after each IV MTX 
 
__________________                                                             ______________ 
Patient name or initials                                                                       DOB 
Consolidation therapy lasts 19 weeks. Start Consolidation on Day 36 of Induction (1 week after the end of Induction) regardless of counts but oral 6-MP should not be started until ANC 
≥ 500/µL and platelets ≥75,000/µL. This Therapy Delivery Map is on three (3) pages. See Section 4.12 .for full treatment details. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Mercaptopurine (MP) 
PO 
50 mg/m2/dose* 
Days 1-133 
See Section 4.12 & Appendix III for administration 
guidelines. *For TMPT and NUDT15 based dosing 
see Section 5.9 
a. 
Hx/PE/Wt., Ht. 
b. 
CBC/Diff/Platelets 
c. 
CSF cell count, cytospin 1 
d. 
Bilirubin , ALT, & 
Creatinine 
e. 
Serum creatinine & plasma 
MTX levels 2 
 
1 Obtain with each IT 
administration 
2 See Section 7.1b for details of 
monitoring. 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
1.5 mg/m2/dose 
Days 15, 22, 78, and 85 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Dexamethasone (DEX) 
PO (may give IV) 
3 mg/m2/dose BID 
Days 15-21 and 78-84 
 
Total daily dose: 
6 mg/m2/day, divided BID 
See Section 4.12 for admin guidelines 
Methotrexate (MTX) 
IV over 24 hours 
1000 mg/m2 
Days 8, 29, 50, 71, 92, and 113  
See Section 4.12 for administration guidelines 
Leucovorin (LCV) 
PO# 
10 mg/m2/dose q6 hrs 
Days 9-10, 30-31, 51-52, 72-73, 93-94, 
and 114-115 
See Section 4.12 for administration guidelines 
42, 48 hrs after the START of each IV MTX and q6 
hours until the MTX level falls below 0.2μM. 
#Continue until MTX level is < 0.2µM. 
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 
Days 8, 29, 50, 71, 92, and 113 
See Section 4.12 for administration guidelines. 
Deliver IT therapy within 6 hrs of the beginning of the 
IV methotrexate infusion. (Hour -6 to +6, with hour 0 
being the start of the MTX bolus) 
Note age-based dosing 
 
 
 
 
Ht____________cm         Wt___________kg 
         BSA__________m2 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
VCR 
____mg 
DEX (BID Dosing) 
____mg ____mg 
IV MTX 
____mg 
IT MTX 
_____mg 
LCV 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
 
 
 
 
 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
8 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
9 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
10 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
15 
____mg 
____mg ____mg 
 
 
 
a% 
 
 
 
16 
 
____mg ____mg 
 
 
 
 
 
 
 
17 
 
____mg ____mg 
 
 
 
 
 
 
 
18 
 
____mg ____mg 
 
 
 
 
 
 
 
19 
 
____mg ____mg 
 
 
 
 
 
 
 
20 
 
____mg ____mg 
 
 
 
 
 
 
 
21 
 
____mg ____mg 
 
 
 
 
 
 
 
22 
____mg 
 
 
 
 
a 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
29 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
30 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
31 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
This Therapy Delivery Map continues on the next two (2) pages. 
% Note: Height (Ht) is only required at the beginning of this course.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 3 

 
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4.12.1b  Consolidation (19 weeks) – LR B-ALL Patients Randomized to Arm LR-M   
 
 (Continued) 
Leucovorin rescue will be given after each IV MTX 
 
__________________                                          _____________ 
Patient name or initials                             
              DOB 
Consolidation therapy lasts 19 weeks. Start Consolidation on Day 36 of Induction (1 week after the end of Induction) regardless of counts but oral 6-MP should not be started until ANC 
≥ 500/µL and platelets ≥ 75,000/µL. This Therapy Delivery Map is on three (3) pages. See Section 4.12 .for full treatment details. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Mercaptopurine (MP) 
PO 
50 mg/m2/dose* 
Days 1-133 
See Section 4.12 & Appendix III for administration 
guidelines. *For TMPT and NUDT15  based dosing 
see Section 5.9 
a. 
Hx/PE/Wt., Ht. 
b. 
CBC/Diff/Platelets 
c. 
CSF cell count, cytospin 1 
d. 
Bilirubin, ALT, & Creatinine 
e. 
Serum creatinine & plasma 
MTX levels 2 
 
1 Obtain with each IT administration 
2 See Section 7.1b for details of 
monitoring. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
1.5 mg/m2/dose 
Days 15, 22, 78, and 85 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
Dexamethasone (DEX) 
PO (may give IV) 
3 mg/m2/dose BID 
Days 15-21 and 78-84 
 
Total daily dose: 
6 mg/m2/day, divided BID 
See Section 4.12 for admin guidelines 
Methotrexate (MTX) 
IV over 24 hours 
1000 mg/m2 
Days 8, 29, 50, 71, 92, and 113  
See Section 4.12 for administration guidelines 
Leucovorin (LCV) 
PO# 
10 mg/m2/dose q6 hrs 
Days 9-10, 30-31, 51-52, 72-73, 93-
94, and 114-115 
See Section 4.12 for administration guidelines 
42, 48 hrs after the START of each IV MTX and q6 
hours until the MTX level falls below 0.2μM. 
#Continue until MTX level is < 0.2µM. 
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 
Days 8, 29, 50, 71, 92, and 113 
See Section 4.12 for administration guidelines. 
Deliver IT therapy within 6 hrs of the beginning of 
the IV methotrexate infusion. (Hour -6 to +6, with 
hour 0 being the start of the MTX bolus) 
Note age-based dosing 
 
 
 
Ht____________cm 
        Wt___________kg 
         BSA__________m2 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
VCR 
____mg 
DEX (BID Dosing) 
____mg ____mg 
IV MTX 
____mg 
IT MTX 
_____mg 
LCV 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
43 
____mg 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
50 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
51 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
52 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
71 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
72 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
73 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
78 
____mg 
____mg ____mg 
 
 
 
a% 
 
 
 
79 
 
____mg ____mg 
 
 
 
 
 
 
 
80 
 
____mg ____mg 
 
 
 
 
 
 
 
81 
 
____mg ____mg 
 
 
 
 
 
 
 
82 
 
____mg ____mg 
 
 
 
 
 
 
 
83 
 
____mg ____mg 
 
 
 
 
 
 
 
84 
 
____mg ____mg 
 
 
 
 
 
 
 
85 
____mg 
 
 
 
 
a% 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
This Therapy Delivery Map continues on the next page. 
% Note: Height (Ht) is only required at the beginning of this course.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 2 of 3 

 
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89 
 
4.12.1c Consolidation (19 weeks) – LR B-ALL Patients Randomized to Arm LR-M (Continued) 
Leucovorin rescue will be given after each IV MTX 
 
__________________                                _____________ 
Patient name or initials                                          DOB 
Consolidation therapy lasts 19 weeks. Start Consolidation on Day 36 of Induction (1 week after the end of Induction) regardless of counts but oral 6-MP should not be started until 
ANC > 500/µL and platelets > 75,000/µL. This Therapy Delivery Map is on three (3) pages. See Section 4.12 for full treatment details. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Mercaptopurine (MP) 
PO 
50 mg/m2/dose* 
Days 1-133 
See Section 4.12 & Appendix III for 
administration guidelines. *For TMPT and 
NUDT15  based dosing see Section 5.9 
a. Hx/PE/Wt., Ht. 
b. CBC/Diff/Platelets 
c. CSF cell count, cytospin 1 
d. Bilirubin, ALT, & Creatinine 
e. Serum creatinine & plasma 
MTX levels 2 
 
1 Obtain with each IT 
administration 
2 See Section 7.1b for details of 
monitoring. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
1.5 mg/m2/dose 
Days 15, 22, 78, and 85 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
Dexamethasone (DEX) 
PO (may give IV) 
3 mg/m2/dose BID 
Days 15-21 and 78-84 
 
Total daily dose: 
6 mg/m2/day, divided BID 
See Section 4.12 for admin guidelines 
Methotrexate (MTX) 
IV over 24 hours 
1000 mg/m2 
Days 8, 29, 50, 71, 92, and 113  
See Section 4.12 for administration guidelines 
Leucovorin (LCV) 
PO# 
10 mg/m2/dose q6 hrs 
Days 9-10, 30-31, 51-52, 72-73, 93-
94, and 114-115 
See Section 4.12 for administration guidelines 
42, 48 hrs after the START of each IV MTX 
and q6 hours until the MTX level falls below 
0.2μM. 
#Continue until MTX level is < 0.2µM. 
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 
Days 8, 29, 50, 71, 92, and 113 
See Section 4.12 for administration guidelines. 
Deliver IT therapy within 6 hrs of the 
beginning of the IV methotrexate infusion. 
(Hour -6 to +6, with hour 0 being the start of 
the MTX bolus) 
Note age-based dosing 
 
 
 
 
 
Ht____________cm 
        Wt___________kg 
         BSA__________m2 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
VCR 
____mg 
DEX (BID Dosing) 
____mg ____mg 
IV MTX 
____mg 
IT MTX 
_____mg 
LCV 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
92 
____mg 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
93 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
94 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
99 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
106 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
113 
 
 
_____mg 
_____mg 
 
a%, b, c, d 
 
 
 
114 
 
 
 
 
_____mg 
_____mg 
e 
 
 
 
115 
 
 
 
 
e 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
120 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
127 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
133 
 
 
 
 
 
 
 
 
 
134 
Start next course (Maintenance Arm LR-M – Cycle 1, Section 4.13) on Day 134 or when blood count parameters are met (whichever occurs later) 
% Note: Height (Ht) is only required at the beginning of this course.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 3 of 3 

 
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90 
 
4.13 
Maintenance Arm LR-M – Cycle 1 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Criteria to begin Maintenance 
Begin Maintenance therapy on Day 134 of Consolidation or when peripheral counts recover to ANC 
≥ 750/µL and platelets ≥ 75 000/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. Only oral Mercaptopurine and Methotrexate will be interrupted for myelosuppression as 
outlined in Section 5.9. IT MTX, VCR and DEX will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, and 106. Omit Day 1 and Day 85 dose as it coincides 
with IT MTX 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
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91 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* (Note Higher 6-MP Dose than in Consolidation) 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Days 1 and 85 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 1 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 1, the next course (Maintenance Arm LR-M Cycle 
2, Section 4.14) starts on Day 113.  
 

 
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92 
 
4.13.1 Maintenance Arm LR-M (Cycle 1) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________    
 
 ___________________ 
Patient name or initials     
 
 
DOB 
Maintenance Cycle 1 lasts 16 weeks. Therapy begins on Day 134 of Consolidation or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/µL, (whichever occurs later) for Cycle 1. For subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.13 and 5.9 
for details. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht. 
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine,  
 
! Obtain with each IT 
administration 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.13 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.13 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 8, 15, 22, 29, 36, 43, 50, 
57, 64, 71, 78, 92, 99, and 106 
Omit Day 1 and 85 dose as it coincides with IT 
MTX 
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 
Day 1 and 85 
 
See Section 4.13 for administration guidelines 
 
Note age-based dosing 
 
Ht__________cm 
Wt_______ kg 
 
 
BSA_________m2 
 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
_______mg 
 
a%, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
_______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 2 (Section 4.14). Repeat cycles based on dose modifications for low counts or low platelets until 
2½ yrs from diagnosis for both boys and girls. 
% Note: Height (Ht) is only required at the beginning of this course/cycle.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
93 
4.14 
Maintenance Arm LR-M – Cycle 2 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, and 106. Omit Day 57 dose as it coincides with 
IT MTX 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
94 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Day 57 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 2 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 2, the next course (Maintenance Arm LR-M Cycle 
3, Section 4.15) starts on Day 113.  
  
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
95 
4.14.1 Maintenance Arm LR-M (Cycle 2) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________    
 
 ___________________ 
Patient name or initials       
 
 
 DOB 
 
Maintenance Cycle 2 lasts 16 weeks. Therapy begins on Day 113 of Maintenance Cycle 1. This Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht. 
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine,  
 
! Obtain with each IT 
administration 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.14 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.14 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 1, 8, 15, 22, 29, 36, 43, 50, 
64, 71, 78, 85, 92, 99, and 106 
Omit Day 57 dose as it coincides with IT MTX 
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 
Day 57 
 
See Section 4.14 for administration guidelines 
 
Note age-based dosing 
 
 _______Ht__________cm 
Wt_______ kg 
 
BSA_________m2 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
 
______mg 
a%, b, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
_______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
 
_______mg a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 3 (Section 4.15). Repeat cycles based on dose modifications for low counts or low platelets until 
2½ yrs from diagnosis for both boys and girls. 
% Note: Height (Ht) is only required at the beginning of this course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
96 
4.15 
Maintenance Arm LR-M – Cycle 3 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106. Omit Day 29 dose as it coincides with 
IT MTX 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
97 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Day 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 3 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 3, the next course (Maintenance Arm LR-M Cycle 
4, Section 4.16) starts on Day 113. 
  
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
98 
4.15.1 Maintenance Arm LR-M (Cycle 3) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________     
 
 ___________________ 
Patient name or initials     
 
 
 DOB 
Maintenance Cycle 3 lasts 16 weeks. Therapy begins on Day 113 of Maintenance Cycle 2. This Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine 
 
! Obtain with each IT 
administration 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.15 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.15 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 1, 8, 15, 22, 36, 43, 50, 57, 
64, 71, 78, 85, 92, 99, and 106 
Omit Day 29 dose as it coincides with IT MTX 
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 
Day 29 
 
See Section 4.15 for administration guidelines 
 
Note age-based dosing 
 
 
 _______Ht__________cm 
Wt_______ kg 
 
BSA_________m2 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
 
______mg 
a%, b, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
_______mg a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 4 (Section 4.16). Repeat cycles based on dose modifications for low counts or low platelets until 
2½ yrs from diagnosis for both boys and girls. 
% Note: Height (Ht) is only required at the beginning of this course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
99 
4.16 
Maintenance Arm LR-M – Cycle 4 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, and 106. Omit Day 1 and 85 dose as it coincides 
with IT MTX 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
100 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Day 1 and 85 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 4 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 4, the next course (Maintenance Arm LR-M Cycle 
5, Section 4.17) starts on Day 113.  
  
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
101 
4.16.1 Maintenance Arm LR-M (Cycle 4) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________    
 
  ___________________ 
Patient name or initials   
 
 
  DOB 
 
Maintenance Cycle 4 lasts 16 weeks. Therapy begins on Day 113 of Maintenance Cycle 3. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine 
 
! Obtain with each IT 
administration 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.16 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.16 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 8, 15, 22, 29, 36, 43, 50, 
57, 64, 71, 78, 92, 99, and 106 
Omit Day 1 and 85 dose as it coincides with IT 
MTX 
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 
Day 1 and 85 
 
See Section 4.16 for administration guidelines 
 
Note age-based dosing 
 
 
 _______Ht__________cm 
  Wt_______ kg 
 
BSA_________m2 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
______mg 
 
a%, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
_______mg a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 5 (Section 4.17). Repeat cycles based on dose modifications for low counts or low platelets until 
2½ yrs from diagnosis for both boys and girls. 
% Note: Height (Ht) is only required at the beginning of this course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
102 
4.17 
Maintenance Arm LR-M – Cycle 5 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, and 106. Omit Day 57 dose as it coincides with 
IT MTX 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
103 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Day 57 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 5 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 5, the next course (Maintenance Arm LR-M Cycle 
6, Section 4.18) starts on Day 113. 
  
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
104 
4.17.1 Maintenance Arm LR-M (Cycle 5) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________     
___________________ 
Patient name or initials      
 
   DOB 
Maintenance Cycle 5 lasts 16 weeks. Therapy begins on Day 113 of Maintenance Cycle 4. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht. 
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine 
 
! Obtain with each IT 
administration 
 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.17 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.17 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 1, 8, 15, 22, 29, 36, 43, 50, 
64, 71, 78, 85, 92, 99, and 106 
Omit Day 57 dose as it coincides with IT MTX 
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 
Day 57 
 
See Section 4.17 for administration guidelines 
 
Note age-based dosing 
 
 
 ______Ht__________cm 
  Wt_______ kg 
 
BSA_________m2 
 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
 
______mg 
a%, b, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
_______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 6 (Section 4.18). Repeat cycles based on dose modifications for low counts or low platelets until 
2½ yrs from diagnosis for both boys and girls. 
% Note: Height (Ht) is only required at the beginning of this course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
105 
4.18 
Maintenance Arm LR-M – Cycle 6 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes one 16 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106. Omit Day 29 dose as it coincides with 
IT MTX 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
106 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 112 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Methotrexate: Intrathecal (IT) 
Day 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 6 is on the following page. 
 
Following completion of Maintenance Arm LR-M Cycle 6, the next course (Maintenance Arm LR-M Cycle 
7, Section 4.19) starts on Day 113. 
  
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
107 
4.18.1 Maintenance Arm LR-M (Cycle 6) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________    
 
___________________ 
Patient name or initials     
 
 
 DOB 
 
Maintenance Cycle 6 lasts 16 weeks. Therapy begins on Day 113 of Maintenance Cycle 5. This Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin! 
d. 
Bilirubin, ALT, 
Creatinine 
 
! Obtain with each IT 
administration 
 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.18 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-112 
*See Section 5.9 for suggested starting dose based 
on TPMT and NUDT15 status 
See Section 4.18 & Appendix I for administration 
guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 1, 8, 15, 22, 36, 43, 50, 57, 
64, 71, 78, 85, 92, 99, and 106 
Omit Day 29 dose as it coincides with IT MTX 
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 
Day 29 
 
See Section 4.18 for administration guidelines 
 
Note age-based dosing 
 
 
 _______Ht__________cm Wt_______ kg 
 
BSA_________m2 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
 
______mg 
a%, b, d 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
______mg 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
______mg 
 
a%, b, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
_______mg a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
85 
 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
92 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
99 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
106 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
112 
 
 
 
 
 
 
 
 
113 
Begin Cycle 7 - last 10 weeks of Maintenance therapy (Section 4.19). 
% Note: Height (Ht) is only required at the beginning of this course/cycle. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
108 
 
4.19 
Maintenance Arm LR-M – Cycle 7 (LR B-ALL Patients Randomized to Arm LR-M) 
 
 
Please follow the dose modifications for low ANC or low platelets. Only oral Mercaptopurine and 
Methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. IT MTX, VCR and DEX 
will be delivered as scheduled despite myelosuppression. 
 
The administration schedule below describes the last 10 weeks of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1 and 8  
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. 
 
Dexamethasone: PO 
Days 1 - 7 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID) x 7 days  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 
Methotrexate: PO  
Days 1, 8, 15, 22, 29, 36, 43, 50, 57 and 64. 
Dose: 20 mg/m2/dose weekly 
 
AFTER ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET, ADDITIONAL PATIENTS 
CLASSIFIED AS AR AND LR B-ALL PATIENTS WILL NOT RECEIVE POST-INDUCTION 
TREATMENT ON AALL0932. FURTHER TREATMENT FOR THESE PATIENTS WILL BE UP 
TO THE DISCRETION OF THE TREATING PHYSICIAN. AR AND LR B-ALL PATIENTS 
RISK ASSIGNED BEFORE ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET WILL 
CONTINUE TO RECEIVE POST INDUCTION THERAPY ON THIS PROTOCOL. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
109 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 70 
Dose: 75 mg/m2 once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details.  
 
Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the 
date of diagnosis is reached for both boys and girls. Therapy may be stopped on that date if the 7 day 
dexamethasone is completed for the cycle (i.e. complete all 7 days of dexamethasone before ending 
therapy). Otherwise continue current cycle through dexamethasone administration. 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm LR-M Cycle 7 is on the following page. 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
110 
4.19.1  Maintenance Arm LR-M (Cycle 7) – LR B-ALL Patients 
 
Randomized to Arm LR-M 
 
_____________________      
 
  ___________________ 
Patient name or initials      
 
 
   DOB 
Maintenance Cycle 7 lasts 10 weeks. Therapy begins on Day 113 of maintenance Cycle 6. This Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose  
Days 1 and 8  
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht. 
b. 
CBC/diff/platelets 
c. 
Bilirubin, ALT, 
Creatinine  
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-7 (do not taper) 
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.19 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* 
Days 1-70 
*See Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.19 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week 
Days 1, 8, 15, 22, 29, 36, 43, 50, 
57 and 64 
 
 
 
 ______Ht__________cm 
Wt_______ kg 
 
 
BSA_________m2 
 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____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 
_______mg 
______mg 
a%, b, c 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
______mg 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
15 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
22 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
29 
 
 
______mg 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
36 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
43 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
50 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
57 
 
 
_______mg a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
64 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
70 
 
 
 
 
 
 
 
 
End of therapy^ 
% Note: Height (Ht) is only required at the beginning of this course/cycle.  
^ Maintenance consists of cycles every 16 weeks until a total duration of therapy of 2½ years from the date of diagnosis is reached 
for both boys and girls. Therapy may be stopped on that date if the 7 day dexamethasone is completed for the cycle (i.e. 
complete all 7 days of dexamethasone before ending therapy). Otherwise continue current cycle through dexamethasone 
administration. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0932 
Version Date: 10/26/2017 
  
111 
4.20 
Induction (35 Days) – DS SR B-ALL and DS B-LLy Patients  
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
Cytarabine: Intrathecal (IT) 
Given at the time of diagnostic lumbar puncture (LP) OR on Day 1.May be given up to 72 hours prior to 
the start of protocol therapy for patient convenience . 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
30 mg 
2 – 2.99 
50 mg 
≥ 3 
 
70 mg 
 
For IT administration use 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).  
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 8, 15 and 22 
Dose: 1.5 mg/m2/dose (maximum 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. 
 
Dexamethasone: PO (may be given IV) 
Days 1 - 28 (do not taper) 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (6 mg/m2/day, divided BID) may be used temporarily as 
needed. 

 
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Pegaspargase: IV over 1 - 2 hours. 
Day 4 
Dose: 2,500 International Units/m2/dose 
 
Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Special precautions: 
1. Pegaspargase may affect coagulation factors and predispose to bleeding and/or thrombosis. 
Caution should be used when administering any concurrent anticoagulant therapy. 
2. 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.  
 
Methotrexate: Intrathecal (IT) 
Days 8 and 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Leucovorin: PO  
Days 10 - 11 and 31 - 32 
Dose: 5 mg/m2/dose x 2 doses given 48 and 60 hours after the lumbar puncture. 
Leucovorin rescue will be given after intrathecal methotrexate for patients with Down syndrome during 
ALL applicable phases of therapy EXCEPT Maintenance. The first dose to be given 48 hours after the 
lumbar puncture and the second dose to be given approximately 60 hours after the lumbar puncture  
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 

 
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Disease Evaluations During Induction for DS SR B-ALL Patients: 
 
 
Day 29: Bone marrow sample will be obtained for morphology and a 2 mL aliquot will be shipped 
to a COG-Approved ALL Flow Cytometry Laboratory for MRD determination. 
 
Research Studies (for DS SR B-ALL patients that consented to studies of genomic variation on 
AALL08B1 or APEC14B1 (if available for classification of newly diagnosed ALL patients)) 
 
Day 29: 5 mL of peripheral blood will be obtained and shipped to the COG ALL Molecular 
Reference Laboratory for studies of genomic variation and cell banking. This specimen is very 
important and should be obtained on all patients that have provided consent. 
 
NOTE: FOR DS SR B-ALL PATIENTS, IF DAY 29 BM MRD SAMPLE IS NOT OBTAINED AND 
SHIPPED TO A COG-APPROVED ALL FLOW CYTOMETRY LABORATORY, THEN THE 
PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG ALL TRIAL FOLLOWING 
COMPLETION OF INDUCTION THERAPY 
 
Disease Evaluation for DS B-LLy Patients: 
 
Before starting therapy and on Day 29: patients will have a CT of the neck, chest, abdomen and 
pelvis, CXR, a PET scan, and a bone scan if indicated (Please refer to Section 7.1d for details). 
 
Note: A PET scan is highly recommended but not required at diagnosis, at the end of Induction and if there 
are residual masses at the end of Consolidation. 
 
Optional Research Studies for DS B-LLy Patients (see Section 14.0 for details): 
 
If patient consents, paraffin embedded tissue will be submitted at diagnosis for FISH analysis. 
 
If patient consents, fresh tissue will be submitted at diagnosis for banking. 
 
Day 29: 5 mL of peripheral blood will be obtained and shipped to the COG ALL Molecular 
Reference Laboratory for studies of genomic variation. This specimen is very important and 
should be obtained on all patients that have provided consent. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR 
SUPPORTIVE CARE GUIDELINES. 
 
The therapy delivery map (TDM) for Induction is on the next page.  
 
For DS SR B-ALL and DS B-LLy: Following completion of Induction, the next course (Consolidation, 
Section 4.20) begins on Day 36 or when blood count parameters are met (whichever occurs later), based 
upon the patient’s Day 29 MRD results. 
 
Note: Following completion of Induction, DS B-LLy patients without PD (see Section 11.3 for definition) 
will be eligible to continue Consolidation therapy. DS B-LLy patients with PD at end-Induction will be 
considered off protocol therapy. Consolidation (Section 4.21) starts on Day 36 or when blood count 
parameters are met (whichever occurs later).  
 
 

 
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4.20.1 
Induction—DS SR B-ALL and DS B-LLy Patients (35 days) 
Leucovorin rescue will be given after each IT MTX 
__________________                                   
    ______________ 
Patient name or initials                                
                DOB 
Induction therapy lasts 5 weeks (35 days). See Section 4.20 for full treatment details. This Therapy Delivery Map is on one (1) page 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal Cytarabine  
(IT ARAC) 
IT 
Age (yrs) Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
≥ 3 
70 mg 
Given at time of 
diagnostic LP OR 
Day 1 
See Section 4.20 for administration guidelines 
 
Note age-based dosing 
a. Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
BM eval1 
d. 
PB sample1 
e.  CSF cell count, cytospin2 
f. 
Bilirubin, Albumin  ALT, Creatinine 
g. 
Varicella titer 
h. 
IgG 
i. 
TPMT genotype and NUDT15# 
 
DS B-LLy patients only 
j 
CT (neck, chest, abdomen & pelvis), CXR, 
 PET, bone scan if indicated.3 
k 
Diagnostic biopsy/cytology3  
l 
Biology/banking (optional) 4 
m Pregnancy test5 
1See Section 7.1c for details 
2 Obtain with each IT administration 
3See Section 7.1d for details 
4See Sections 7.1d & 14.0 for details 
5Only for patients of reproductive age 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
1.5 mg/m2/dose 
Days 1, 8, 15 &22 
+ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg 
Dexamethasone (DEX) 
PO (may give IV) 
3 mg/m2/dose BID 
Days 1-28  
(do not taper) 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.20 for admin guidelines 
Pegaspargase (PEG-ASP) IV over 1-2 hours 
2500 International 
Units/m2/dose  
Day 4  
Note: pegaspargase should be administered on Day 4. 
Administer through the tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
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 
Days 8 & 29 
 
 
See Section 4.20 for administration guidelines 
 
Note age-based dosing 
Leucovorin (LCV) 
PO 
5 mg/m2/dose q12 hrs  Days 10-11 & 31-32 
48 & 60 hrs after each IT MTX. See Section 4.20 for 
administration guidelines 
 
 
 
 
Ht____________cm 
        Wt___________kg          BSA__________m2 
Date 
Due 
Date 
Given 
Day 
IT ARAC 
_____mg 
VCR 
____mg 
DEX (BID Dosing) 
____mg ____mg 
PEG-ASP 
_____IU 
IT MTX 
_____mg 
LCV 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
-2/-1/0/LP* 
_____mg 
 
 
 
 
 
(a%-c, e-g, h, [j-m]#) @ 
 
 
 
1 
____mg 
____mg ____mg 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
_____IU 
 
 
 
 
 
 
8 
 
____mg 
 
____mg 
 
a%, b, e 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
_____mg 
_____mg 
 
 
 
 
11 
 
 
 
 
 
 
 
 
15 
 
____mg 
 
 
 
a%, b, i 
 
 
 
22 
 
____mg 
 
 
 
a%, b 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
____mg 
 
a%, b, c**, d***, e 
 
 
 
30 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
_____mg 
_____mg 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
 
j# 
 
 
 
36 
Begin Consolidation (Section 4.21) on Day 36 or when blood count parameters are met (whichever occurs later). DS B-LLy patients with PD at end-Induction are off protocol therapy. 
* On Day 1 OR at the time of diagnostic LP if < 72 hrs from the start of protocol therapy  
% Note: Height (Ht) is only required at the beginning of this course. 
#For DS B-LLy patients ONLY. Note: PET scans are highly recommended not required, and CXR is not required if CT chest is done (See Section 7.1d for details). 
 
@ Baseline  
** Note: for DS SR B-ALL patients, if Day 29 BM MRD sample is not obtained and shipped to a COG-Approved ALL flow cytometry lab, then the patient will not be eligible to continue on a COG ALL trial following completion of 
Induction therapy. # TPMT highly recommended for all subjects; NUDT15 is highly recommended for subjects of Hispanic/Native American or East Asian ancestry, and optional for all other subjects (See Section 5.9) 
***Day 29 PB sample should be shipped to the COG ALL Molecular Reference Laboratory for all DS SR B-ALL patients that consented to studies of genomic variation on AALL08B1 (or APEC14B1 (if open for the classification 
of newly diagnosed ALL patients) and DS B-LLy patients that consent on AALL0932 (see Section 14.0 for specimen shipping and handling). This specimen is very important. 
DO CALL-BACK PRIOR TO BEGINNING CONSOLIDATION THERAPY FOR (1) ALL B-ALL PATIENTS WHO HAVE SIGNED CONSENT FOR POST-INDUCTION THERAPY (2) ALL DS B-LLY PATIENTS WHO DO 
NOT GO OFF PROTOCOL THERAPY AT END-INDUCTION.                              SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE
Page 1 of 1 

 
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4.21 
Consolidation (28 days) –DS SR B-ALL and DS B-LLy Patients 
 
FOR PATIENTS WITH DS SR B-ALL: CONSENT TO POST-INDUCTION THERAPY MUST 
TAKE PLACE BEFORE STARTING CONSOLIDATION THERAPY. DO CALL-BACK PRIOR 
TO BEGINNING CONSOLIDATION THERAPY FOR ALL PATIENTS WHO HAVE SIGNED 
CONSENT FOR POST-INDUCTION THERAPY. PATIENTS WHO ELECT NOT TO CONSENT 
TO THIS THERAPY ARE OFF PROTOCOL THERAPY. 
 
FOR 
PATIENTS 
WITH 
DS 
B-LLy: 
DO 
CALL-BACK 
PRIOR 
TO 
BEGINNING 
CONSOLIDATION THERAPY FOR ALL PATIENTS WHO DO NOT GO OFF PROTOCOL 
THERAPY AT THE END OF INDUCTION. 
    
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC 
≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later) after the post-Induction risk assignment has 
been completed. Patients with severe systemic illness, who will not tolerate initiation of Consolidation on 
Day 1 or without count recovery, should begin this phase of therapy when appropriate in the judgment of 
the treating physician. 
 
Therapy should be interrupted for patients with suspected or proven serious infection and resumed when 
the signs of infection have abated. Therapy should not be interrupted for simple fever, if there are no signs 
of serious infection. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 ONLY 
Dose: 1.5 mg/m2/dose (maximum 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 - 28 
Dose: 75 mg/m2/dose once daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 

 
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The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. Do not escalate dose 
based on blood counts during this cycle (see Section 5.8). 
 
Methotrexate: Intrathecal (IT) 
Days 1, 8, and 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Leucovorin: PO 
Days 3 - 4, 10 - 11, 17 - 18 
Dose: 5 mg/m2/dose x 2 doses given 48 and 60 hours after the lumbar puncture. 
 
Leucovorin rescue will be given after IT MTX for patients with Down syndrome during all applicable 
phases of therapy EXCEPT Maintenance. The first dose to be given 48 hours after the lumbar puncture 
and the second dose to be given approximately 60 hours after the lumbar puncture. Administer with or 
without food. Administer doses on schedule as determined by timing of methotrexate administration. If a 
dose is missed, administer dose immediately. Give the next scheduled dose according to the original dosing 
schedule. Do not deviate from the original schedule. Notify provider if a dose is delayed or missed. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Consolidation is on the next page.  
 
For DS SR B-ALL and DS B-LLy: Following completion of Consolidation, the next course (Interim 
Maintenance I, Section 4.22) starts on Day 29 or when blood count parameters are met (whichever occurs 
later). 
 
Note: Following completion of Consolidation, DS B-LLy patients who fail to achieve CR (see Section 
11.3 for definitions), are off protocol therapy with the exception of DS B-LLy patients with bone 
primaries who will be considered CR if there is resolution of all surrounding soft tissue component 
by the end of Consolidation. 
 
 

 
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4.21.1 Consolidation – DS SR B-ALL and DS B-LLy (28 
days) 
Leucovorin rescue will be given after each IT MTX 
 
______________________                            
_______________ 
    Patient name or initials                                         DOB 
Consolidation is 4 weeks (28 days). Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover 
with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). See Section 4.21 for detailed therapy guidelines. This Therapy 
Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose 
Day 1 ONLY 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. Hx/PE, Wt., Ht.  
b. CBC/diff/platelets 
c. CSF cell count, cytospin! 
d. Bilirubin & ALT 
e. IgG 
 
DS B-LLy patients only 
f  
CT (neck, chest, 
abdomen & pelvis), 
CXR, PET, bone scan (if 
bone involvement). 
 
! Obtain with each IT 
administration. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Mercaptopurine (MP) PO 
75 mg/m2/dose* 
Days 1-28 
See Section 4.21 & Appendix I 
for administration guidelines. 
*for suggested dose based on 
TPMT and NUDT15 status, see 
Section 5.9 
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 
Days 1, 8 & 15 
See Section 4.21 for 
administration guidelines 
 
Note age-based dosing 
Leucovorin (LCV) 
PO 
5 mg/m2/dose q12 hrs  
Days 3-4. 10-11 
& 17-18  
48 & 60 hrs after each IT MTX. 
See Section 4.21 for 
administration guidelines 
 
 
 
Ht___________cm 
Wt__________kg 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
______mg 
MP 
______mg 
IT MTX 
______mg 
LCV 
_____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, c, d, e 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
_____mg 
_____mg 
 
 
 
 
4 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
8 
 
______mg 
 
c 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
_____mg 
_____mg 
 
 
 
 
11 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
15 
 
______mg 
 
c 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
_____mg 
_____mg 
 
 
 
 
18 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
28 
 
 
 
f^ 
 
 
 
29 
Begin next course (Interim Maintenance I, Section 4.22) on Day 29 or when blood count parameters are met 
(whichever occurs later). Note: DS B-LLy patients without CR at end-Consolidation are off protocol therapy, except 
patients with bone primaries who are considered CR if there is resolution of all surrounding soft tissue component by 
the end of Consolidation. 
^ For DS B-LLy patients ONLY. Note: PET scans for residual masses are highly recommended, not required, and CXR is not required if 
CT chest is done (See Section 7.1d for details).  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
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4.22 
Interim Maintenance I (56 days) - DS SR B-ALL and DS B-LLy Patients 
 
Criteria to Start Interim Maintenance I 
Begin IM on Day 29 of Consolidation or when peripheral counts recover with an ANC ≥ 750/µL and 
platelets ≥ 75,000/µL, whichever occurs later. 
 
Interruption and/or Modification of Therapy 
All therapy should be interrupted for patients with presumed or proven severe infections and resumed when 
the signs of infection have abated. Obtain blood counts prior to each dose of methotrexate. 
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts in 
4 days. 
1. In 4 days, if ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as previous 
cycle. 
2. In 4 days, if ANC is still < 500/µL or platelets < 50,000/µL, give VCR (and IT MTX if Day 31) 
(omitting IV MTX) and repeat counts in 7 days to begin next dose of VCR and IV MTX if counts 
are adequate. 
a. If after 7 days, ANC ≥ 500/µL and platelets ≥ 50,000/µL, reduce dose of MTX by 20% (Do 
not make up missed dose of MTX). For subsequent doses, resume escalation as per A-C. 
b. If after 7 days ANC is still < 500/µL or platelets < 50,000/µL, hold therapy until counts 
recover to ANC > 500/µL and platelets > 50,000/µL. When ANC ≥ 500/µL and platelets 
≥ 50,000/µL, resume at 80% of last dose of MTX. For subsequent doses, resume escalation 
as per A - C. 
B) If ANC ≥ 500/µL but < 750/µL and/or platelets ≥ 50,000/µL but < 75,000/µL, give same dose of 
MTX as previously (i.e. no escalation). 
C) If ANC ≥ 750/µL and platelets ≥ 75,000/µL escalate MTX by 50 mg/m2/dose. 
D) Do not escalate MTX dose and resume at 80% of last dose if it had been delayed secondary to 
myelosuppression and/or Grade 3 mucositis. For subsequent doses, resume escalation as per A - C. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusion. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 11, 21, 31, and 41 
Dose: 1.5 mg/m2/dose (maximum 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: IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted). 
Days 1, 11, 21, 31 and 41 
Starting dose of 100 mg/m2/dose; thereafter, escalate by 50 mg/m2/dose  

 
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Methotrexate: Intrathecal (IT) 
Day 31 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Leucovorin: PO  
Days 33 - 34  
Dose: 5 mg/m2/dose x 2 doses given 48 and 60 hours after the lumbar puncture  
 
Leucovorin rescue will be given after IT MTX for patients with Down syndrome during ALL applicable 
phases of therapy EXCEPT Maintenance. The first dose to be given 48 hours after the lumbar puncture 
and the second dose to be given approximately 60 hours after the lumbar puncture 
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Interim Maintenance I is on the next page.  
 
For DS SR B-ALL and DS B-LLy: Following completion of Interim Maintenance I, the next course 
(Delayed Intensification, Section 4.23) starts on Day 57 or when blood count parameters are met (whichever 
occurs later). 
 

 
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4.22.1 Interim Maintenance I– DS SR B-ALL and DS B-LLy (56 
days) 
Leucovorin rescue will be given after each IT MTX 
 
__________________                                        
______________ 
Patient name or initials                                                      DOB 
Interim Maintenance I begins when ANC ≥ 750/µL and platelets ≥ 75,000/µL. This course lasts 8 weeks (56 days) and this Therapy Delivery 
Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
min+ 
1.5 mg/m2/dose 
Days 1, 11, 21, 31 & 
41 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. 
Hx, PE, Wt., Ht.  
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin!  
d. 
Bilirubin, ALT & 
Creatinine 
e. 
IgG 
 
B-LLy patients only 
f. 
CT (neck, chest, 
abdomen & pelvis), 
CXR, bone scan (if 
bone involvement). 
 
! Obtain with each IT 
administration 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Methotrexate (MTX) 
IV over 
2-5 min 
(undiluted) or 
10-15 min 
(diluted) 
Starting dose 100 mg/m2 & 
escalate by 50 mg/m2/dose 
Days 1, 11, 21, 31 & 
41 
Discontinue escalation & resume @ 80% 
of last dose if delay is necessary for 
myelosuppression and/or Grade 3 
mucositis 
See Section 4.22 for administration 
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 
Day 31 ONLY 
See Section 4.22 for administration 
guidelines 
 
Note age-based dosing 
Leucovorin (LCV) 
PO 
5 mg/m2/dose q12 hrs  
Days 33-34 
48 & 60 hrs after each IT MTX. See 
Section 4.22 for administration guidelines 
 
 
 
Ht___________cm 
Wt_______kg  
BSA__________m2 
 
Date Due 
Date Given 
Day 
VCR 
____mg 
IV MTX 
____mg 
(escalating dose) 
IT MTX 
____mg 
LCV 
____mg 
Studies 
Comments (Include 
any held doses, or 
dose modifications 
 
 
 
Enter calculated dose above and actual administered dose below. 
 
 
 
1 
____mg 
____mg 
 
 
a%, b, d, e 
 
 
 
--- 
 
 
 
 
 
 
 
 
11 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
21 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
31 
____mg 
____mg 
____mg 
 
a%, b, c, d,e  
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
____mg 
____mg 
 
 
 
 
34 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
41 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
56 
 
 
 
 
f^ 
 
 
 
57 
Begin next course (Delayed Intensification, Section 4.23) on Day 57 or when blood count 
parameters are met (whichever occurs later) 
% Note: Height (Ht) is only required at the beginning of this course  
^ For B-LLy patients ONLY. Note: CXR is not required if CT chest is done (See Section 7.1d for details).  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
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4.23 
Delayed Intensification (56 days) - DS SR B-ALL and DS B-LLy Patients 
 
Criteria to Start Delayed Intensification 
Delayed intensification begins on Day 57 of Interim Maintenance I, or when ANC  750/L and platelets 
 75,000/L, whichever occurs later. 
 
Interruption and/or Modifications of Therapy 
All therapy should be interrupted for presumed or proven serious infection. Myelosuppression alone does 
not delay therapy on Days 1 - 28 or Days 30 - 43, but Day 29 does not begin unless ANC  750/L and 
platelets  75,000/L. Therapy interruptions should be made-up. In case of delays of 3 weeks or longer, 
notify the Study Chair.  
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
Dexamethasone: PO (may give IV) 
All patients, regardless of age or response, receive discontinuous dexamethasone. 
Days 1 - 7 and 15 - 21 
Dose: 5 mg/m2/dose BID (i.e., total daily dose: 10 mg/m2/day, divided BID)  
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations 
are also acceptable. Intravenous preparation (10 mg/m2/day, divided BID) may be used temporarily as 
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.” 
 
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. 
 
DOXOrubicin: IV push/infusion over 1 - 15 minutes 
Days 1, 8 and 15. 
Dose: 25 mg/m2/dose 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 1 - 15 minutes. 
Short infusion times may be lengthened slightly (and up to 60 minutes) if institutional policies mandate. It 
is suggested that DOXOrubicin be administered through the tubing of rapidly infusing solution of D5W or 
0.9% NaCl and that it is infused into a large vein or central venous access device. 

 
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Pegaspargase: IV over 1 - 2 hours. 
Day 4 
Dose: 2,500 International Units/m2/dose 
Administer through the tubing of a freely 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.  
 
Cyclophosphamide: IV over 30 - 60 minutes 
Day 29 
Dose: 1,000 mg/m2/dose  
 
Hydrate according to institutional guidelines. Suggested hydration: Pre-hydrate using fluids containing at 
least 0.45% NaCl. Achieve urine specific gravity of ≤ 1.010 prior to start of cyclophosphamide. Continue 
hydrating at a rate of 125 mL/m2/hour IV/PO for at least 8 hours after cyclophosphamide administration. 
 
Mesna is not required for this dose of cyclophosphamide, but may be administered at institutional 
discretion. 
 
Thioguanine: PO 
Days 29 - 42. 
Dose: 60 mg/m2/dose/once daily* 
 
*See Section 5.11 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that thioguanine be taken at the same time each day. 
 
Tablets are scored and doses can be rounded to half tablet. Adjust dose using ½ tablets and different doses 
on alternating days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. See 
Appendix II for details. 
 
Cytarabine: IV over 1 - 30 minutes or subcutaneous  
Days 29 - 32 and 36 - 39 
Dose: 75 mg/m2/dose/day  
 
When given subcutaneously, reconstitute to a concentration not to exceed 100 mg/mL. Rotate injection 
sites to thigh, abdomen, and flank regions. Avoid repeated administration to a single site. Aspirate prior to 
injection to avoid injection into a blood vessel. 

 
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Methotrexate: Intrathecal (IT) 
Days 1 and 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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Leucovorin: PO  
Days 3 - 4 and 31 - 32  
Dose: 5 mg/m2/dose x 2 doses given 48 and 60 hours after the lumbar puncture  
 
Leucovorin rescue will be given after IT MTX for patients with Down syndrome during ALL applicable 
phases of therapy EXCEPT Maintenance. The first dose to be given 48 hours after the lumbar puncture 
and the second dose to be given approximately 60 hours after the lumbar puncture 
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery maps (TDMs) for Delayed Intensification are on the next two (2) pages. 
 
For DS SR B-ALL and DS B-LLy: Following completion of Delayed Intensification, the next course 
(Interim Maintenance II, Section 4.24) starts on Day 57 or when blood count parameters are met (whichever 
occurs later). 
 
 

 
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4.23.1a  Delayed Intensification — DS SR B-ALL and DS B-LLy (56 days) 
Leucovorin rescue will be given after each IT MTX 
________________                                      __________________ 
Patient name or initials                                                   DOB 
 
Delayed Intensification is 8 weeks (56 days). Begin DI on Day 57 of IM I or when ANC ≥ 750/µL and platelets ≥ 75,000/µL, whichever occurs later. See Section 4.23 for detailed therapy interruption 
guidelines. This therapy delivery map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, divided BID 
See Section 4.23 for administration guidelines 
a. Hx, PE, Wt., Ht.  
b. CBC/diff/platelets 
c. CSF cell count, cytospin 1 
d. Bilirubin, ALT, Creatinine 
e. IgG 
f. 
Echocardiogram2 
 
1 Obtain with each IT 
administration 
2 Prior to first dose of doxorubicin 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m2/dose 
Days 1, 8 & 15 
+ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg 
DOXOrubicin (DOXO) 
IV push/infusion over 1-15 min 25 mg/m2/dose 
Days 1, 8 & 15 
See Section 4.23 for guidelines 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International 
Units/m2/dose 
Day 4  
Administer through the tubing of a freely infusing solution 
of D5W or 0.9% NaCl 
Cyclophosphamide (CPM) 
IV over 30-60 min 
1000 mg/m2/dose 
Day 29 
See Section 4.23 for guidelines 
Thioguanine (TG) 
PO 
60 mg/m2/dose/day 
Days 29-42 
See Section 4.23 & Appendix II for guidelines 
*for suggested dose based on TPMT and NUDT15 status, 
see Section 5.11 
Cytarabine (ARAC) 
IV over 1-30 min or SubQ 
75 mg/m2/dose/day 
Days 29-32 & 36-39 
 
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 
Days 1 & 29 
See Section 4.23 for administration guidelines 
 
Note age-based dosing 
Leucovorin (LCV) 
PO 
5 mg/m2/dose q12 hrs  
3-4 & 31-32  
48 & 60 hrs after each IT MTX. See Section 4.23 for 
administration guidelines 
 
 
 
Ht__________cm                      Wt_________kg 
BSA_________m2 
Date 
Due 
Date 
Given 
Day 
DEX 
____mg ____mg 
VCR 
_____mg 
DOXO 
_____mg 
PEG-ASP 
_____IU 
CPM* 
_____mg 
TG* 
______mg 
ARAC* 
______mg 
IT MTX 
______mg 
LCV 
______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, e, f^ 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
______mg 
______mg 
 
 
 
 
4 
 
 
_____IU 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
_____mg 
_____mg 
 
 
 
 
 
 
a%, b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
____mg ____mg 
_____mg 
_____mg 
 
 
 
 
 
 
a%, b 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
This Therapy Delivery map continues on the next page. 
% Note: Height (Ht) is only required at the beginning of this course.  
* Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL to begin Day 29 therapy 
 
^ Prior to first dose of doxorubicin 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
Page 1 of 2 

 
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4.23.1b Delayed Intensification — DS SR B-ALL and DS B-LLy (56 days) -Continued 
Leucovorin rescue will be given after each IT MTX 
______________                             ______________ 
Patient name or initials                          DOB 
Delayed Intensification is 8 weeks (56 days). Begin DI on Day 57 of IM I or when ANC ≥ 750/µL and platelets ≥ 75,000/µL, whichever occurs later. See Section 4.23 for detailed 
therapy interruption guidelines. This therapy delivery map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO (may give IV) 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, divided BID 
See Section 4.23 for administration guidelines 
a. 
Hx, PE, Wt  
b. 
CBC/diff/platelets 
c. 
CSF cell count, cytospin 1 
d. 
Bilirubin, ALT, Creatinine 
e. 
IgG 
f. 
Echocardiogram2 
 
1 Obtain with each IT 
administration 
2 Prior to first dose of doxorubicin 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV push over 1 minute+ 
1.5 mg/m2/dose 
Days 1, 8 & 15 
+ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg 
DOXOrubicin (DOXO) 
IV push/infusion  
over 1-15 min 
25 mg/m2/dose 
Days 1, 8 & 15 
See Section 4.23 for guidelines 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
2500 International 
Units/m2/dose 
Day 4  
Administer through the tubing of a freely infusing solution of 
D5W or 0.9% NaCl 
Cyclophosphamide (CPM) IV over 30-60 min 
1000 mg/m2/dose 
Day 29 
See Section 4.23 for guidelines 
Thioguanine (TG) 
PO 
60 mg/m2/dose/day 
Days 29-42 
See Section 4.23 & Appendix II for guidelines 
*for suggested dose based on TPMT and NUDT15 status, 
see Section 5.11 
Cytarabine (ARAC) 
IV over 1-30 min or SubQ 75 mg/m2/dose/day 
Days 29-32 & 36-39  
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 
Days 1 & 29 
See Section 4.23 for administration guidelines 
 
Note age-based dosing 
Leucovorin (LCV) 
PO 
5 mg/m2/dose q12 hrs  3-4 & 31-32  
48 & 60 hrs after each IT MTX. See Section 4.23 for 
administration guidelines 
 
 
Ht__________cm 
 
Wt_________kg  
BSA_________m2 
Date 
Due 
Date 
Given 
Day 
DEX 
____mg ____mg 
VCR 
_____mg 
DOXO 
_____mg 
PEG-ASP 
_____IU 
CPM* 
_____mg 
TG* 
______mg 
ARAC* 
______mg 
IT MTX 
______mg 
LCV 
______mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
29* 
 
 
 
 
_____mg 
______mg ______mg 
______mg 
 
a%, b, c, d, e 
 
 
 
30 
 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
______mg 
______mg 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
36 
 
 
 
 
 
______mg 
 
 
b 
 
 
 
37 
 
 
 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
 
 
 
43 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
 
 
 
 
 
57 
Begin next course (Interim Maintenance II, with IV MTX Section 4.24) on Day 57 or when blood count parameters are met (whichever occurs later). 
% Note: Height (Ht) is only required at the beginning of this course.  
* Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL to begin Day 29 therapy 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 2 of 2 

 
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4.24 
Interim Maintenance II (56 days) - DS SR B-ALL and DS B-LLy Patients 
 
Criteria to Start Interim Maintenance II 
Begin IM II on Day 57 of DI, or when peripheral counts recover with an ANC ≥ 750/µL and platelets 
≥ 75,000/µL, whichever occurs later. 
 
Interruption and/or Modification of Therapy 
All therapy should be interrupted for patients with presumed or proven severe infections and resumed when 
the signs of infection have abated. Obtain blood counts prior to each dose of methotrexate. 
A) If ANC is <500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts in 4 days. 
1. In 4 days, if ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as previous 
cycle. 
2. In 4 days, if ANC is still < 500/µL or platelets < 50,000/µL, give VCR (and IT MTX if Day 31) 
(omitting IV MTX) and repeat counts in 7 days to begin next dose of VCR and IV MTX if counts 
are adequate.  
a. If after 7 days, ANC ≥ 500/µL and platelets ≥ 50,000/µL, reduce dose of MTX by 20% 
(Do not make up missed dose of MTX). For subsequent doses, resume escalation as per A-
C. 
b. If after 7 days ANC is still < 500/µL or platelets < 50,000/µL, hold therapy until counts 
recover to ANC > 500/µL and platelets > 50,000/µL. When ANC ≥ 500/µL and platelets 
≥ 50,000/µL, resume at 80% of last dose of MTX. For subsequent doses, resume escalation 
as per A - C. 
B) If ANC ≥ 500/µL but < 750/µL and/or platelets ≥ 50,000/µL but < 75,000/µL, give same dose of 
MTX as previously (i.e. no escalation). 
C) If ANC ≥ 750/µL and platelets ≥ 75,000/µL escalate MTX by 50 mg/m2/dose. 
D) Do not escalate MTX dose and resume at 80% of last dose if it had been delayed secondary to 
myelosuppression and/or Grade 3 mucositis. For subsequent doses, resume escalation as per A - C. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days 1, 11, 21, 31, and 41. 
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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Methotrexate: IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted). 
Days 1, 11, 21, 31 and 41 
Starting dose is two-thirds of the maximum tolerated dose attained in Interim Maintenance I. For example, 
if a patient has toxicity at 250 mg/m² on Interim Maintenance I, the starting dose for Interim Maintenance 
II will be two-thirds of 200 mg/m2 (or 130 mg/m2) IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes 
(diluted). Subsequent doses will be escalated by 50 mg/m² every 10 days (± 2 days) for 4 doses, to toxicity 
Days 11, 21, 31 and 41. 
 
Methotrexate: Intrathecal (IT) 
Days 1 and 31 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
Leucovorin: PO  
Days 3 - 4 and 33 - 34  
Dose: 5 mg/m2/dose x 2 doses given 48 and 60 hours after the lumbar puncture  
 
Leucovorin rescue will be given after IT MTX for patients with Down syndrome during ALL applicable 
phases of therapy EXCEPT Maintenance. The first dose to be given 48 hours after the lumbar puncture 
and the second dose to be given approximately 60 hours after the lumbar puncture 
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Interim Maintenance II is on the next page.  
 
For DS SR B-ALL and DS B-LLy: Following completion of Interim Maintenance II, the next course 
(Maintenance Arm DS, Section 4.25) starts on Day 57 or when blood count parameters are met (whichever 
occurs later). 
 

 
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4.24.1 Interim Maintenance II - DS SR B-ALL and DS B-LLy (56 
days) 
Leucovorin rescue will be given after each IT MTX 
 
________________                           
__________________ 
Patient name or initials                                   DOB 
Interim Maintenance II begins on Day 57 of DI or when ANC ≥ 750/µL and platelets ≥ 75,000/µL whichever occurs later. This course lasts 
8 weeks (56 days) and this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
min+ 
1.5 mg/m2/dose 
Days 1, 11, 21, 
31 & 41 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose: 2 mg 
a. Hx, PE, Wt., Ht.  
b. CBC/diff/platelets 
c. CSF cell count, cytospin1 
d. Bilirubin, ALT, 
Creatinine. 
e. IgG 
 
1 Obtain with each IT 
administration 
 
 
 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR 
GOOD PATIENT CARE 
Methotrexate 
(MTX) 
IV over 2-5 min 
(undiluted) or 10-
15 min (diluted) 
____mg/m2/dose* 
Days 1, 11, 21, 
31 & 41 
*Starting dose for IM II is two-thirds of 
the maximum tolerated dose attained in 
Interim Maintenance I (see Section 
4.23 for details). Thereafter, escalate 
by 50 mg/m2/dose 
See Section 4.23 for administration 
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 
Days 1 and 31  See Section 4.23 for administration 
guidelines 
 
Note age-based dosing 
Leucovorin 
(LCV) 
PO 
5 mg/m2/dose q12 hrs  
3-4 & 33-34 
48 & 60 hrs after each IT MTX. See 
Section 4.23 for administration 
guidelines 
 
 Ht___________cm 
Wt__________kg 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
____mg 
(escalating dose) 
IT MTX 
____mg 
LCV 
______mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual administered dose below. 
 
 
 
1 
____mg 
____mg 
____mg 
 
a%, b, c, d, e 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
____mg 
 
 
 
 
4 
 
 
 
____mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
11 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
21 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
31 
____mg 
____mg 
____mg 
 
a%, b, c, d, e 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
____mg 
 
 
 
 
34 
 
 
 
____mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
41 
____mg 
____mg 
 
 
a%, b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
57 
Begin next course (Maintenance Arm DS, Section 4.25) on Day 57 or when blood count parameters are 
met (whichever occurs later) 
% Note: Height (Ht) is only required at the beginning of this course.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
Page 1 of 1 

 
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4.25 
Maintenance Arm DS - DS SR B-ALL and DS B-LLy Patients 
 
DS SR-ALL and DS B-LLy patients will be non-randomly assigned to Maintenance treatment Arm DS: 
 
Vincristine/dexamethasone pulses at 12 week intervals,  
 
IT methotrexate every 12 weeks  
 
Oral methotrexate at 20 mg/m2/week.  
 
Criteria to begin Maintenance  
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets 
≥ 75,000/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. Intrathecal methotrexate, vincristine and dexamethasone will be delivered as scheduled, despite 
myelosuppression. 
 
Maintenance consists of cycles every 12 weeks until a total duration of therapy of 2 years is reached 
for both female and male patients from the start of Interim Maintenance I, which differs from the 
gender-based duration of therapy in children without DS. 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. 
 
The administration schedule below describes one 12 week cycle of Maintenance therapy. 
 
Dosing should be based on actual BSA. There is no maximum dosing, except for vincristine, which is 
capped at a maximum dose of 2 mg. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusions. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
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. 
 
Dexamethasone: PO 
Days 1 - 5(do not taper). 
Dose: 3 mg/m2/dose BID (i.e., total daily dose: 6 mg/m2/day, divided BID)  
 
Dose is adjusted upward to the nearest 0.25 mg as necessary for tablet size. Liquid preparations are also 
acceptable. Intravenous preparation (6 mg/m2/dose/day, divided BID) may be used temporarily as needed. 
 

 
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Methotrexate: PO  
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Omit Day 1 dose as it coincides with IT MTX. 
Dose: 20 mg/m2/dose weekly 
 
Administer the tablets on an empty stomach (at least 1 hour before or 2 hours after food or milk). Food or 
milk delays absorption and decreases the peak concentration. For ease of swallowing, methotrexate 
injection can be administered orally (see drug monograph). 
 
Mercaptopurine: PO 
Days 1 - 84 
Dose: 75 mg/m2/dose daily* 
 
*See Section 5.9 for suggested starting dose based on TPMT and NUDT15 status (if status is known) 
 
It is strongly recommended that mercaptopurine be taken at the same time each day. 
 
The liquid or tablet formulation may be used. Tablets are scored and doses can be rounded to half tablet. If 
using tablets, adjust dose using ½ tablets and different doses on alternating days in order to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.8 for 
dose modifications during Maintenance. 
 
Methotrexate: Intrathecal (IT) 
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 
 
For IT administration, use 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). 
 
Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the patient 
remaining lying down 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. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE 
SECTION 8.0 FOR SUPPORTIVE CARE 
 
The therapy delivery map (TDM) for Maintenance Arm DS is on the following page. 
 
 

 
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4.25.1 Maintenance Arm DS - DS SR B-ALL and DS B-LLy 
 
 
_____________________                                             ___________________ 
Patient name or initials                                                                               DOB 
Maintenance begins on Day 57 of IM II or when peripheral counts recover to ANC ≥ 750/µL and platelets ≥ 75,000/µL, (whichever occurs later) for 
Cycle 1. For subsequent cycles, follow dose modifications for low counts and platelets. See Sections 4.25 and 5.9 for details. This Therapy Delivery Map 
is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose  
Day 1 
 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose: 2 mg 
a. Hx, PE, Wt  
b. CBC/diff/platelets 
c. CSF cell count, cytospin! 
d. Bilirubin, ALT & Creatinine 
e. IgG 
 
DS B-LLy patients only 
f. CT (neck, chest, abdomen & 
pelvis), CXR, bone scan (if bone 
involvement)^ 
 
! Obtain with each IT 
administration 
^Please refer to Section 7.1d for 
details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Dexamethasone 
(DEX) 
PO 
3 mg/m2/dose BID  
Days 1-5 (do not taper)  
 
Total daily dose: 6 mg/m2/day, divided BID 
See Section 4.25 for administration guidelines 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose/day* Days 1-84 
*See Section 5.9 for suggested starting dose 
based on TPMT and NUDT15 status 
See Section 4.25 & Appendix I for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose/week Days 8, 15, 22, 29, 36, 
43, 50, 57, 64, 71 & 78 
Omit Day 1 dose as it coincides with IT MTX 
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 
Day 1 
 
See Section 4.25 for administration guidelines 
 
Note age-based dosing 
Enter Cycle # _______Ht__________cm 
  Wt_______ kg 
 
BSA_________m2 
\ 
Date Due Date 
Given 
Day 
VCR 
______mg 
DEX 
_____mg _____mg 
MP 
_______mg 
IT MTX 
_______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 
_______mg 
_______mg 
 
a%, b, c, d, e 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
8 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
 
 
 
______mg 
a%, b, e 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
 
 
 
______mg 
a%, b, e 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
 
______mg 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
f^ 
 
 
 
85 
Repeat next cycle based on dose modifications for low counts or low platelets until 2 yrs (both male and female) from start of IM I  
% Note: Height (Ht) is only required at the beginning of each course/cycle.  
^At completion of Maintenance therapy. Note: CXR is not required if CT chest is done (see Section 7.1d for details). 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 
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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 [E.coli, Pegaspargase (PEG-Asparaginase) or Erwinia] 
 
Allergy 
Local Allergic Reactions (inflammation at injection site, swelling): Continue pegaspargase administration 
in the presence of Grade 1 allergy as defined by CTCAE v4.0 (transient flushing or rash; drug fever < 38ºC).  
 
Systemic Allergic reactions: Discontinuation may be considered for Grade 2 or higher allergic reactions as 
defined by the CTCAE v4.0  
 
Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms has been 
discouraged in the past since anti-histamine use may mask the appearance of systemic allergy and fail to 
alert the provider of the presence of asparaginase neutralizing antibodies, which renders asparaginase 
therapy ineffective. Asparaginase activity assays are now commercially available so that in the face of 
premedication; if allergy is suspected, or; if a provider seeks to monitor asparaginase therapy, a sample can 
be sent to determine activity and evaluate the patient for the presence of neutralizing antibodies. In the event 
of severe systemic or recurrent local allergic reaction, or if activity level is not detectable in an appropriately 
drawn sample, Erwinia asparaginase (now FDA-approved for this indication) should be substituted. 
 
Anaphylaxis  
Discontinue pegaspargase if the patient develops Grade 3 anaphylaxis as defined by CTCAE v4.0 
(symptomatic bronchospasm, with or without urticaria, parenteral intervention indicated; allergy-related 
edema/angioedema; hypotension). If this occurs, Erwinia asparaginase (now FDA-approved for this 
indication) should be substituted. 
 
Erwinia asparaginase has a shorter half life and is associated with a shorter duration of asparagine depletion 
than native E. coli asparaginase, with “head-to-head” comparisons of Erwinia and E. coli asparaginase, 
using the same dose and schedule for both preparations, demonstrating a superior outcome, favoring E. coli 
asparaginase.50,51 Pegaspargase has a longer half-life and is associated with more prolonged asparagine 
depletion than native E. coli asparaginase, but the largest randomized trial comparing weekly native to bi-
weekly pegaspargase wasn’t powered to detect a difference in outcome.52 Current COG trials have adopted 
pegaspargase as the preparation of choice, based on the results of CCG 1962.53 COG AALL07P2 showed 
that Erwinia asparaginase was well tolerated and achieved nadir serum asparaginase activity at both 48 and 
72 hours after dosing that was similar to that achieved with pegaspargase. Based on these and other data, 
the FDA approved Erwinia asparaginase for use following allergy to pegaspargase, with a dose of Erwinia 
25,000 IU/m2 x 6 doses IM on a Monday/Wednesday/Friday schedule substituted for a single dose of 
pegaspargase. 
 
The dose modification guidelines for ALL trials recommend the substitution for replacement of Erwinia 
asparaginase for either native or pegaspargase utilizing the following schedule: 
 
Phase(s) of Treatment 
Replacement Schedule for Erwinia asparaginase# 
Any Phase 
25,000 IU/m2/dose IM or IV 
M/W/F x 6 doses for each dose of pegaspargase 
#If a patient develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future asparaginase therapy. Consider 
discontinuation for severe Grade 2 or higher allergic reactions  
 

 
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To replace a dose of intravenous pegaspargase that was discontinued during the infusion due to an allergic 
reaction, the following recommendations may be used to guide patient care.  
 
In the event that a pegaspargase infusion is discontinued for an allergic reaction, regardless of amount 
received, substitution with Erwinia asparaginase should begin approximately 48 hours after pegaspargase 
has been discontinued and preferably to coincide with the recommended Monday/Wednesday/Friday 
administration schedule detailed above in patients who are clinically stable. Up to 6 doses of Erwinia 
asparaginase may be administered, as tolerated, to replace the incomplete intravenous pegaspargase dose. 
Of note, Erwinia asparaginase is recommended only for pegaspargase hypersensitivity reactions, and not 
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 bilirubin, since 
asparaginase has been associated with hepatic toxicity. There are no specific guidelines available. 
 
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 (Grade 3-4): Discontinue asparaginase in the presence of hemorrhagic pancreatitis or severe 
pancreatitis (abdominal pain > 72 hours and ≥ Grade 3 amylase elevation (≥ 2.0x ULN). In the case of mild 
pancreatitis, asparaginase should be held until symptoms and signs subside, and amylase levels return to 
normal and then resumed. Severe pancreatitis is a contraindication to additional asparaginase 
administration. 
 
Thrombosis: Withhold asparaginase until resolved, and treat with appropriate antithrombotic therapy, as 
indicated. Upon resolution of symptoms consider resuming asparaginase, while continuing LMWH or 
antithrombotic therapy. Do not withhold dose for abnormal laboratory findings without clinical correlate. For 
significant thrombosis, not line related, consider evaluation for inherited predisposition to thrombosis. 
 
CNS Events (bleed, thrombosis or infarction): Hold asparaginase. Treat with fresh frozen plasma (FFP), factors 
or anticoagulation as appropriate. Resume at full dose when all symptoms have resolved (and evidence of 
recanalization in case of thrombosis by CT/MRI). Consider evaluation for inherited predisposition to 
thrombosis.  
 
Centers may elect to discontinue pegaspargase and switch to Erwinia asparaginase based upon laboratory 
evidence of silent inactivation of asparaginase activity in the absence of clinical symptoms of 
hypersensitivity at their discretion. 
 
5.2 
Cyclophosphamide 
 
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of previous significant 
hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010 and hydrate at 125 mL/m2/hr 
for 24 hours after dose. Monitor for adequate urine output as per institution guidelines. Give IV mesna at a 

 
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total dose that is 60% of the cyclophosphamide dose divided to 3 doses (e.g., if the cyclophosphamide dose 
is 1,000 mg/m2, the total mesna dose is 600 mg/m2 or 200 mg/m2/dose). Give the first mesna dose 15 
minutes before or at the same time as the cyclophosphamide dose and repeat 4 and 8 hours 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 8 hours after the end of 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. 
 
 
5.3 
Cytarabine (ARAC) IV 
 
ARAC Syndrome: Do not withhold ARAC for fever if it is likely to have been caused by the ARAC. 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. Once Delayed Intensification (DI) has 
started do not interrupt for uncomplicated myelosuppression; do hold for ANC < 500/µL and severe 
infection. Do make up missed doses. 
 
5.4 
Intrathecal Cytarabine 
Do not withhold dose given on Day 1 of Induction in front-line protocols 
 
5.5 
Doxorubicin (Anthracyclines) 
 
Cardiac Toxicity: Discontinue for clinical or echocardiographic evidence of cardiomyopathy (SF < 27% or 
EF < 50%) or Grade 3 - 4 left ventricular systolic dysfunction (LVSD) per CTCAE version 4.0. 
 
Doxorubicin is contraindicated in congestive heart failure and cardiac dysfunction (SF < 27%). 
Resuming Doxorubicin therapy depends on the cause of the cardiac dysfunction and the results of further 
cardiac evaluation. Notify Study Chair if patient cannot have further anthracycline therapy. 
 
Severe infection or severe mucositis (Grade 3 - 4)  
Therapy should be interrupted for patients who are febrile, neutropenic and have proven or suspected 
serious infection and resumed when the signs of infection have resolved  
 
Myelosuppression: Do not hold for myelosuppression on Days 8 and 15.  
 
Hyperbilirubinemia:54 
 
Direct Bilirubin  
% Dose Reduction 
< 1.2 mg/dl 
 
Full dose 
1.2 – 3.0 mg/dl  
50% 
3.1 – 5.0 mg/dl  
75% 
> 5.0 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 

 
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https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf  for COG 
guidelines. 
 
5.6 
Intrathecal Methotrexate 
 
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 12 
hours x 2 doses, beginning 48 hours after the IT therapy has been delivered. This may reduce the risk of 
worsening already existent myelosuppression (ANC < 500/µL) or mucositis. Do not administer leucovorin 
solely to prevent myelosuppression. For patients with Down syndrome, leucovorin should be administered 
after every dose of IT MTX during ALL phases of therapy EXCEPT Maintenance. 
 
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.55-57 These toxicities are poorly understood and 
currently it is impossible to predict who will suffer these complications. In addition, there are no data clearly 
linking the occurrence of an acute neurotoxic event with an increased risk of long-term neurocognitive 
dysfunction, nor do changes present on MRI at the time of an acute event clearly correlate with or predict 
outcome.57-62 It is clear however, that CNS prophylaxis is a mandatory component of curative therapy for 
children with ALL. Effective prophylaxis generally takes 2 forms; cranial, or less commonly, craniospinal 
radiation, with a limited number of doses of IT therapy or prolonged IT therapy with either IT MTX or 
triple IT therapy (MTX, ARAC and hydrocortisone). Certain protocols, for example BFM 2000,63 include 
fewer doses of IT MTX, with an acceptably low frequency of CNS relapse, but the backbone of the BFM 
therapies is not the same as those currently used by the Children’s Oncology Group. The exclusive use of 
IT ARAC has not been studied or described in the context of ALL therapy nor can one demonstrate the 
safety of omitting multiple doses of IT therapy without concomitant use of cranial irradiation or high dose 
methotrexate. 
 
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. Thus the treating physician must evaluate 
the patient and, with the family, make the best possible decision with respect to the relative risk and benefit 
of continued therapy. 
 
Following an acute neurotoxic event, a history and physical exam should guide the differential diagnosis. 
A neurology consult may be of value and should be considered. Seizures and other transient events may be 
linked to fever, infection, encephalitis, meningitis, hypertension, electrolyte disturbance, hypoglycemia, 
trauma, intracranial hemorrhage or thrombosis, narcotic withdrawal, illicit drug use, or other causes in 
addition to the direct side effects of chemotherapy. Appropriate laboratory studies may include, but are not 
limited to, blood cultures, a CBC, electrolytes, including glucose, calcium, magnesium and phosphorus, 
renal and liver function studies and/or an examination of the CSF. Imaging studies may include a CT scan 
and/or an MRI. The CT is commonly normal, in the absence of stroke, but if calcifications are present, this 
finding may be indicative of a more severe mineralizing leukoencephalopathy.64  MRI abnormalities may 
be pronounced, but transient. Posterior reversible encephalopathy may be present on MR with extensive 
diffusion abnormalities, but these do not appear to correlate with subsequent demyelination or gliosis.65-67 
Additional studies, including MR angiography and/or venogram should be considered, if clinically 
indicated (e.g. focal deficits). 
 
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.68 For patients who 
return to their “pre-event” status, without residual deficits on physical or neurologic exam, there are few 
data to support or guide therapeutic interventions. It is reasonable to hold the next dose of IT therapy, or, 

 
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substitute IT ARAC for 1 dose of IT MTX, or triple IT therapy. It is also reasonable to include leucovorin 
rescue at a dose of 5 mg/m2 q 12 hrs x 2 doses beginning 48 hours after the LP. This pattern of rescue was 
associated with a clear diminution in the incidence of acute neurotoxicity in 1 case series.68 There have been 
questions about potential interference of leucovorin with the efficacy of the IT MTX, but there is little data 
to support or refute this position. Moreover, the administration 48 hours later would minimize any potential 
interference. If the event does not recur, resumption of standard therapy should be considered, following 1 
modified or omitted IT dose. In the face of multiply recurrent events, or evidence of progressive 
encephalopathy, another evaluation is warranted and the treating physician may consider a more prolonged 
or definitive change in therapy. These decisions are extremely difficult and may hinge on an individual’s 
view of the importance of quality of life versus an increase in the risk of relapse. Since the greatest impact 
of CNS prophylaxis occurs early in therapy, the timing of these events may also influence clinical decisions. 
Cranial radiation has been suggested as an alternative to continued IT therapy though much of the literature 
on long-term neurocognitive dysfunction supports a more deleterious effect from CRT than IT therapy.69-72 
Dramatic deviations from protocol recommended therapy might result in the child being taken off protocol 
therapy. 
 
The use of dextromethorphan (DM) has been suggested as a neuroprotectant, capable of preventing NMDA 
mediated neurotoxicity without prohibitive toxicity. Low dose therapy has been recommended, in part, 
based on data suggesting that DM is concentrated in brain relative to serum. However, the literature on the 
use of DM supports a tight dose response relationship, with the likelihood of sparing an initially unaffected 
area, following ischemic damage, linked to dose, in both clinical trials and animal models of CNS 
ischemia.73-76 At doses thought to be therapeutic, side effects have included nystagmus, nausea and 
vomiting, distorted vision, ataxia, and dizziness. In addition, Hollander et al77 have raised concerns about 
the potential deleterious effects of long-term NMDA receptor blockade on memory because hippocampal 
long-term potentiation is dependent on the activation of the NMDA receptor. Thus in the absence of a 
clinical trial there are few data to support the addition of DM. 
 
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. 
 
 
 

 
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5.7 
IV Methotrexate  
 
5.7.1 
IV Methotrexate in Interim Maintenance (AR B-ALL, LR B-ALL randomized to Arm LR-C, DS 
SR B-ALL, B-LLy and DS B-LLy)  
 
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 dose 
10 – 20 X ULN for 2 consecutive doses Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at the dose that 
was previously administered at point of interruption. 
Do not skip doses. 
> 20 X ULN 
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 for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serology. 
Consider liver biopsy before additional therapy given.   
* Please see COG Supportive Care Guidelines at:  
https://members.childrensoncologygroup.org/index.php/cog-supportive-care-guidelines  for TMP/SMX 
substitutions. 
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
Nephrotoxicity: Postpone course if serum creatinine is > 1.5 x baseline or GFR creatinine clearance is 
< 65 mL/1.73m²/minute. 
 
Mucositis: For Grade 3 - 4 mucositis, withhold IV MTX until resolved. Decrease subsequent IV MTX dose by 
20% of the dose that was previously administered. If subsequent cycle is not associated with Grade 3 - 4 
mucositis, attempt to increase to full dose MTX for next cycle. Consider culturing lesions for herpes simplex 
if mucositis persists or recurs. 
 
Myelosuppression: 
 
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts in 
4 days. 
1. In 4 days, if ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as 
previous cycle. 
 
2. In 4 days, if ANC is still < 500/µL or platelets < 50,000/µL, give VCR (and IT MTX if Day 31) 
(omitting IV MTX) and repeat counts in 7 days to begin next dose of VCR and MTX if counts are 
adequate.  
a. If after 7 days, ANC ≥ 500/µL and platelets ≥ 50,000/µL, reduce dose of MTX by 20% (Do not 
make up missed dose of MTX). For subsequent doses, resume escalation as per A - C. 
b. If after 7 days ANC is still < 500/µL or platelets < 50,000/µL, hold therapy until counts recover 
to ANC > 500/µL and platelets > 50,000/µL. When ANC ≥ 500/µL and platelets ≥ 50,000/µL, 
resume at 80% of last dose of MTX. For subsequent doses, resume escalation as per A - C. 

 
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B) If ANC ≥ 500/µL but < 750/µL and/or platelets ≥ 50,000/µL but < 75,000/µL, give same dose of 
MTX as previously (i.e., no escalation). 
C) If ANC > 750/µL and platelets > 75,000/µL escalate MTX by 50 mg/m2. 
 
5.7.2 
IV Intermediate Dose (ID – 1,000 mg/m2) Methotrexate and Leucovorin Rescue in Consolidation 
for B-ALL patients randomized to Arm LR-M.  
 
Day 1 of Consolidation begins 1 week after the end of Induction regardless of counts. 
 
However, oral 6-MP should not be started until ANC ≥ 500/µL and platelets ≥ 75,000/µL. 
 
If the start of oral 6-MP is delayed, DO NOT “make up” missed doses. It is recommended to repeat a CBC 
every 2 to 3 days and start oral 6-MP when counts meet criteria; deliver initial IV MTX 2 weeks after end 
of Induction (if count parameters) met regardless of the length of 6-MP administration. 
 
Each MTX infusion is to begin when ANC ≥ 500/μL and platelets ≥ 75,000/μL; ALT < 20 x upper 
limit of normal and bilirubin and creatinine normal for age. 
 
After an IV dose of MTX is given continue with oral 6-MP for the next 3 weeks even in the face of 
uncomplicated myelosuppression. 
 
When a course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, delay IV MTX 
administration and HOLD 6-MP until ANC ≥ 500/μL and platelets ≥ 75,000/μL, then restart at 100% 
dosing. 
 
When a subsequent course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, delay IV 
MTX administration and HOLD 6-MP until recovery and then restart at 75% dose. 
 
Also consider TMP/SMX as possible cause of neutropenia. Consider discontinuing TMP/SMX in favor of 
an alternative approach to pneumocystis prophylaxis, as per COG Supportive Care Guidelines (see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
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 hour 0 being the start of the MTX infusion). 
 
Hold TMP-SMX on the days 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 0.4 μM. In the presence of delayed clearance continue to hold 
TMP-SMX until MTX level is less than 0.1 µM. 
 
Hold 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 0.4 μM. In the presence of delayed clearance continue to 
hold these medications until MTX level is less than 0.1 µM. 
 
Pre-hydrate with D5 ¼ NS with 30 mEq/L sodium bicarbonate at 100 mL/m2/hour until urine specific gravity 
is ≤ 1.010 and urine pH is ≥ 6.5 and ≤ 8.0. 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 and pH at above parameters.   
 
Continue hydration and alkalinization until plasma MTX level is < 0.2μM. In patients with delayed MTX 
clearance, continue hydration until the plasma MTX concentration is below 0.1 µM (see below for details). 
A bicarbonate bolus (25 mEq/m2 over 15 minutes) may be given to raise the urine pH relatively quickly; a 
normal saline bolus may also be helpful in facilitating hydration. 
 

 
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Hours 24, (36), (42) and 48: Draw MTX level and serum creatinine; NOTE: the 36 & 42 hour levels are 
only drawn if needed (see below) 
 
If serum creatinine rises significantly, at any time point, assure appropriate urine pH and urine volume as 
above and draw a 42 hour level. If urine output fails to continue at 80% of the fluid intake, consider 
furosemide. 
 
If the 24 hour level is ≤ 20 M draw the next level at hour 48 and continue with hydration at 100 mL/m2 
and continue leucovorin at 10 mg/m2 q 6h until MTX level < 0.2 M  
 
If the 24 hour level is > 20 M and/or creatinine > 125% baseline, repeat level if MTX contamination 
is possible. While waiting for the result and if the value is “real”, refer to the changes in hydration described 
below and repeat the level with a serum creatinine at hour 36. If the 36 hour level is ≥ 3 micromolar, 
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 urine output fails to continue 
at 80% of the fluid intake, consider furosemide. Regardless of urine output, also consider 
Carboxypeptidase G2 (glucarpidase) if 36 hour MTX level exceeds 10 micromolar.  
 
Management of the patient with markedly delayed MTX clearance: If MTX level ≥ 2 μM at Hour 48, 
increase hydration to 200 mL/m2/hour post chemotherapy hydration. Maintain urine pH > 6.5. Continue 
leucovorin at 100 mg/m2 q 6hr. Check levels every 12 to 24 hours and discontinue leucovorin as soon as 
MTX level is < 0.1 μM. Do not give additional MTX if renal function is not normal. If it is, decrease next 
MTX doses by 50% with standard rescue and hydration at 200 mL/m2/hour post chemotherapy hydration. 
If tolerated without delayed excretion, increase dose of MTX by 25% (of the original MTX dose) for each 
course until administration of full dose MTX is achieved  
 
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, assure appropriate urine pH and urine volume as above and draw a 42 hour 
level. If urine output fails to continue at 80% of the fluid intake, consider furosemide. Regardless of urine 
output, also consider glucarpidase. 
 
DO NOT EXTEND leucovorin or modify subsequent courses unless the patient experienced Grade 3 or 4 
mucositis or > 1 week delay in administration of chemotherapy. However, if patient again has delayed 
clearance, treat as in section above.  
 
For patients with marked delayed clearance (48 hour level > 2 µM) or who had clinical toxicity in a prior 
course (≥ Grade 2 mucositis or > 1 week delay in administration of chemotherapy) during a previous course, 
begin the following course with the increased hydration (200 mL/m2/hr). If subsequent course is not 
associated with delayed clearance, attempt to use standard hydration. 
 
(36 hr MTX level) 
(if needed)+ 
42 hr MTX level 
(if needed)+ 
48 hr MTX 
level 
Hydration and Leucovorin Rescue++ 
 
< 0.5 µM  
< 0.2 µM 
Continue with hydration at 100 mL/m2 until 
plasma MTX level is < 0.2 μM. 
 
Continue leucovorin at 10 mg/m2 q 6 hr x 2 
doses given at hours 42 and 48 after the 
start of the MTX infusion. 
 

 
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If the patient has had clinical toxicity (see 
definition below) on a prior cycle, consider 
giving the 54 hour dose of leucovorin  
 
0.51 to < 2.5 µM 
0.21 to < 2 µM 
Increase hydration to 200 mL/m2 until 
plasma MTX level is < 0.2 μM. 
 
Continue leucovorin at 10 mg/m2 q 6hr until 
MTX level < 0.2 M (draw q 6-24 hr). 
> 3 µM 
> 2.5 µM 
> 2 µM 
Increase hydration to 200 mL/m2 until 
plasma MTX level is < 0.2 μM. 
 
Increase to leucovorin to 100 mg/m2 q 6 hr 
until MTX level < 0.1 M (draw q 6-24 hr). 
Consider glucarpidase 
+ Only required if 24 hr level is > 20 µM. See above for guidelines 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of 
< 0.5 and/or < 0.2 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine 
output remains satisfactory. 
 
Nephrotoxicity: Postpone course if pre-treatment (MTX) serum creatinine is > 1.5 x baseline or GFR 
creatinine clearance < 65 mL/minute/1.73m2. If renal function does not recover, delay MTX for up to 
2 weeks until these parameters are met. Do not give IDMTX to a patient with this degree of renal 
impairment, assuming that prolonged excretion can be managed with glucarpidase. If IDMTX is delayed 
more than 2 weeks, omit this dose and resume with the next scheduled dose if parameters are met. Patients 
who must omit more than 1 course of IDMTX may remain on study. 
 
NOTE: For patients who have markedly delayed MTX clearance secondary to renal dysfunction, consider 
using glucarpidase (carboxypeptidase G2, VoraxazeTM).78,79 ASD Healthcare is the sole supplier of 
glucarpidase in the US. 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 
http://www.btgplc.com/products/specialty-pharmaceuticals/voraxaze. 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 may remain on study, and may receive further courses of IDMTX at investigator discretion if renal 
function is adequate as per parameters above. 
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn 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 dose 
10 – 20 X ULN for 2 consecutive doses 
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 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at 
point of interruption. 
Do not skip doses. 

 
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> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serology. 
Consider liver biopsy before additional therapy given.   
* Please see COG Supportive Care Guidelines at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp for 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 3 to 5 doses on a q6 hr schedule. If subsequent course is not associated with Grade 3 - 4 
mucositis, attempt to decrease the leucovorin. 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 tolerated, use a stepwise approach to resuming a standard approach to drug delivery. 
Consider culturing lesions for herpes simplex if mucositis persists or recurs. 
 
Myelosuppression:  
 
After an IV dose of MTX is given, continue with oral 6-MP for the next 3 weeks even in the face 
of uncomplicated myelosuppression.   
 
 
When a course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, delay IV MTX 
administration and HOLD 6-MP until ANC ≥ 500/μL and platelets ≥ 75,000/μL, then restart 6-MP 
at 100% dosing.  
 
 
When a subsequent course of IV MTX is due and ANC < 500/μL and/or platelets < 75,000/μL, 
delay IV MTX administration and HOLD 6-MP until count recovery and then restart 6-MP at 75% 
dose. 
 
 
Also consider TMP/SMX as possible cause of neutropenia. Consider discontinuing TMP/SMX in 
favor of an alternative approach to pneumocystis prophylaxis, as per COG Supportive Care 
Guidelines (see https://members.childrensoncologygroup.org/prot/reference_materials.asp.) 
 
 
Consider TPMT testing at diagnosis and also consider TPMT genotyping in patients encountering 
significant myelosuppression during Consolidation therapy.  
 
 
If prolonged myelosuppression (ANC < 500/µL or platelets < 75,000/µL for more than 7 days) 
recurs with these modifications then reduce methotrexate dose by 20%. 
 
5.8 
PO 6-Mercaptopurine (6-MP) - Consolidation  
 
5.8.1 
PO 6-mercaptopurine (6-MP) - Consolidation for AR B-ALL, LR B-ALL randomized to Arm 
LR-C, DS SR B-ALL, B-LLy and DS B-LLy 
 
For low blood counts: 
a) ANC  750/L and < 1,000/L and/or platelets  75,000/L and < 100,000/L 
Do not modify dose but recheck CBC in one week. If during subsequent 4 weeks CBCs, ANC 
remains  750/L and platelets remain  75,000/L, continue at 100% doses and monitor CBC 
every 2 - 4 weeks. 
 
b) ANC  500/L and < 750/L and and/or platelets  50,000/L and < 75,000/L 

 
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Reduce dose to 50% of original dose until ANC recovers to  750/L and platelets recover to 
 75,000/L. Increase dose approximately every two weeks, first to 75% of the original dose and 
then to full dose, provided ANC remains  750/L and platelets remain  75,000/L. 
 
c) 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., does not tolerate at least half dose 6-MP, 
see Section 5.9 on thiopurine pharmacology testing.  
 
For patients with known TPMT or NUDT15 mutations see Section 5.9 for starting doses of 6-MP. 
 
Do not increase doses for persistent high ANC during Consolidation. 
 
Liver Dysfunction 
For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN consistent with 
Grade 3 toxicity, obtain total bilirubin. Monitor SGPT/ALT or SGOT/AST and total bilirubin weekly during 
Consolidation as long as transaminases remain over 5x ULN. 
 
Continue full dose therapy unless either of the following occurs: 
1) Direct bilirubin > 2.0 mg/dL  
2) SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) on 2 determinations at 
least 1 week apart. 
 
If either of these occurs, hold 6-MP monitor labs as above, weekly. Restart at full dose therapy when the 
transaminases are less than 5x ULN, if bilirubin is normal.  
 
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT or SGOT/AST above 
5x ULN. 
 
5.8.2 
PO 6-mercaptopurine (6-MP) Consolidation for B-ALL patients randomized to Arm LR-M. 
 
Do not hold PO 6-MP for uncomplicated myelosuppression. If subsequent course of IV MTX is delayed, 
HOLD 6-MP until ANC > 500/μL and platelets > 75,000/μL, then restart at 100% dose. Objective is to 
deliver IV MTX on schedule. If ANC again drops below 500/μL, hold 6-MP until recovery and then restart 
at 75% dose. Also consider TMP/SMX as possible cause of neutropenia. 
 
For patients with TPMT mutations see Section 5.9 for starting doses of 6-MP. 
 

 
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5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (6-MP) – Maintenance for all Arms 
In Maintenance, DEX and VCR will be given regardless of blood counts. See Section 5.10 and 5.12 for 
other adjustments to DEX and VCR. 
 
For patients with TPMT or NUDT15 mutations see below for starting doses of 6-MP. 
 
For low blood counts (without known TPMT or NUDT15 mutations): 
 
If absolute neutrophil count (ANC) falls below 500/L or if platelet count falls below 50,000/L 
during Maintenance, 6-MP and MTX only will be held until recovery above these levels.  
 
For the first drop below 500/L or if platelet count falls below 50,000/L , resume chemotherapy at 
the same dose the child was taking prior to the episode of myelosuppression when ANC ≥ 500 /L 
and platelet count ≥ 50,000/L. 
 
If ANC falls below 500/L or if platelet count falls below 50,000/L for a second (or greater) 
time, discontinue 6-MP and MTX until ANC is ≥ 750/µL and platelets are ≥ 75,000/µL. Consider 
discontinuing TMP/SMX in favor of an alternative approach to Pneumocystis prophylaxis, as per 
COG Supportive Care Guidelines (see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. When ANC ≥ 750/µL and 
platelet count ≥ 75 000/µL restart 6-MP and MTX at 50% of the dose prescribed at the time that 
the medications were stopped. 
 Consider obtaining thiopurine metabolites ~ 3 - 4 weeks after restarting the 6-MP and MTX at 50% 
dose, and following the flow chart below. Consider obtaining repeat thiopurine metabolites ~ 3-
4 weeks after the next dose adjustment and using TGN level to guide dosing based on flow chart 
below. See below if TGN level unknown or unavailable 
 
 
 
 
 
TGN > 230 pmol/8 x 108 RBC 
TGN < 230 pmol/8 x 108 RBC 
1. Increase doses of 6-MP and MTX to 75% (of the dose 
prescribed prior to stop), and consider rechecking thiopurine 
metabolites in 3 - 4 weeks  
2. If TGN < 230 pmol/8 x 108 RBC when on 75% dosing (of the 
dose prescribed prior to stop), increase to 100% (of the dose 
prescribed prior to stop) of 6-MP and MTX if TGN < 230 pmol/8 
x 108 RBC (obtained 3 - 4 weeks after last dose adjustment) or (if 
repeat TGN not obtained) as long as ANC ≥ 750 /L and platelet 
count ≥ 75,000/L or 
3. If TGN > 230 pmol/8 x 108 RBC, increase MTX only to 100% 
(of the dose prescribed prior to stop) and continue 6-MP at 
current dosing 
4. Continue to follow ANC q 2 - 4 weeks with target ranges ANC 
500 – 1,500/L and platelet count ≥ 50,000/L. 
1. Increase dose of MTX to 100% 
of dose prescribed prior to stop as 
long as ANC ≥ 750 /L and 
platelet count ≥ 75,000/L and 
continue 6-MP at current dosing. 
2. Continue to follow ANC  
q 2 - 4 weeks with target ranges 
ANC 500 - 1500/L and platelet 
count ≥ 50,000/L. 
TGN Level 

 
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If TGN level unknown or unavailable 
 
1. 
Increase doses of 6-MP and MTX to 75% and then 100% of dose prescribed prior to stopping the 
medications at 2 - 4 week intervals provided ANC remains > 750 /L and platelets remain 
> 75,000/L. May increased both 6-MP and MTX simultaneously. Once at 100% of the dose 
prescribed prior to stopping, see below for instructions regarding further dose escalation. 
2. 
Continue to follow ANC q 2 - 4 weeks with target ranges ANC 500 – 1,500/L and platelet count 
≥ 50,000/L 
 
If patient develops severe or unexpected myelosuppression, i.e., doesn’t tolerate at least half dose 6-MP, 
strongly consider evaluation of TPMT and NUDT15 status (see Section below on thiopurine pharmacology 
testing). 
 
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. 
 
For persistent ANC ≥ 1,500/L 
No dose escalations are recommended during the first cycle of Maintenance. 
 
For ANC ≥ 1,500/L on 3 CBC(s) done over 6 weeks or 2 successive monthly CBC(s), alternately 
increase doses of MTX or 6-MP by 25% Always wait at least 4 weeks before making another dose 
adjustment.  
 
If both MTX and MP are increased once without a fall in ANC, consider noncompliance as a 
possibility. Noncompliance can be assessed by obtaining a sample for thiopurine metabolites. A TGN 
value of < 100 supports non-compliance. Also consider observing the administration of an oral dose 
of MTX and checking plasma MTX concentration 2 - 4 hours later; this value should be 
≥ 0.2 micromolar. This will document whether or not poor absorption contributes to lack of response 
and may facilitate discussions about noncompliance. 
 
If ANC remains high after intervention for possible noncompliance. 
o 
For patients who are heterozygous or homozygous deficient for TPMT and have high ANCs as 
described above, increase MTX alone by 25% and repeat evaluation. Unless noncompliance is 
suspected, increase MTX preferentially over 6-MP unless TGN is consistently < 230 pmol/8 x 
108 RBC. 
o 
For patients who are homozygous wild type for TPMT and have high ANCs as described above, 
consider increasing the 6-MP 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 6-MP dose increases with MTX dose increases. 
o 
Re consider the possibility of non compliance and/or inappropriate administration of the 
antimetabolites with food or milk prior to dose escalation.  
 
Thiopurine Pharmacology Testing and Dosage Adjustments:  
6-MP and 6-TG 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 1 variant (non-functional) TPMT allele (i.e., 
heterozygotes).80-83 Patients with low TPMT form higher concentrations of the thioguanine nucleotides 
(TGNs) and are more susceptible to acute thiopurine toxicity (primarily myelosuppression, involving 
neutropenia, thrombocytopenia, and anemia). Patients with the complete deficiency of TPMT tolerate less 

 
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than 10% of protocol doses of 6-MP (10 - 30 mg/m2/day, 3 days per week). About 35% of heterozygotes 
require a lower dose of 6-MP to avoid dose-limiting myelosuppression.17  
 
Recently, germline variants in the gene encoding the nucleoside diphosphate-linked moiety X-type motif 
15 (NUDT15) were reported in approximately 4% of Hispanic/Native American and nearly 10% of East 
Asian children with ALL; these polymorphisms are strongly associated with 6-MP intolerance. There are 
now CLIA certified tests for TPMT genotype and phenotype, for thiopurine metabolites (MMP and TGN 
measurements), and for NUDT15 polymorphisms. 
 
Only 3 TPMT SNPs constitute well over 90% of the inactivating mutations in the gene, based on studies in 
numerous racial and ethnic groups worldwide.80,84-87 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. 
 
Consider TPMT and NUDT15 testing at diagnosis and also consider TPMT genotyping in patients 
encountering significant myelosuppression during Consolidation 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 could be performed: 
-  
For subjects 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 subjects, 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 for Patients with Known TPMT Status: 
-  
If the subject is homozygous deficient for TPMT or NUDT15, the thiopurine dose should be 
reduced to 10-20 mg/m2/day 3 days per week. If the SUBJECT is heterozygous for TPMT and 
has experienced significant myelosuppression, the thiopurine dose should be reduced by 30%-
50%. It is not yet clear how the dose of thiopurine should be adjusted for patients who are 
heterozyogous for NUDT15 but such patients should be monitored carefully while on 
thiopurines. If a patient has two polymorphisms in NUDT15 (i.e. heterozygous for both the 
R139C and R139H), they should be treated as if they were homozygous deficient. Gradual dose 
escalations should be attempted as outlined below. 
 
 
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 subject is homozygous wild-type (high activity) for TPMT or NUDT15, then discontinue 
TMP/SMX and use pentamidine or dapsone. For modifications of the oral MP and MTX see 
the beginning of this section (5.9). 

 
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In Consolidation (AR B-ALL, LR B-ALL randomized to Arm LR-C, DS SR B-ALL, B-LLy and DS 
B-LLy) consider the following 6-MP dosing based on TPMT status: 
 
Homozygous wild type: 75 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on 
alternating days in order to attain a weekly cumulative dose as close to 525 mg/m2/week as possible. 
See Appendix I. 
 
 
Heterozygous: 60 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on alternating 
days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. 
 
 
Homozygous Deficient: 10 mg/m2/dose, 3 days/week. A liquid suspension can be prepared. See 
drug monograph for details. 
 
 
Do not increase doses for persistent high ANC during Consolidation 
 
In Consolidation (B-ALL patients randomized to Arm LR-M) consider the following 6-MP dosing 
based on TPMT status: 
 
Homozygous wild type: 50 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on 
alternating days in order to attain a weekly cumulative dose as close to 350 mg/m2/week as possible 
See Appendix III. 
 
 
Heterozygous: 40 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on alternating 
days in order to attain a weekly cumulative dose as close to 280 mg/m2/week as possible. 
 
 
Homozygous Deficient: 10 mg/m2/dose, 3 days/week. A liquid suspension can be prepared. See 
drug monograph for details. 
 
 
Do not increase doses for persistent high ANC during Consolidation. 
 
In Maintenance (all Arms) consider the following 6-MP dosing based on TPMT status: 
 
Homozygous wild type: 75 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on 
alternating days in order to attain a weekly cumulative dose as close to 525 mg/m2/week as possible. 
See Appendix I  
 
 
Heterozygous: 60 mg/m2/dose/day. Adjust dose using ½ tablets and different doses on alternating 
days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. 
 
 
Homozygous Deficient: 10 mg/m2/dose, 3 days/week. A liquid suspension can be prepared. See 
drug monograph for details. 
 
 
Please note that 65% of heterozygous patients will tolerate full dose 6-MP. During Maintenance 
(but not Consolidation), adjust as in Section 5.9 if ANC > 1,500/L persistently. For patients with 
homozygous deficiency of TPMT, increasing the dose of 6-MP is not recommended. 
 
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 dose escalation. If mucositis persists or 
recurs, consider culturing for herpes simplex. 
 
Liver Dysfunction 

 
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For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN consistent with 
Grade 3 toxicity, obtain total bilirubin. Monitor SGPT/ALT or SGOT/AST and total bilirubin every 4 weeks 
during Maintenance as long as transaminases remain over 5x ULN. 
Continue full dose therapy unless either of the following occurs: 
1) Direct bilirubin > 2.0 mg/dL  
2) SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) on 2 determinations at 
least 1 week apart. 
 
If either of these occurs, hold 6-MP and MTX and monitor labs as above, weekly. Restart at full dose therapy 
when the transaminases are less than 5x ULN, if bilirubin is normal. If liver dysfunction persists, consider a 
trial period with MTX but without 6-MP, especially if red cell meTIMP is elevated. Notify Study Chair if both 
6-MP and MTX cannot be resumed within 2 weeks. Also consider liver biopsy. 
 
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT or SGOT/AST above 
5x ULN. 
 
5.10 
Steroid (Dexamethasone) 
Hypertension: Dose should not be reduced. Sodium restriction and anti-hypertensives should be employed 
in an effort to control hypertension. Avoid calcium channel blockers due to their potential pro-hemorrhagic 
effect.  
 
Hyperglycemia: Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be employed 
to control the blood glucose level. 
 
Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase. Discontinue steroids, 
except for stress doses, in the presence of hemorrhagic pancreatitis or severe pancreatitis (abdominal 
pain > 72 hours and > Grade 3 amylase elevation (> 2.0x ULN). 
 
Osteonecrosis (ON): Do not modify corticosteroid therapy for osteonecrosis (also referred to as avascular 
necrosis) during Induction or Delayed Intensification. Omit Maintenance steroid for osteonecrosis Grade 2 or 
greater. Consider resuming Maintenance steroid 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 contacting the study coordinator. 
Later in therapy, one may consider holding steroid until patient achieves cardiovascular stability, except for 
“stress doses.” 
 
Severe psychosis: steroid dose may be reduced by 50%. 
 
5.11 
PO 6-Thioguanine (6-TG) - Delayed Intensification: 
Oral 6-TG will be held for suspected or proven serious infection. 
In Delayed Intensification: consider the following 6-TG dosing based on TPMT status: 
 
Homozygous wild type: 60 mg/m2/dose/day, etc 
 
Heterozygous: 50 mg/m2/dose/day, etc 
 
Homozygous Deficient: 10 mg/m2/dose, 3 days/week 

 
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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. 
 
Hyperbilirubinemia88,89  
 
Direct Bili 
 
Dose adjustment 
 < 3.1 mg/dL 
 
None (maximum dose: 2 mg), 
3.1- 5.0 mg/dL  
50% of calculated dose (maximum dose: 1 mg), 
5.1-6.0 mg/dL  
25% 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.  
 
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://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for COG 
guidelines. 
 

 
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5.13 
Drug Interactions 
Since concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and 
carbamazepine) with antileukemic 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.90 Neither Gabapentin nor Levetiracetam induce hepatic drug metabolizing enzymes and may be 
suitable alternative anticonvulsant. 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 antileukemic drugs (e.g. vincristine and anthracyclines) may experience excess 
toxicity when these agents are given concomitantly; alternate antifungal and antibacterial therapy should 
be used when possible (see below).  
 
DRUGS 
POTENTIAL INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug metabolizing 
enzymes 
Lowered EFS 
AVOID phenytoin, Phenobarbital, 
carbamazepine 
Consider Gabapentin or Levetiracetam 
(Keppra) as alternative 
Rifampin 
Induction of drug metabolizing 
enzymes  
DO NOT USE 
Azole Antifungals 
fluconazole, itraconazole*, 
posaconazole, voriconazole, 
ketoconazole 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE MEDICATIONS 
May need dose reductions of vincristine, 
anthracyclines, 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.83, 84  
 
For a more complete list of CYP 3A 4/5 Inhibitors and Inducers, go to: http://medicine.iupui.edu/flockhart/ 
Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
 
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. 
 
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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Possible drug interactions with Capizzi methotrexate: 
Avoid non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole (TMP/SMX), 
penicillins, probenicid, IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin. Urinary 
acidifiers can cause methotrexate to precipitate in the urinary tract. 
 
Possible drug interactions with intermediate dose methotrexate: 
When IT therapy and intermediate dose methotrexate are scheduled for the same day, deliver the IT therapy 
within 6 hours of the beginning of the IV methotrexate infusion (hour -6 to +6, with 0 being the start of the 
methotrexate bolus). 
 
Hold non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole (TMP/SMX), 
penicillins, probenecid, IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin on the days of 
intermediate dose methotrexate infusion and for at least 72 hours after the start of the intermediate dose 
methotrexate infusion and until the methotrexate level is less than 0.4 M. In the presence of delayed clearance, 
continue to hold these medications until methotrexate level is less than 0.1 M. 
 
 
6.0 
DRUG INFORMATION  
See the consent document for toxicities. All other information is available on the COG website in the 
manual titled “Drug Information for Commercial Agents used by the Children’s Oncology Group” at: 
https://www.cogmembers.org/_files/disc/Pharmacy/CommercialAgentsMonographs.pdf under Standard 
Sections for Protocols. Also see drug package inserts for added information on toxicities. 
 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below.  
 
7.1a 
Required and Optional Clinical, Laboratory and Disease Evaluations – AR B-ALL and LR 
 
B-ALL Randomized to Arm LR-C 
 
 
ONLY APPLIES TO PATIENTS ENROLLED BEFORE ACCRUAL GOALS 
FOR AR PATIENTS HAVE BEEN MET 
Studies  
Induction 
Consolidation IM I 
DI 
IM II 
Maintenance 
REQUIRED 
Hx/PE/Wt /Ht1 
Weekly 
Start of Phase 
Prior to each 
IV MTX dose 
Days 1, 8, 15, 29 
Prior to each IV 
MTX dose 
Every 4 weeks 
CBC/diff/platelets 
Weekly 
Day 1  
Prior to each 
IV MTX dose 
Days 1, 8, 15, 29, 
36 
Prior to each IV 
MTX dose 
Every 4 weeks 
Bone Marrow 
Baseline & 292  
 
 
 
 
Peripheral Blood 
Days 83, 293 
 
 
 
 
 
CSF cell count and 
cytospin 
With each IT  
With each IT 
With each IT 
With each IT 
With each IT 
With each IT 
Bilirubin, Albumin4, ALT 
and Creatinine 
Baseline 
Start of Phase 
Prior to each 
IV MTX dose 
Days 1, 29 
Prior to each IV 
MTX dose 
Day 1 of each 12 
week cycle 
Varicella titer 
Baseline 
 
 
 
 
 
Echocardiogram 
 
 
 
Prior to first 
doxorubicin dose5 
 
 
OPTIONAL 
TPMT and NUDT15 
genotype  
During 
Induction 
 
 
 
 
As clinically 
indicated6 
Thiopurine metabolites7 
 
 
 
 
 
As clinically 
indicated7 
Patient Leukemia 
Experience Study 
surveys8,^ 
 
After Day 15 but 
prior to start of 
IM I^ 
 
 
 
Day 299,^ 
Leukemia Physical 
Functioning Study 
evaluations10,^ 
 
After Day 15 but 
prior to start of 
IM I^ 
 
 
 
Day 2911,^ 
1 The measurement of height (Ht.) for the calculation of BSA is only required at the start of each treatment course/cycle. 
2Send Day 29 BM to both the ALL Molecular Lab and a COG-Approved ALL Flow Cytometry Lab (see AALL08B1 or APEC14B1 (if open for the 
classification of newly diagnosed ALL patients) for shipping requirements and addresses).  
3 Send Day 8 PB sample to a COG-Approved ALL Flow Cytometry Lab for MRD and Day 29 PB sample to ALL Molecular Reference Lab for studies of 
genetic variation (see AALL08B1 or APEC14B1 (if open for the classification of newly diagnosed ALL patients) for shipping requirements). Day 8 PB 
sample must be collected prior to Day 8 IV/IT chemotherapy. 
NOTE: IF DAY 8 PB AND 29 BM MRD SAMPLES ARE NOT OBTAINED AND SHIPPED TO A COG-APPROVED ALL FLOW CYTOMETRY 
LABORATORY, THEN THE PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG ALL TRIAL FOLLOWING COMPLETION OF 
INDUCTION THERAPY. 
4 Albumin is collected only during Induction. 
                                5Patients with a normal echocardiogram earlier in treatment do not need a repeat study. 
6For AR B-ALL patients in whom TPMT or NUDT15 genotyping was not previously performed (see Section 5.9). 
7 Optional. RBC TGN (or 6-TGN level) & RBC Methyl MP (or 6-MMPN level). Recommended only for AR B-ALL patients during any Maintenance cycle 
in which 6-MP/MTX has been held and restarted or in case of persistent ANC elevation and concern for non-compliance (see Section 5.9). 
8 Only for AR B-ALL patients already enrolled on Patient Leukemia Experience Study; see Section 15.0 for details of evaluation schedule  
9 Evaluations to be completed on Day 29 (or within 1 month afterwards) of Cycles 1, 4, 7 and end of therapy for boys and Cycles 1, 4, and end of therapy for 
girls. See Section 15.0 for details of evaluation schedule. 
10 Only for AR B-ALL patients already enrolled on Leukemia Physical Functioning Study (selected institutions-available on the COG AALL0932 protocol 
webpage); See Section 16.0 for details.  
11 Evaluations to be completed on Day 29 (or within 1 month afterwards) of Cycles 1, 7 and also 1 year post-end of therapy ; evaluations for girls are 
due on Day 29 (or within 1 month afterwards) of Cycle 1, end of therapy and 1 year post therapy. See Section 16.0 for details.  
^ The PLES and LPFS have met accrual goals and are closed to new patient enrollment. However, institutions are required to continue data 
collection at remaining evaluation time points for patients already enrolled. 
 
 
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).  

 
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7.1b 
Required and Optional Clinical, Laboratory and Disease Evaluations – LR B-ALL 
Randomized to Arm LR-M 
 
 
ONLY APPLIES TO PATIENTS ENROLLED BEFORE 
ACCRUAL GOALS FOR AR PATIENTS HAVE BEEN MET 
Studies 
Induction 
Consolidation 
Maintenance 
REQUIRED 
Hx/PE/Wt/Ht1 
Weekly 
Days 1, 15, 22, 78 & 85  
AND  
Prior to each IV MTX dose (Days 8, 29, 
50, 71, 92 & 113) 
Every 4 weeks 
CBC/diff/platelets 
Weekly 
Day 1  
AND  
Prior to each IV MTX dose 
Every 4 weeks 
Bone Marrow 
Baseline, 292 
 
 
Peripheral Blood 
Days 83, 293 
 
 
CSF cell count and cytospin 
With each IT  
With each IT 
With each IT 
Bilirubin, Albumin4, ALT and 
Creatinine 
Baseline 
Prior to each IV MTX dose 
Day 1 of each 16 week cycle 
Varicella titer 
Baseline 
 
 
Serum Creatinine & MTX levels5 
 
After each IV MTX dose 
 
OPTIONAL 
TPMT and NUDT15 genotype  
During Induction  
As clinically indicated6 
Thiopurine metabolites7 
 
 
As clinically indicated7 
1 The measurement of height (Ht.) for the calculation of BSA is only required at the start of each treatment course/cycle. 
2 Send Day 29 BM to both the ALL Molecular Lab and a COG-Approved Flow Cytometry Lab (see AALL08B1 or APEC14B1 (if open for 
the classification of ALL patients) for shipping requirements and addresses).  
NOTE: IF DAY 8 PB AND 29 BM MRD SAMPLES ARE NOT OBTAINED AND SHIPPED TO A COG-APPROVED ALL FLOW 
CYTOMETRY LABORATORY, THEN THE PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG ALL TRIAL 
FOLLOWING COMPLETION OF INDUCTION THERAPY. 
3 Send Day 8 PB sample to a COG-Approved ALL Flow Cytometry Lab for MRD and Day 29 PB sample to ALL Molecular Reference Lab 
for studies of genetic variation (see AALL08B1 or APEC14B1 (if open for the classification of newly diagnosed ALL patients) for shipping 
requirements). Day 8 PB sample must be collected prior to Day 8 IV/IT chemotherapy. 
4 Albumin is collected only during Induction. 
5Monitor levels at the end of the MTX infusion (hour 24), 36 & 42 (only if hour 24 is high) and 48 hours after beginning of the infusion, and 
every 12-24 hours until the MTX level falls below 0.2μM. See section 5.7.2 for details. 
5 For LR B-ALL patients in whom TPMT or NUDT15 genotyping was not previously performed (see Section 5.9). 
6 Optional. RBC TGN (or 6-TGN level) & RBC Methyl MP (or 6-MMPN level). Recommended only for LR B-ALL patients during any 
Maintenance cycle in which 6-MP/MTX has been held and restarted or in case of persistent ANC elevation and concern for non-compliance 
(see Section 5.9). 
 
 
 

 
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7.1c 
Required and Optional Clinical, Laboratory and Disease Evaluations – DS SR B-ALL 
Studies  
Induction 
Consolidation 
IM I 
DI 
IM II 
Maintenance 
REQUIRED 
Hx/PE/Wt/Ht1 
Weekly 
Start of Phase 
Prior to each IV 
MTX dose 
Days 1, 8, 
15, 29 
Prior to each 
IV MTX dose 
Every 4 weeks 
CBC/diff/platelets 
Weekly 
Day 1 
Prior to each 
IV MTX dose 
Days 1, 8, 
15, 29, 36 
Prior to each 
IV MTX 
dose 
Every 4 weeks 
Bone Marrow 
Baseline & 
Day 292 
 
 
 
 
 
Peripheral Blood 
Day 293 
 
 
 
 
 
CSF cell count and 
cytospin 
With each IT  
With each IT 
With each IT 
With each 
IT 
With each IT 
With each IT 
Bilirubin, Albumin4, 
ALT and Creatinine 
Baseline 
Start of Phase 
Prior to each IV 
MTX dose 
Days 1, 29 
Prior to each 
IV MTX dose 
Day 1 of each 
12 week cycle 
Varicella titer 
Baseline 
 
 
 
 
 
IgG  
Baseline 
Start of Phase 
Start of phase 
Start of 
phase 
Start of phase 
Day 1 of each 
12 week cycle 
Echocardiogram  
 
 
 
Prior to first 
doxorubicin 
dose5 
 
 
OPTIONAL 
TPMT and NUDT15 
genotype 
During 
Induction 
 
 
 
 
As clinically 
indicated6 
Thiopurine 
metabolites7 
 
 
 
 
 
As clinically 
indicated7 
1 The measurement of height (Ht.) for the calculation of BSA is only required at the start of each treatment course/cycle. 
2 Send Day 29 BM to both the ALL Molecular Lab and a COG-Approved ALL Flow Cytometry Lab (see AALL08B1 or APEC14B1 (if open for 
the classification of ALL patients) for shipping requirements and addresses). 
NOTE: IF DAY 29 BM MRD SAMPLE IS NOT OBTAINED AND SHIPPED TO A COG-APPROVED ALL FLOW CYTOMETRY 
LABORATORY, THEN THE PATIENT WILL NOT BE ELIGIBLE TO CONTINUE ON A COG ALL TRIAL FOLLOWING 
COMPLETION OF INDUCTION THERAPY. 
3 Send Day 29 PB sample to ALL Molecular Reference Lab for studies of genetic variation (see AALL08B1 or APEC14B1 (if open for the 
classification of newly diagnosed ALL patients) for shipping requirements). 
4 Albumin is collected only during Induction. 
5Patients with a normal echocardiogram earlier in treatment do not need a repeat study. 
6 For DS SR B-ALL patients in whom TPMT or NUDT15 genotyping was not previously performed (see Section 5.9). 
7 Optional. RBC TGN (or 6-TGN level) & RBC Methyl MP (or 6-MMPN level). Recommended only for DS SR B-ALL patients during any 
Maintenance cycle in which 6-MP/MTX has been held and restarted or in case of persistent ANC elevation and concern for non-compliance 
(see Section 5.9). 
 
 

 
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7.1d 
Required and Optional Clinical, Laboratory and Disease Evaluations – B-LLy and DS-B-LLy 
Studies  
Induction 
Consolidation IM I 
DI 
IM II 
Maintenance 
REQUIRED 
Hx/PE/Wt /Ht1 
Weekly 
Start of Phase 
Prior to each 
IV MTX dose 
Days 1, 8, 15, 29 
Prior to each IV 
MTX dose 
Every 4 weeks 
Pregnancy test for females 
of childbearing potential 
Baseline13 
 
 
 
 
 
CBC/diff/platelets 
Weekly 
Day 1 
Prior to each 
IV MTX dose 
Days 1, 8, 15, 
29, 36 
Prior to each 
IV MTX dose 
Every 4 weeks 
Bone Marrow 
Cytomorphology 
Baseline  
 
 
 
 
 
CSF cell count and 
cytospin 
With each IT  
With each IT 
With each IT 
With each IT 
With each IT 
With each IT 
Bilirubin, Albumin2, ALT, 
and Creatinine 
Baseline 
Start of Phase 
Prior to each 
IV MTX dose 
Days 1, 29 
Prior to each IV 
MTX dose 
Day 1 of each 
12 week cycle 
Varicella titer 
Baseline 
 
 
 
 
 
IgG 3 
Baseline 
Start of Phase 
Start of phase 
Start of phase 
Start of phase 
Day 1 of each 
12 week cycle 
Echocardiogram  
 
 
 
Prior to first 
doxorubicin dose4 
 
 
CT (neck, chest, abdomen 
and pelvis) 5 
Baseline & End 
of Induction 
End of course 
 
 
 
Completion of 
Therapy 
Chest X-ray6 
Baseline & End 
of Induction 
End of course 
 
 
 
Completion of 
Therapy 
Bone scan 7 
Baseline & End 
of Induction 
End of course 
 
 
 
Completion of 
Therapy 
Diagnostic 
Biopsy/Cytology 
Baseline 
 
 
 
 
 
OPTIONAL 
PET scan  
Baseline & End 
of Induction7 
End of course8 
 
 
 
 
TPMT and NUDT15 
genotype 
During 
Induction 
 
 
 
 
As clinically 
indicated9 
Thiopurine metabolites10 
 
 
 
 
 
As clinically 
indicated10 
 
 
 
 
 
 
 
Optional Biology 
Banking11 
Baseline 
 
 
 
 
 
Genetic variation studies 
(Peripheral Blood) 11 
Day 2912 
 
 
 
 
 
1 The measurement of height (Ht.) for the calculation of BSA is only required at the start of each treatment course/cycle. 
2 Albumin is collected only during Induction. 
3 For Down syndrome patients only 
4 Patients with a normal echocardiogram earlier in treatment do not need a repeat study. 
5 Repeat all CTs positive at baseline at the end of Induction. For those positive at the end of Induction, repeat at the end of Consolidation. 
6 A chest X-ray is not required if CT chest was performed. 
7A bone scan at diagnosis is only required in patients with bone symptoms who do not have a PET scan; follow-up scans are only required if the initial 
scan was positive  
8 A PET scan is highly recommended but not required at diagnosis, at the end of Induction and if there are residual masses at the end of Consolidation. 
9 For all B-LLy patients in whom TPMT or NUDT15 genotyping was not previously performed (see Section 5.9). 
10 Optional. RBC TGN (or 6-TGN level) & RBC Methyl MP (or 6-MMPN level). Recommended only for DS B-LLy patients during any Maintenance 
cycle in which 6-MP/MTX has been held and restarted or in case of persistent ANC elevation and concern for non-compliance (see Section 5.9). 
11 See Section 14.0 for guidelines on sample handling and shipping. 
12 For patients who consent, send Day 29 PB sample to ALL Molecular Reference Lab for studies of genetic variation (see Section 14.0 for shipping 
requirements). 
13 Only for patients of reproductive age. 
 
 

 
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7.2 
Studies Suggested to be Obtained After Stopping Therapy (B-ALL Patients) 
Note: Refer to COG’s Long-term Follow-Up Guidelines for monitoring of long-term complications of 
therapy, available at: http://www.survivorshipguidelines.org  
1st year   
PE, CBC/diff/plts q 4-8 weeks, ALT q 2 months until normal 
BMA, CSF, as clinically indicated*  
Note: for AR patients enrolled on ancillary study(ies); see Sections 15.0 and 16.0 
for details of off therapy evaluation schedule.  
2nd year  
PE, CBC/diff/ platelets q 2 months 
3rd year  
PE, CBC/diff/ platelets q 3 months 
4th year  
PE, CBC/diff/ platelets q 6 months 
5th year  
PE, CBC/diff/ platelets q 6-12 months  
 
* Obtain at any point after the end of therapy when it is clinically indicated. 
 
7.3 
Studies Suggested to be Obtained After Stopping Therapy (B-LLy Patients) 
Note: Refer to COG’s Long-term Follow-Up Guidelines for monitoring of long-term complications of 
therapy, available at: http://www. survivorshipguidelines.org 
1st year   
PE, CBC/diff/platelets q 3 months 
 
 
CT of primary site, BMA, CSF, as clinically indicated*  
2nd year  
PE, CBC/diff/ platelets q 3 months 
 
 
CT of primary site, as clinically indicated*  
3rd year  
PE, CBC/diff/ platelets q 4 months  
CT of primary site, as clinically indicated*  
4th year  
PE, CBC/diff/ platelets q 6 months 
 
 
CT of primary site, as clinically indicated*  
5th year  
PE, CBC/diff/ platelets q 12 months  
 
* Obtain at any point after the end of therapy when it is clinically indicated. 
 
7.4 
At Relapse 
B-ALL patients who relapse and have consented to cell banking when they consented to AALL08B1 or 
APEC14B1 (if open for the classification of newly diagnosed ALL patients), should have samples of bone 
marrow sent to the Molecular Reference Laboratory for cell banking as described in AALL08B1 or 
APEC14B1 
 
 
 

 
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7.5 
Sample and Shipping Information 
 
For a list of COG-Approved Flow Cytometry Labs, see : 
https://members.childrensoncologygroup.org/_files/admin/mrdflowlabs.pdf 
 
Molecular Laboratory 
Julie Gastier-Foster, PhD 
COG ALL Reference Laboratory 
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 
 
 
 
 

 
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8.0 
SUPPORTIVE CARE GUIDELINES  
 
8.1 
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://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
See Section 8.3 for DS patients. 
 
8.1.1 
Blood Components 
Blood products should be irradiated following current FDA guidelines found at: 
http://www.fda.gov/OHRMS/DOCKETS/98fr/981218g2.pdf 
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components 
CAN/CSA-Z902-04 issued in March 2004 and available at: http://www.shopcsa.ca 
 
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. 
 
8.1.2 
Infection Prophylaxis 
 
Pneumocystis jiroveci 
All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 5 mg/kg/day 
divided bid 2 - 3 sequential days per week. For patients allergic to or experiencing excessive 
myelosuppression with TMP/SMX, alternative prophylaxis with dapsone (1 - 2 mg/kg/day, maximum dose 
100 mg/day), aerosolized pentamidine (300 mg/q month ≥ 5 years of age), or atovaquone (30 mg/kg/day if 
< 3 months or > 2 years, 45 mg/kg/day if between 3 months & 2 years) 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 opportunistic infections among hematopoietic stem cell transplant recipients: 
recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood 
and 
Marrow 
Transplantation. 
MMWR 
2000; 
49(No. 
RR-10):1-125. 
Available 
at 
http://www.cdc.gov/mmwr/PDF/rr/rr4910.pdf. Accessed December 1, 2007.)  
 
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. 
 

 
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Antifungals 
Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently with 
vincristine may increase the risk of neurotoxicity. Caution is advised if azole antifungals are used.   
 
8.1.3 
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 morality is higher during Induction and during profound neutropenia. 
The specific choice of antibiotics to be used in empiric treatment of febrile neutropenia is dependent on 
each institution’s experience regarding the type of infecting organisms, and their antibiotic sensitivity 
patterns. 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.pdf  
 
Primary Varicella Infection (Chickenpox) 
Patients should be treated promptly with acyclovir 1,500 mg/m²/day intravenously divided q 8 hours, and 
monitored closely for the development of invasive systemic disease. 
 
Empiric Management of Pulmonary Infiltrates 
Pulmonary infiltrates should be evaluated in the context of the patient’s clinical and laboratory profile as 
well as institutional infection patterns. If the patient is not neutropenic, and the pulmonary lesions on CT 
scan are not particularly suggestive of a fungal infection (Aspergillus, mucor), consider using broad 
spectrum antibiotics. If the patient develops progressively worsening clinical or laboratory features, or if, 
the pulmonary lesions on CT scan are suggestive of a fungal infection (Aspergillus, mucor), then more 
aggressive diagnostic measures should be undertaken. Pulmonary infiltrates may be evaluated with 
bronchoscopy and biopsy, lavage or open lung biopsy. If a procedure cannot be tolerated, and/or if there is 
high clinical suspicion consider beginning empiric treatment with amphotericin B given the high likelihood 
of fungal disease. It is advisable to seek an infectious disease consult under these circumstances. Empiric 
coverage may 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. Caution is advised if 
azole antifungals are used.   
 
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 + 

 
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metronidazole; or piperacillin-tazobactam + aminoglycoside), Sitz baths, a strong barrier technique and 
effective analgesia. 
 
8.1.4 
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://childrens
oncologygroup.org/downloads/COG_SC_CINV_Guideline_Document.pdf. 
 
The routine use of steroids including dexamethasone, is discouraged but may be appropriate in select 
patients with demonstrated intolerance to higher-dose chemotherapeutic agents.  
 
8.1.5 
Use of Filgrastim 
The routine use of filgrastim is not generally recommended, but may be used at the discretion of the 
investigator in situations of serious infection with neutropenia. 
 
8.1.6 
Osteonecrosis (ON) 
Osteonecrosis (also referred to as avascular necrosis) may develop during or following therapy and often 
involves multiple joints over time. ON is not limited to weight bearing joints; common sites include hip, 
knee, ankle, heel, shoulder and elbow. Symptoms and exam findings may include joint pain, joint stiffness, 
limited range of motion (e.g. pain with internal rotation of the hip), limited mobility or ambulation, and/or 
gait abnormalities. Diagnostic imaging is indicated in any patient with suggestive findings. MRI is superior 
in sensitivity and specificity to other modalities, especially with early bone changes. Patients with negative 
studies, but who have persisting, progressive, or recurrent symptoms, should be re-imaged. For 
modifications of ALL therapy, see Section 5.10. 
 
8.1.7 
GI Protection 
While patients are on steroid therapy, consider using an H2 blocker. 
 
8.2 
Guidelines for Induction 
8.2.1 
Acute Tumor Lysis Syndrome 
Patients with ALL at high risk of tumor lysis should be assessed rapidly for evidence of symptomatic 
hyperleukocytosis, tumor lysis syndrome, and coagulopathy. Suggested initial studies, obtained prior to 
initiating antileukemia therapy, may include a complete blood count (CBC), prothrombin and activated partial 
thromboplastin times, fibrinogen, D-dimer, and serum electrolytes, including creatinine, BUN, uric acid, 
phosphorus, and calcium. Continued monitoring of these studies should be carried out at suitable intervals until 
abnormalities have resolved or the risk has abated. 
The risk for serious acute tumor lysis syndrome (TLS) is usually restricted to the first 72 hours after 
initiation of therapy; however, it may spontaneously occur prior to treatment. To manage the metabolic 
derangements caused by hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia, the 
following steps should be initiated: 
1. 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 also be appropriate to use rasburicase. 
2. Hydrate at 2,400-3,000 mL/m²/day to maintain urine output > 100 mL/m²/hour until peripheral blasts 
and extramedullary disease are reduced. Potassium should not be added to the hydration fluids. 
3. Urine alkalinization is NOT necessary for TLS prophylaxis. There is paucity of evidence 
demonstrating benefit of urine alkalinization and it can potentially lead to calcium phosphate 
precipitation and/or metabolic acidosis. 
If the patient has oliguria or severe renal dysfunction, consider the use of rasburicase at 0.1 to 0.2 mg/kg/dose 
(or as per institutional guidelines) and obtaining a nephrology consult. In patients with a prior history of 

 
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glucose-6-phosphate dehydrogenase (G-6PD) deficiency, rasburicase is contraindicated and allopurinol 
should be utilized instead of rasburicase. 
 
Refer also to the discussion of TLS in the Supportive Care Manual (Supportive Care of Children with 
Cancer, ed A Altman, 3rd edition, 2004). 
 
8.2.2 
Diagnostic Lumbar Puncture 
As there are data that suggesting that traumatic diagnostic lumbar punctures may have an adverse effect on 
prognosis, consider interventions to minimize the chances of a traumatic diagnostic lumbar puncture (LP).91 
These interventions may include: 
 
a) Correcting any coagulopathy or thrombocytopenia (goal: platelets > 100 000/µL) present prior to the 
diagnostic LP 
b) Performing the diagnostic LP while the patient is in a controlled environment such as under deep 
sedation.91  
c) Administering intrathecal cytarabine at the time of the diagnostic lumbar puncture. 
d) Having the diagnostic lumbar puncture performed by an experienced provider to minimize unintentional 
trauma. 
 
8.2.3 
Induction – Infectious Complications 
Since the induction phase is associated with a higher rate of toxicity, investigators are cautioned to pay close 
attention to a number of factors during the early phases of treatment. 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, the warning signs of septic shock 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 several 
serious toxic events have had an intestinal component. Patients with subtle GI symptoms should be monitored 
very closely. 
 
8.3 
Patients with Down syndrome 
Patients with DS B-ALL and DS B-LLy have a significantly increased risk of morbidity and treatment-
related mortality in most published series.37 Therefore, they require diligent and conservative supportive 
care. Infectious complications during times of neutropenia are of greatest concern. The pattern of treatment-
related mortality among HR-DS-ALL patients enrolled on AALL1131 as of May 2015 suggests there may 
be an increased risk associated with age greater than or equal to 15 years and/or obesity during the following 
treatment phases: Induction, Consolidation, and Delayed Intensification. Infections in children with Down 
syndrome may be sudden in onset and progress rapidly mandating close surveillance and aggressive 
intervention or treatment.. 
 
It is strongly recommended that children with Down syndrome be monitored in the hospital during 
Induction and Delayed Intensification until they show signs of bone marrow recovery (and, is afebrile, and 
clinically stable). If a patient experiences profound myelosuppression at any other time, there should also 
be a very low threshold for hospitalization and inpatient management until there is evidence of bone marrow 
recovery. Antibiotic prophylaxis against Gram-positive and Gram-negative organisms (e.g. 
Levofloxacin92, 93) may be considered during periods of severe myelosuppression until patients meet criteria 
for discharge with a switch to broad-spectrum intravenous antibiotics per institutional guidelines if a patient 
develops febrile neutropenia while receiving prophylactic antibiotics. Antifungal prophylaxis may also be 
considered during periods of myelosuppression. Options include an echinocandin such as caspofungin or 
micafungin, or an azole. Investigators should be cautious however as azole antifungal agents (i.e., 

 
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fluconazole, itraconazole, voriconazole) given concurrently with vincristine may increase the risk of 
neurotoxicity. 
 
IgG levels should be monitored monthly and strong consideration given to IVIG therapy for levels less than 
500 mg/dL. IgG levels and route of IVIG administration should be recorded on study CRF. 
 
Children with DS B-ALL and DS B-LLy may not develop fever in response to infection, even with sepsis, 
particularly when they are receiving steroids. Therefore extra vigilance is needed, with a lower threshold 
for drawing cultures and starting antibiotics, even for subtle changes in clinical status. Aggressively manage 
episodes of fever (≥ 100.5ºF/38.05°C) during Induction and Delayed Intensification or when the patient is 
neutropenic with an ANC ≤ 1,000/L. The risk of life threatening infection is high so these patients should 
be hospitalized with immediate institution of broad spectrum IV antibiotics adjusted appropriately for local 
patterns of antibiotic resistance. Adequate coverage for gram negative and positive organisms including 
viridans streptococci is recommended. Broad spectrum antibiotics, once started, should continue until 
evidence of bone marrow recovery. In the absence of response after 3 – 5 days, institution of antifungal 
therapy should be strongly considered. Stress-dose steroids and/or filgrastim should be considered in DS 
B-ALL and DS B-LLy patients with fever and neutropenia who are very ill or not responding appropriately 
to antibiotic therapy. 
 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
9.1 
Criteria for Removal from Protocol Therapy for B-ALL and B-LLy Patients 
a) 
Identification of Very High Risk B-ALL features at the end of Induction. 1 
b) 
Recurrent leukemia following complete remission. (B-ALL only) 
c) 
Identification of High Risk B-ALL features at the end of Induction. 2 
d) 
Refusal of further protocol therapy by patient/parent/guardian. 
e) 
Identified as Philadelphia chromosome-positive (BCR-ABL1). 3 
f) 
Completion of planned therapy. 
g) 
Down syndrome patients identified as Induction failure (M3 at Day 29) (B-ALL only) 
h) 
Physician determines it is in patient’s best interest. 
i) 
Development of a second malignancy. 
j) 
Adverse Event/Side Effects/Complications 
k) 
Incomplete Induction data for risk stratification. (B-ALL only) 
l) 
Down syndrome patient identified to be Down syndrome high risk B-ALL.4 
m) 
Inevaluable 
n) 
Progressive disease at any time point prior to the end of Consolidation (B-LLy only) 
o) 
Failure to achieve CR at the end of Consolidation (B-LLy only). 
p) 
Relapsed biopsy proven lymphoma following CR (B-LLy only) 
q) 
Identification of Average Risk B-ALL features at the end of Induction.5 
r) 
Identification of Low Risk B-ALL features at the end of Induction.5 
 
1 M3 marrow at end of Induction; or KMT2A (MLL) gene rearrangement; or hypodiploid; or iAMP21, or no favorable 
cytogenetics with Day 29 MRD ≥ 0.01%. 
2 Favorable cytogenetics with Day 29 MRD ≥ 0.01%; or no favorable cytogenetics with Day 8 MRD >1% and Day 29 
MRD < 0.01% MRD.   
3 B-ALL Ph+ patients are eligible for enrollment on AALL1122 or successor study by Day 15 of Induction. 
4 Eligible for post-Induction therapy on the High Risk study. 
5 Only applies to patients enrolled after accrual goals for AR patients have been met. 
 

 
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B-ALL and B-LLy 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. 
 
9.2 
Off Study Criteria (B-ALL and B-LLy Patients) 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Enrollment onto another COG study with tumor therapeutic intent (e.g., at recurrence) with the 
exception of COG AALL1421, a Phase 2 study of IV pegcristantaspase, a pegylated Erwinia 
asparaginase, as a replacement for pegaspargase in patients with pegaspargase hypersensitivity. 
d) 
Withdrawal of consent for any further data submission. 
e) 
Tenth anniversary of study entry. 
 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Statistical Design 
Primary Endpoint 
A primary endpoint for the Average Risk (AR) patients will be the improvement in 5-year disease free 
survival (DFS) from 93% to 96% based on the MTX randomization. The second endpoint is to determine 
if the 5-year DFS is adversely affected by the reduced pulses in Maintenance (every 4 weeks vs. every 12 
weeks). DFS for the AR patients is defined as the time from randomization at the end of IM II to first event 
(relapse, second malignancy, remission death) or date of last contact. Another endpoint is to determine if 
less intensive therapy will maintain a 5-year DFS ≥ 95% for the Low Risk (LR) patients, where patients 
will be randomized 1:1 to one of two low intensity regimens (Arm LR-C vs. Arm LR-M). The primary 
objective is not to compare outcomes on the 2 arms but to determine if outcomes on each arm are ≥ 95%. 
The 5-year DFS for the DS patients will also be estimated on modified therapy. For the LR and DS patients, 
DFS is defined as the time from end of Induction to first event (relapse, second malignancy, remission 
death) or date of last contact. 
 
Secondary Endpoint – See Correlative Studies in Sections 15.0 and 16.0. 
 
10.2 
Patient Accrual and Expected Duration of Trial 
Total Expected Accrual: 5,872 over 4.9 years. Of 1,200 NCI SR patients, a total of 1,186 patients (less 
12 CNS3 patients and 2 patients with testicular disease at diagnosis) will be enrolled on this study annually. 
Patients with CNS3 or testicular disease will be eligible for COG AALL1131. About 32 of these will be 
patients with DS. These patients will be assigned to a separate stratum and will receive separate Induction 
and post-Induction therapy. All other patients will receive standard 3 drug Induction. At the end of 
Induction, patients identified to be LR (250 patients/year) will be assigned to a separate stratum to receive 
less intensive post-Induction therapy. They will be randomized 1:1 to two low-intensity therapeutic 
regimens at the end of Induction. We estimate that 89 NCI SR patients without favorable cytogenetics, will 
be removed from this study per year at the end of Induction due to Day 8 MRD > 1%, with Day 29 MRD 
< 0.01%. These patients will be eligible to participate in post-Induction therapy assignment/randomization 
on the HR trial. Patients with favorable cytogenetics who have Day 29 BM MRD > 0.01% (70 patients/year) 
will be removed from this study at the end of Induction and will also be eligible for post induction therapy 
on the HR study. Patients without favorable cytogenetics that have Day 29 MRD > 0.01% (79 patients/year) 
will be removed from therapy at the end of induction and will be eligible to receive post induction therapy 
on the VHR study. About 38 patients/year with other high risk features (KMT2A (MLL), hypodiploid, M3 
marrow end Induction, iAMP21) will be removed from therapy at the end of Induction and may be eligible 
for the VHR study. About 12 patients/year will be found to be Ph+ and will be removed from therapy by 
Day 15 of Induction and may be eligible for AALL1122 or successor COG Ph+ ALL trial. About 5 DS 
patients will be Day 29 MRD positive and will be eligible to transfer to the HR study. The remaining 

 
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616 patients/year will be the AR patients. These patients will be randomized at the end of IM II to 2 
questions. The first is a randomization between 20 mg/m2 and 40 mg/m2 of weekly oral MTX in 
Maintenance. The second is a randomization between every 4 weeks and every 12 weeks VCR/DEX pulses 
in Maintenance. The first question is a therapy intensification question and will look for an improvement 
in DFS while the second will be a reduction in therapy question looking for non-inferiority in DFS.  
 
Amended Accrual (Amendment #2A):  
Assuming an accrual rate of 15 patients/year with Murphy Stages I and II B-Lymphoblastic Lymphoma (B-
Lly) would result in a total accrual of about 60 B-Lly patients over the remaining 4 years of accrual of the 
study. All patients with Murphy Stages I and II B-Lly (without Down syndrome) will be non-randomly 
assigned to post-Induction therapy similar to patients with AR B-ALL, with a modified Maintenance Arm 
A (Arm LLy), on AALL0932. Down syndrome B-Lly patients will be non-randomly assigned post-
induction to DS SR B-ALL with Maintenance “Arm DS”. 
 
Amended Accrual (Amendment #3A): The enrollment of this study will be extended until AALL1131 
meets accrual goals (anticipated December 2017). All enrolled patients will receive Induction treatment on 
AALL0932. Once the Average Risk (AR) arm meets accrual goals (i.e. 2,396 randomized evaluable 
patients), both the AR and LR arms will be closed to accrual and all patients who are classified as AR or 
LR will come off protocol therapy upon completion of Induction. The Down syndrome (DS) and B-
lymphoblastic lymphoma (B-LLy) strata will remain open until the end of the study accrual. Patients who 
are classified as HR or VHR at end of Induction will continue to be eligible for enrollment on AALL1131. 
 
As of 12/31/2014, the study has accrued a total of 5,269 patients, including 531 evaluable LR, 129 eligible 
SR-DS and 18 eligible B-LLy patients. With extended accrual to the end of 2017, the total number of 
patients to be enrolled to the study is estimated to be 9,022 (accrual rate is ~ 1,251/year) and the total 
number of eligible patients to be enrolled to the SR-DS and B-LLy groups are around 222 (accrual rate is 
~ 31/year) and 48 (accrual rate is ~ 10/year), respectively. 
 
In order to accrue the 2,396 patients who complete the Maintenance therapy randomization, the study is 
projected to enroll approximately 3,195 AR patients to account for those who decline randomization. As of 
12/31/2014, a total 2,764 AR patients have been enrolled to the post-Induction therapy. With the estimated 
accrual rate of 657/year, the AR group is projected to meet accrual goals in August 2015. Given the 
observed accrual of 125/year for LR patients, the total number of evaluable patients to be enrolled to the 
LR randomization is approximately 614. 
 
Amended Accrual (Amendment #4): The enrollment of this study will be extended until AALL1131 meets 
accrual goals (anticipated April 2018). All enrolled patients will receive Induction treatment on AALL0932. 
The Average Risk (AR) and Low Risk (LR) arms were closed to accrual on 05/29/2015, and since then, all 
enrolled patients after who are classified as AR or LR will come off protocol therapy upon completion of 
Induction. The Down syndrome (DS) and B-lymphoblastic lymphoma (B-LLy) strata will remain open until 
the end of the study accrual. Patients who are classified as HR or VHR at end of Induction will continue to 
be eligible for enrollment on AALL1131. 
 
As of 03/28/2016, the study has accrued a total of 6,862 patients, including 603 randomized LR, 3125 AR 
(2365 randomized at the start of Maintenance), 165 eligible SR-DS and 28 eligible B-LLy patients. With 
extended accrual to the end of April 2018, the total number of patients to be enrolled to the study is estimated 
to be 9,483 (accrual rate is ~ 1,258/year) and the total number of eligible patients to be enrolled to the SR-
DS and B-LLy groups are around 228 (accrual rate is ~ 30/year) and 47 (accrual rate is ~ 9/year), 
respectively. 
 

 
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10.3 
Statistical Analysis Methods 
Sample size with power justification 
The study will be powered to answer the reduction in therapy question among the Average Risk (AR) 
patients (5 year DFS 93% on every 4 weeks vs. 90% on every 12 weeks reduced pulses). A total of 2,396 
patients will give 90% power (alpha = 10%, one-sided), to detect a reduction in 5 year DFS from 
93% to 90% (HR = 0.689; 204 events). Accounting for 25% loss to randomization due to various reasons, 
a total of 2,996 AR patients will be accrued over 4.9 years. A total of 2,396 eligible, evaluable patients will 
give 93.6% power (alpha = 5%, one-sided) to detect an improvement in 5 year DFS from 93% vs. 96% for 
the MTX question (HR: 0.5625; 132 events). All patients will be followed for a minimum of 3 years. 
 
If it is found that there is a decrease in DFS due to the reduced pulses, comparison of outcomes between 
the two MTX regimens will be restricted to the q4 week pulses arms. With half the sample size (N = 1,198) 
there will be 72.5% power to detect a difference in 5 year DFS from 93% to 96% (alpha = 5%, 66 events) 
on the two MTX regimens; and 92.9% power to detect an improvement from 93% to 97%. As and when 
interim monitoring indicates erosion in DFS due to the reduced pulses, that randomization will be closed 
and accrual to the MTX randomization (with all patients receiving every 4 week pulses) will continue until 
a total of 1486 patients are accrued on the two MTX (with 4 week steroid pulses) regimens. A total of 1,486 
pts would give 80% power to see an improvement in DFS from 93% to 96%. 
 
A Cox proportional hazards model will be used to test for quantitative interaction in this 2x2 factorial 
design. But the sample sizes will not be large enough to power it to detect interactions of the same 
magnitude as the main effects size. If there is significant interaction between the 2 factors, the 4 regimens 
can be compared using an adjusted alpha level.  
 
A total of 1,200 eligible, evaluable LR patients will be accrued over 4.9 years randomized 1:1 to either of 
the 2 low intensity regimens. The 5 year DFS for these patients will be estimated on the 2 low intensity 
regimens. The objective is not to compare the 2 regimens with respect to outcomes, but estimate the DFS 
on each low intensity regimen. With a sample of 600 patients on each regimen, the DFS can be estimated 
for each regimen with a maximum standard error of 2%. The expected 5 year DFS on each of these regimens 
is at least 95%. If so, either would be deemed suitable for future use in this patient population. Assuming a 
baseline 5 year DFS of 95%, there is 83.3% power to detect a difference (95% vs. 98%) using a 2 sided log 
rank test with alpha = 5%. The sample size is not large enough to design this as an equivalence study. 
 
A total of 130 eligible, evaluable DS patients will be enrolled during this study. The 5 year DFS for these 
patients will be estimated. A sample of 130 pts will allow the DFS to be estimated with a maximum standard 
error of 4.4%.  
 
All power calculations are based on the assumption of proportional hazards, and using the log rank test 
(alpha = 5%) with 5 planned analyses of the data for interim monitoring purposes (MTX question for AR 
patients). The efficacy stopping boundaries to be used will allocate greater importance to the later analyses. 
The upper boundaries selected are based on the alpha  (time)2 spending function. The study will also be 
monitored for futility. The lower boundaries are based on testing the alternative hypothesis at the 0.005 
level.94 This monitoring rule can be applied to any interim analysis schedule and maintains the overall 
significance level of 0.05 approximately. The comparative analyses of regimen outcome will occur at 
approximately 20%, 40%, 60%, 80% and 100% of the projected combined DFS event horizon (total events 
= 132) for the overall randomized group.  
 
At the time of each interim monitoring, we will also monitor for a decrease in DFS due to the reduced 
pulses. Interim monitoring will be based on the alpha  (time)2 spending function (alpha =10%, one-sided 
test) and will be conducted at the same time as the interim analyses for the MTX question. If it is found that 

 
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there is erosion in outcomes on the reduced pulses arm compared to the 4 week pulses regimen, this 
randomization will be closed and all patients will be assigned to the 4 week pulses arm.  
 
Interim analysis will also be conducted for each of the 2 low intensity regimens to protect against lower 
DFS for the LR patients. A 5 year DFS of 95% translates to a hazard rate of 0.0103. Interim analysis will 
be based on the estimated hazard rate. The αt2 spending function will be used to maintain an overall one-
sided Type I error rate of 10%. Interim analyses will be done at the time of the above analyses.  
 
Amendment #3A: An estimate of 614 eligible, evaluable LR patients will be randomized 1:1 to the 2 low-
intensity regimens. The 5 year DFS for these patients will be estimated on the 2 arms. The objective is not 
to compare the 2 regimens with respect to outcomes, but estimate the DFS on each low-intensity regimen. 
With a sample of 307 patients on each regimen, the DFS can be estimated for each regimen with a maximum 
standard error of 2.9%. The expected 5 year DFS on each of these regimens is at least 95%. If so, then either 
would be deemed suitable for future use in this patient population. Assuming a baseline 5 year DFS of 95%, 
there is 52.2% power to detect a difference (95% vs. 98%) between the two arms using a 2-sided log rank 
test with alpha = 5%.  
 
A total of 222 eligible, evaluable DS patients will be enrolled during this study. The 5-year DFS for these 
patients will be estimated. A sample of 222 patients will allow the DFS to be estimated with a maximum 
standard error of 3.6%.  
 
Interim analysis will also be conducted for each of the 2 low intensity regimens to protect against lower 
DFS for the LR patients. A 5-year DFS of 95% translates to a hazard rate of 0.0103. Interim analysis will 
be based on the estimated hazard rate. The alpha  (time)2 spending function will be used to maintain an 
overall one-sided Type I error rate of 10%. Interim analyses will be done at the time of the above analyses. 
There was no reported DFS event for LR patients as of the last reporting cycle of Fall 2014. 
 
All the above primary analyses of DFS comparisons between randomized groups are intent-to-treat 
analyses. Secondary analyses will include DFS comparisons accounting for the number of patients on each 
arm who were also enrolled on AALL1421 in order to adjust for any potential impacts on DFS with the use 
of PEG-Erwinia. 
 
Amendment #4:  
The 5 year DFS for LR patients will be estimated on the 2 arms. The objective is not to compare the 2 
regimens with respect to outcomes, but estimate the DFS on each low-intensity regimen. With the 603 LR 
patients randomized to the 2 low-intensity regimens, the DFS can be estimated for each regimen with a 
maximum standard error of 2.9%. The expected 5 year DFS on each of these regimens is at least 95%. If 
so, then either arm would be deemed suitable for future use in this patient population. Assuming a baseline 
5 year DFS of 95%, there is 51.9% power to detect a difference (95% vs. 98%) between the two arms using 
a 2-sided log rank test with alpha = 5%.  
 
A total of 228 eligible, evaluable DS patients will be enrolled during this study. The 5-year DFS for these 
patients will be estimated. A sample of 228 patients will allow the DFS to be estimated with a maximum 
standard error of 3.3%.  
 
Interim analysis will also be conducted for each of the 2 low intensity regimens to protect against lower 
DFS for the LR patients. Interim analysis will be based on the Woolson’s one-sample logrank test, assuming 
the survival time for LR patients follows a cure-rate model with exponential distribution assumed during 
the first 4 years followed by a flat curve. The alpha  (time)2 spending function will be used to maintain an 
overall one-sided Type I error rate of 10%. Interim analyses will be done at the time of the above analyses. 
There were 2 reported DFS events for LR patients as of the last reporting cycle of Fall 2015. 

 
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All the above primary analyses of DFS comparisons between randomized groups are intent-to-treat 
analyses. Secondary analyses will include DFS comparisons accounting for the number of patients on each 
arm who were also enrolled on AALL1421 in order to adjust for any potential impacts on DFS with the use 
of PEG-Erwinia. 
 
Amended Design (Amendment #2A):  
From past studies, almost 100% of B-LLy patients have submitted biospecimens. Study pathologists 
estimate viable samples for 90% of enrolled patients resulting in a total of 54 B-LLy patients available for 
analyses. The 5 year EFS for these patients is around 90% from past studies (A5971). The 5 year EFS rate 
will be estimated for this group of patients. The 95% confidence interval will be computed for the same. 
We will monitor outcomes for these patients to ensure against significant erosion in EFS rates. Assuming 
that most events have occurred within 5 years and that the survival curve is relatively flat beyond this time 
point, the binomial distribution can be used to model the number of events at the 5-year time point. If at 
least 8 events (induction failures, progressive disease, relapse, second malignancy, or death) occur among 
the 54 B-LLy patients, it will be concluded that the 5 year EFS is less than 90%. With this design there is a 
16.8% chance of erroneously concluding that there is a decrease in EFS when in fact the true 5 year EFS is 
90%. The probability is 87.2% of concluding there is a decrease in EFS when the true 5 year EFS is 80%. 
The 5 year EFS and OS will be estimated separately for the B-LLy patients. Biology data captured for these 
patients will be summarized. Due to small patient numbers, analyses will be descriptive. 
 
Amendment #3A: The actual accrual rate for B-LLy is about 10 patients per year, which is less than the 
previously projected rate of 15 per year. With the extended accrual to the end of 2017, the total number of 
B-LLy patients to be accrued to the study is approximately 48. Study pathologists estimate viable samples 
for 90% of enrolled patients resulting in a total of 43 B-LLy patients available for analyses. The 5 year EFS 
for these patients is around 90% from past studies (A5971). The 5-year EFS rate will be estimated for this 
group of patients. The 95% confidence interval will be computed for the same. We will monitor outcomes 
for these patients to ensure against significant erosion in EFS rates. Assuming that most events have 
occurred within 5 years and that the survival curve is relatively flat beyond this time point, the binomial 
distribution can be used to model the number of events at the 5 years time point. If at least 7 events 
(induction failures, progressive disease, relapse, second malignancy, or death) occur among the 43 B-LLy 
patients, it will be concluded that the 5 year EFS is less than 90%. With this design there is a 13.3% chance 
of erroneously concluding that there is a decrease in EFS when in fact the true 5 year EFS is 90%. The 
probability is 78.4% of concluding there is a decrease in EFS when the true 5 year EFS is 80%. The 5 year 
EFS and OS will be estimated separately for the B-LLy patients. Biology data captured for these patients 
will be summarized. Due to small patient numbers, analyses will be essentially descriptive in nature. 
 
Amendment #4: The current accrual rate for eligible B-LLy is about 9 patients per year, which is less than 
the previously projected rate of 15 per year. With the extended accrual to the end of April 2018, the total 
number of eligible B-LLy patients to be accrued to the study is approximately 47. Study pathologists 
estimate viable samples for 90% of enrolled patients resulting in a total of 42 B-LLy patients available for 
analyses. The 5 year EFS for these patients is around 90% from past studies (A5971). The 5-year EFS rate 
will be estimated for this group of patients. The 95% confidence interval will be computed for the same. 
We will monitor outcomes for these patients to ensure against significant erosion in EFS rates. Assuming 
that most events have occurred within 5 years and that the survival curve is relatively flat beyond this time 
point, the binomial distribution can be used to model the number of events at the 5 years time point. If at 
least 8 events (induction failures, progressive disease, relapse, second malignancy, or death) occur among 
the 42 B-LLy patients, it will be concluded that the 5 year EFS is less than 90%. With this design there is a 
5.4% chance of erroneously concluding that there is a decrease in EFS when in fact the true 5 year EFS is 
90%. The probability is 62.2% of concluding there is a decrease in EFS when the true 5 year EFS is 80%. 
The 5 year EFS and OS will be estimated separately for the B-LLy patients. Biology data captured for these 

 
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patients will be summarized. Due to small patient numbers, analyses will be essentially descriptive in 
nature. 
 
The following specific toxicities identified by the ALL Toxicity Reporting Task Force will be collected on 
all future COG ALL trials (including this one) in addition to any Grade 4 non-hematologic toxicities for all 
patients on study (B-ALL and B-LLy): 
1. 
CNS hemorrhage requiring medical intervention (Grade 2 or 3) 
2. 
GI bleed requiring operative or interventional radiology intervention (Grade 3) 
3. 
Pancreatitis requiring medical intervention (Grade 2 or 3) 
4. 
Osteonecrosis interfering with function (Grade 2 or 3) 
5 
Transient ischemic attacks (All grades)  
6. 
Stroke (All grades) 
7. 
Encephalopathy (Grade 3) 
8. 
Neuropathy; motor or sensory, interfering with ADL (Grade 3) 
9. 
Seizure (Grade 2 or 3) 
10. 
Allergic reaction (Grade 3) 
11 
Ileus (Grade 3) 
12. 
Mucositis/stomatitis; functional (Grade 3) 
13. 
Bilirubin (Grade 3) 
14. 
Thrombosis (Grade 3) 
 
Additional reporting requirements for AR B-ALL patients: 
Detailed dosing data on 6-MP and MTX will be collected during Maintenance, in order to assess the ability 
to deliver the protocol specific methotrexate dose intensity. On the previous Standard Risk ALL trial (CCG-
1991), some dosing data was collected. That data suggests that approximately 50% of patients have dose 
reductions during each Maintenance cycle. There is concern that patients assigned to the higher dose of 
MTX (40 mg/m2) may have lower doses of mercaptopurine administered and/or may have medications held 
more frequently than patients assigned to the lower dose of MTX (20 mg/m2). The doses of 6-MP and oral 
MTX in Maintenance will be collected to assess the therapy received by patients on each randomized 
regimen. Exploratory analyses of the TGN and Methyl MP levels will be conducted to study the possible 
interaction between 6-MP and MTX dosing in Maintenance, and will be used as additional information to 
evaluate the treatment regimen with higher intensity MTX dosing. 
 
Additional reporting requirements for patients with DS SR B-ALL and DS B-LLy: 
In addition to the routine AE required for all patients on this trial, the following additional AEs are required 
to be reported for patients with Down syndrome: 
1. All Grade 3 and higher infectious toxicities 
2. Grade 3-4 febrile neutropenia 
3. Immunologic Serum IgG levels at the start of each reporting period and whether intravenous 
infusion of immunoglobulins (IVIG) was administered during that reporting period. 
 
IgG levels and whether IVIG was administered will be collected in order to assess the effectiveness of the 
supportive care changes implemented on this study. These data will be used to evaluate whether DS patients 
on this study who suffer severe or fatal infectious complications were hypogammaglobulinemic at the time, 
and whether they received IVIG replacement. These patients, as well as patients that experience toxic 
events, will be very few and, hence, these data will be evaluated individually and summarized descriptively. 
 
10.4 
Gender and Minority Accrual Estimates 
Based on the distribution of patients enrolled on COG AALL0331, the gender and minority distribution of the 
AALL0932 study population is expected to be: 
 

 
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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
793 
891 
1,684 
Not Hispanic or Latino 
3,481 
4,318 
7,799 
Ethnic Category: Total of all subjects 
4,274 
5,209 
9,483* 
Racial Category 
 
American Indian or Alaskan Native 
20 
40 
60 
Asian 
131 
198 
329 
Black or African American 
220 
283 
503 
Native Hawaiian or other Pacific Islander 
19 
12 
31 
White 
3,884 
4,676 
8,560 
Racial Category: Total of all subjects 
4,274 
5,209 
9,483* 
* These totals must agree. 
 
 
 
11.0 
EVALUATION CRITERIA  
 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE version 4.0 of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the NCI website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Additionally, toxicities are to 
be reported on the appropriate case report forms. 
 
11.2 
Response Criteria for Patients with Leukemia (B-ALL) 
See Section 3.3 
 
11.3 
Response Criteria for Patients with B-LLy95,96 
 
11.3.1 Complete Response (CR) 
Defined as disappearance of all detectable clinical evidence of disease from all sites. Lymph nodes must 
have decreased to less or equal 1.5 cm. This will be determined by physical exam and CT.  
 
For patients with a previous positive PET scan, PET scan must be negative. 
 
A post-treatment residual mass of any size is considered a CR as long as it is PET negative. A negative PET 
is required in patients with post-treatment residual masses to be considered a CR. Patients with post-
treatment residual masses must be followed by PET and remain PET negative to be considered CR. 
 
Bone lesions that remain positive by MRI and/or PET will be considered CR if there is resolution of all 
surrounding soft tissue component by the end of Consolidation. No new lesions. 
 
11.3.2 Partial Response (PR) 
At least a 50% decrease in the sum of the product of diameters (SPD) of the lesions of up to six of the 
largest dominant nodes or nodal masses. Splenic and hepatic nodules must decrease by at least 50% in their 
SPD. No new lesions. 

 
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In patients with a positive PET scan prior to therapy, the post-treatment PET must be positive in at least 
one previously involved site. 
 
11.3.3 Stable Disease (SD) 
Failure to qualify for a PR or PD. No new lesions. 
 
In patients with a positive PET scan prior to therapy, the PET must be positive at prior sites of disease with 
no new areas of involvement on the posttreatment CT or PET. 
 
11.3.4 Relapsed/Progressive Disease (PD) 
Greater than 50% increase in the size of any lesions or appearance of new lesion(s) more than 1.5 cm in 
any axis. 
 
In patients with a positive PET scan prior to therapy, lesions must be PET positive. 
 
 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Purpose 
Adverse event 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.  
 
12.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of the adverse event 
including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the prior 
experience (expectedness) of the adverse event. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. In some cases an agent obtained commercially may be used for indications not included in the 
package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in 
these cases, the agent is still considered to be a commercial agent and the procedures described below 
should be followed. 
 
Determine the prior experience Expected events are those that have been previously identified as resulting 
from administration of the agent. An adverse event is considered unexpected, for reporting purposes only, 
when either the type of event or the severity of the event is not listed in:  
 
 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group posted on 
the COG website; or 
 
the drug package insert. 
 
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.  
 
All secondary malignancies that occur following treatment need to be reported via CTEP-AERS. Three 
options are available to describe the event:  

 
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 
Leukemia secondary to oncology chemotherapy   
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
12.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting System), 
accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used in this study 
are listed in the front of this protocol immediately following the Study Committee roster.  
 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting 
and are located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment 
areas should have access to a copy of the CTCAE. 
 
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 
1 This 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 which can be attributed (possibly, probably, or definitely) to the agent and is not 
due to cancer recurrence must be reported via CTEP-AERS. 
*Note: Table A –CTEP-AERS Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days1 of the Last Dose of an Investigational Agent has been deliberately omitted as it is not relevant to 
this study in which only commercial agents are used. 
 
As of August 25, 2010 all secondary malignancies should be reported via CTEP-AERS. 
 
12.4 
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. 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is accomplished via the 
Adverse Event (AE) Case Report Form (CRF) within the study database. For this study, routine reporting 
will include all CTEP-AERS reportable events and non-hematologic Grade 4 and higher Adverse Events 

 
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as well as the following specific toxicities identified by the ALL Toxicity Reporting Task Force to be 
collected on all future COG ALL trials.  
 
1. 
CNS hemorrhage requiring medical intervention (Grade 2 or 3) 
2. 
GI bleed requiring operative or interventional radiology intervention (Grade 3) 
3. 
Pancreatitis requiring medical intervention (Grade 2 or 3) 
4. 
Osteonecrosis interfering with function (Grade 2 or 3) 
5 
Transient ischemic attacks (All grades)  
6. 
Stroke (All grades) 
7. 
Encephalopathy (Grade 3) 
8. 
Neuropathy; motor or sensory, interfering with ADL (Grade 3) 
9. 
Seizure (Grade 2 or 3) 
10. 
Allergic reaction (Grade 3) 
11 
Ileus (Grade 3) 
12. 
Mucositis/stomatitis; functional (Grade 3) 
13. 
Bilirubin (Grade 3) 
14. 
Thrombosis (Grade 3) 
 
Additional reporting requirements for patients with DS SR B-ALL and DS B-LLy: 
1. 
All Grade 3 - 4 infections 
2. 
Grade 3 - 4 febrile neutropenia* 
3. 
Immunologic Serum IgG levels at the start of each reporting period and whether intravenous 
infusion of immunoglobulins (IVIG) was administered during that reporting period. 
 
* 
Note: for EACH infection and febrile neutropenia event reported, the CTCAE event “neutrophil count 
decreased” should also be reported separately using a new AE form, should it occur. “Neutrophil count 
decreased” can be found under “Investigations”. DO NOT report low platelets or any other low 
hematologic AE for this study. 
 
 
 
13.0 
RECORDS AND REPORTING 
The Case Report Forms and the submission schedule are posted on the COG web site with each protocol 
under “Data Collection/Specimens”.  
 
13.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 1.1. 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. 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES FOR B-LLy PATIENTS 
 
14.1 
Pathology Goals 
1. Provide quality control by central pathologic review with accurate diagnosis and classification of 
pediatric non-Hodgkin lymphoma. This is to be based on both morphologic and immunophenotypic 
criteria. This study is limited to B-cell lymphoblastic lymphoma. Patients with T-lineage 
lymphoblastic lymphoma are not eligible for this study. 
2. Employ the 2008 World Health Organization (WHO) Lymphoma Classification97 to facilitate 
concordance in diagnosis. 
3. Correlate morphologic, immunophenotypic and cytogenetic data for the lymphomas included in this 
treatment protocol. 

 
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14.2  
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
 
14.2.1 Tissue Specimens 
Tissue should preferentially, whenever possible, be obtained fresh and delivered immediately to the 
Pathology Laboratory for optimal handling and distribution (fixation, snap freezing, cytogenetics, etc.). 
Refer to diagram entitled “Lymph Node Processing For Institutional Diagnosis And Research Studies In 
Children‘s Oncology Group” (Figure 14.1). Submit representative tissue sections for fixation including at 
least 1 block with 10% buffered formalin. 
 
Figure 14.1 
 
Lymph Node Processing for Institutional Diagnosis 
and Children’s Oncology Group Research Studies
Lymph node 
(unfixed)
Flow 
cytometry 
(unfixed)
Histopathologic diagnosis and 
immunohistochemistry
Cytogenetics
Gene rearrangement 
studies
Formalin fixation, 
paraffin embedding 
(FFPE)
Fix in 10% formalin.
Snap frozen for 
tissue banking
Research studies on FFPE 
tissues
 
 
14.2.2 Cytology Specimens 
Cytology or body fluid specimens (i.e. pleural fluid) should be delivered promptly to the pathology 
laboratory, and handled per primary institutional procedures. Sufficient material should be utilized for 
morphologic evaluation by cytocentrifuge preparations stained with a Romanowsky stain (i.e. Giemsa or 
Wright‘s stains). Provided enough specimen is available, at least 1 cell block should be prepared with 
specification of the fixative utilized (formalin preferred) and the time in fixative. 
 
14.3 
Immunophenotyping Recommendations for Primary Institutions 
For eligibility in this study, the methodology and criteria for immunophenotypic analysis defined by the 
submitting institution will be accepted. Recognized methods include: flow cytometry, paraffin section 
immunohistochemistry, and cytocentrifuge (cytospin) immunocytochemistry. For eligibility in this study, 
a panel of antibodies should be employed for immunophenotypic evaluation. This can be done on fresh 
tissue by flow cytometry, on paraffin embedded tissue by immunohistochemistry, and on body 
fluid/cytology specimens by flow cytometry or cytocentrifuge (cytospin) immunocytochemistry. The panel 
of antibodies is listed as follows: 
 
T-Cell:  CD3. 

 
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B-Cell:  CD19, CD20, CD22, CD79a, PAX5, Kappa, Lambda. 
Myeloid:  CD13, CD15, CD33. 
Other:  CD10, CD34, CD45, TdT. 
 
For cases in which no paraffin embedded tissue has been prepared, and only stained cytospin slides remain 
available, these cases will be acceptable for protocol submission and pathology review when adequate 
immunophenotypic data is available from the primary institution. This situation may occur with cases 
evaluated by cytospin immunocytochemistry or flow cytometry immunophenotyping. If specimen is limited 
preventing a complete immunophenotypic evaluation, a recommended minimum panel of antibodies should 
include: CD3, CD19, CD20, Ig kappa, Ig lambda, and TdT. If specimen is limited to paraffin embedded 
tissue only, a preferred panel of antibodies should include at least: CD3, CD79a, and TdT, and either CD19 
or PAX5 as an additional B-cell marker. The method of TdT evaluation should be specified (i.e. flow 
cytometry or immunohistochemistry). If immunophenotyping studies are not available locally, the case may 
be sent as a consultation case for evaluation including immunophenotyping studies to Dr. Sherrie Perkins 
(see address in Section 14.5.6). 
 
14.4 
Pathology Staging Criteria 
Cerebrospinal Fluid: Leukocyte count greater than or equal to 5/μL, with presence of blasts. TdT evaluation 
is strongly recommended. 
Bone Marrow: The presence of greater than 5% and less than 25% blasts in a bone marrow aspirate, or focal 
infiltration in a bone marrow biopsy, represents involvement of the marrow by lymphoblastic lymphoma. 
 
14.5 
Retrospective Central Pathology Review 
 
14.5.1 Required Materials 
Materials to be submitted for retrospective pathology review to the COG Biopathology Center include the 
following: 
 
1) 
Initial diagnostic material prior to therapy. 
2) 
Specimens demonstrating relapse of lymphoma at any time. 
3) 
Specimens from residual masses demonstrating residual lymphoma or complete response to therapy. 
4) 
A copy of all final pathology reports (see details in Section 14.5.1.4). 
5) 
Pathology Data Collection Form (Institutional Pathology Form). 
6) 
Transmittal Form. 
 
Please label all materials with the patient’s COG patient identification number and the institutional 
pathology number and block number found on the corresponding pathology report. The materials to be 
submitted are described below and listed in Table 14-1. 
 
14.5.1.1 Paraffin Blocks 
If possible, it is preferred that paraffin blocks be submitted to the COG Biopathology Center. For surgical 
biopsy specimens, this should include a paraffin block of tissue prepared in 10% Buffered Formalin (as 
described in Section 14.2.1). For cytology specimens, a paraffin block may be available as a cell block 
preparation (see Section 14.2.2). If paraffin blocks cannot be submitted, then submit twenty (20) unstained 
sections (4 microns thick) of unbaked slides air-dried at room temperature from one representative block 
and two (2) H&E stained slides from each block. These sections should be place on sialinized slides (i.e. 
Fisher Superfrost Plus). 
 
14.5.1.2 Cytology Slides 
When paraffin blocks have not been prepared, a cytologic preparation of one stained, air-dried cytospin 
slide (i.e. Romanowsky stain such as Giemsa or Wright’s stain) and 10 unstained slides should be submitted. 

 
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14.5.1.3 Biopsies of Residual Masses 
For these biopsy specimens, send a recut slide (hematoxylin and eosin stain) from all of the paraffin blocks 
for review. The corresponding pathology report should accompany the slides for review. 
 
 
14.5.1.4 Pathology Reports 
A copy of all pathology reports on each case should be submitted. This should include: 
1. 
Final reports of diagnostic biopsy and bone marrow specimens (even if negative) 
2. 
All immunophenotyping reports of diagnostic biopsy and bone marrow specimens (if available); also 
include copies of flow cytometry histograms (if available) 
3. 
Results of any genotypic studies (i.e. gene rearrangement studies) 
4. 
Results of any cytogenetic (karyotypic) analysis 
 
14.5.1.5 Pathology Data Collection Forms/COG Pathology Center 
A separate pathology data collection form (Institutional Pathology Form) should be completed and 
submitted along with the above materials. Also, indicate the primary institution pathology diagnosis 
utilizing the 2008 WHO Lymphoma Classification97 on the data collection form. 
 
14.5.2 Transmittal Form 
A specimen transmittal form must be submitted along with the pathology review materials. 
 
14.5.3 Biopathology Center Address 
All material submitted for retrospective central pathology review should be sent via regular mail or using 
your institutional courier account to: 
 
COG Biopathology Center 
Nationwide Children‘s Hospital 
700 Children's Drive, WA 1340* 
Columbus, OH 43205 
Phone: (614) 722-2894 
Fax: (614) 722-2897 
 
* The room number is required. Packages not listing the room number could be denied and returned to 
sender. 
 
14.5.4 Paraffin Blocks and Cytologic Slides-Storage/Return 
Paraffin blocks and cytologic slides will be retained at the COG Biopathology Center indefinitely, unless 
the institution requests their return. 
 
14.5.5 Lymphoma Classification 
Morphologic evaluation and classification of the study cases will utilize the criteria described in the 2008 
WHO Lymphoma Classification.97 Eligible pediatric lymphomas will be classified as precursor B-cell 
lymphoblastic lymphoma. 
 
14.5.6 Review Pathologists 
For any questions regarding the pathology protocol, please contact: 
 
Sherrie Perkins, MD, PhD 
University of Utah and ARUP Laboratories 
Department of Hematology 
500 Chipeta Way 

 
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Salt Lake City, UT 84108 
Phone: (801) 581-5854 
Fax: (801) 585-3831 
 
 
TABLE 14-1: MATERIALS TO SEND FOR RETROSPECTIVE CENTRAL PATHOLOGY REVIEW 
 
1. Paraffin Blocks 
Send one of the following: 
a. Surgical biopsy specimen: One paraffin block (formalin preferred). 
b. Cytology cell block: One paraffin block (specify fixative). 
c. If blocks cannot be sent, submit twenty unstained and unbaked sections 
(4 μm) from 1 representative block and 2 (two) H&E stained sections from each block on 
sialinized slides. 
 
2. Cytology Slides 
Send one stained slide (Romanowsky stain) and 10 unstained slides 
 
3. Biopsies of Residual Masses 
a. Send a recut slide (hematoxylin and eosin stain) from all of the paraffin blocks from each of 
these types of biopsy specimens. 
b. Send corresponding pathology report. 
 
4. Pathology Reports 
Send all of the following: 
a. Final reports of diagnostic biopsy and bone marrow specimens (even if negative). 
a. 
All immunophenotyping reports of diagnostic biopsy, and bone marrow specimens (if 
available); also include copies of flow cytometry histograms (if available). 
c. Results of any genotypic studies (i.e. gene rearrangement studies). 
d. Results of any cytogenetic (karyotypic) analysis. 
 
5. Pathology Data Collection Form (Institutional Pathology Form) 
 
6. Transmittal Form 
 
14.6 
Optional Minimal Marrow Disease (MMD) Biology Studies 
 
Effective Amendment #5, the Optional Minimal Marrow Disease Biology is closed. Do not collect or 
submit samples for testing. 
 
14.6.1  Sample Collection. 
A single bone marrow specimen will be obtained at diagnosis to assess disease involvement in the bone 
marrow. This sample will be shipped to the COG ALL Reference Flow Cytometry Lab using the same 
shipping and handling requirements as B-ALL patients enrolled on this study. Samples are to be shipped to 
either Dr. Brent Wood at the University of Washington, or Dr. Michael Borowitz at John Hopkins. The 
Specimen Transmittal Form is to be submitted with each sample submitted to the COG Reference 
Laboratory. The specimen transmittal form information should always include the name and telephone 
number of a person designated by the PI to receive calls from the Reference Laboratory directors. The PI’s 
FAX number must also be noted on each sample inclusion form. Always include the patient’s name, COG 
number and date of birth on any sample submitted. This is a joint Commission and College of American 
Pathologists (CAP) requirement. COG ALL Reference Laboratories may be unable to analyze specimens 
if adequate patient identifiers are not provided. B-LLy samples for the Reference Laboratories are to be 

 
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collected in special 15 mL conical tubes (SM) containing EDTA/RPMI as the anticoagulant and media 
diluent. These tubes will be prepared in the Reference Laboratories and mailed 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, 
click on the ‘Biopathology Center Application’ link on either the Protocol or the CRA Home Page of the 
COG web site. On the Biopathology Center Applications page, select the BPC Kit Management link to 
enter the Kit Management application. Please select the protocol ‘AALL08B1’ to order the shipping tubes 
required for MMD samples. Even though B-LLy patients are not enrolled on ‘AALL08B1’, the supplies 
are still ordered through that protocol. 
 
14.6.2 Bone Marrow Collection Procedures for Reference Laboratories for B-LLy. 
a. Collect BM into a syringe and transfer the specimen immediately into the 15 mL shipping media conical 
tube with RPMI/EDTA. 
b. Mix well. Up to 5 mL of BM can be placed in one 15 mL tube with RPMI/EDTA. If you don’t have 
shipping media 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 shipping media tubes. 
c. 5 mL of BM will be sufficient for MMD analysis at diagnosis. 
 
14.6.3 Sample Shipping 
B-LLy bone marrow samples for optional MMD studies will be shipped to Michael Borowitz, MD, PhD at 
the Eastern Flow Cytometry Laboratory or to Brent Wood, MD, PhD at the Western Flow Cytometry 
Laboratory according to location (see Geographical Sample Distribution map, Section 7.5): 
 
Eastern Flow Cytometry Reference Laboratory 
Michael Borowitz, MD, PhD 
John Hopkins Medical Institution 
Flow Cytometry Lab 
Weinberg Building, Room 2300 
401 N Broadway 
Baltimore, MD 21231-2410 
Phone: (410) 614-2968 
Fax: (410) 502-1493 
Email: mborowit@jhmi.edu 
 
Western Flow Cytometry Reference Laboratory 
Brent Wood, MD PhD 
SCCA 
Hematopathology Laboratory 
Room G7-800 
825 Eastlake Ave. E. 
Seattle, WA 98109-1028 
Phone: 206-288-7060 
FAX: 206-288-7127 
Email: woodbl@u.washington.edu  
 
FOR SAMPLES THAT ARE EXPECTED TO BE DELAYED FOR MORE THAN 48 HOURS - 
PLACE A COLD PACK (NOT ICE PACK) IN SHIPMENT. ALL TUBES SHOULD BE LABELED 
WITH AT LEAST THREE PATIENT IDENTIFIERS, INCLUDING THE NAME, DATE OF 
BIRTH, AND THE COG NUMBER. IN ADDITION, A SPECIMEN TRANSMITTAL FORM 
AVAILABLE ON THE RDE SHOULD ALWAYS BE SUBMITTED WITH EACH SAMPLE. 
 

 
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Call Reference Laboratory only when shipping a sample to be delivered on Saturday.  
 
Samples for the Flow Cytometry Reference Laboratory should be mailed by FEDERAL EXPRESS 
PRIORITY (DELIVERY BEFORE 10 AM) using the COG Federal Express account number available at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf 
 
14.7 
Optional Tissue Banking and Subsequent Biologic Studies 
Although the collection of fresh frozen tissue is desirable for tissue banking and potential future studies, 
the planned biologic studies described below will utilize formalin fixed, paraffin embedded (FFPE) tissues 
due to the low frequency of receiving frozen tissues in previous trials. Therefore, FFPE specimens will be 
requested on all cases for the proposed studies, and fresh frozen tissue will be collected for banking when 
available. Specimens to characterize the biologic nature of the disease will focus on 2 major areas: 1) 
cytogenetic characterization by FISH and 2) SNP array profiling. Tissue collection is requested prior to 
treatment initiation and also at the time of relapse. It is anticipated that there will be variability in the type 
and amount of tissue submitted based upon the accessibility of the tumor tissue and the feasibility of 
obtaining it (i.e. patients with large masses who are sedation risks and needle core biopsy specimens will 
be expected to have limited tissue available). Minimum requirements for study entry will include sufficient 
tissue to confirm the diagnosis. All available biologic specimens will be sent to the COG Biopathology 
Center, which will serve as the central repository for this component of the study. The study committee will 
assess the state and quantity of material for subsequent studies with allocation to designated laboratories, 
placing priority in the studies in the rank order listed below. The collection, processing, shipping and 
analysis of the tissue have been incorporated into the AALL0932 protocol in order to prevent any 
modification or amendment of the ALL Classification Study (AALL08B1) or Project:EveryChild 
(APEC14B1). Specific details of the biologic studies include: 
 
1. Cytogenetic Analysis: Limited cytogenetic analysis (via FISH) will be pursued in all specimens 
with sufficient tissue given the great paucity of data available characterizing the nature of 
cytogenetic abnormalities in B lymphoblastic lymphoma (B-LLy). Conventional cytogenetic 
analysis on fresh tissue will not be attempted as prior studies have failed to yield sufficient 
specimens to warrant a commitment of resources to this endeavor. FISH targeted at genetic lesions 
known to characterize B-ALL combined with SNP array studies below will allow a more detailed 
characterization of the genetic abnormalities in B-LLy and comparison to the genetic abnormalities 
of B-ALL. 
 
2. SNP Array Profiling: We have recently piloted the feasibility of high resolution single nucleotide 
polymorphism (SNP) analysis to characterize gene copy number alterations and allelic imbalance 
in B-LLys using DNA isolated from FFPE tissues. The ability to use fixed tissue to assess genetic 
alternations will expand the ability to study genetic alterations in B-LLy, which have been difficult 
to assess due to the limited tissue typically available for cytogenetic analysis. Based upon the 
availability of resources, a targeted approach will be expanded to gain more extensive 
characterization of the incidence of genetic aberrations in B-LLy and their correlation to clinical 
outcome. This may potentially lead to insight of the important genetic features of high risk disease 
and possibly reveal potential targets for new therapies. 
 
For cases with a limited amount of tissue available for analysis, the AALL0932 and NHL Biology 
Committee will prioritize specimens for studies.  
 
14.8 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse 
For every case, even if frozen tissue is obtained, FFPE tissue should be submitted by sending a 
representative block. If this is not possible, then ten 5 µm unstained slides should be submitted for FISH, 
and two 50 µm tissue sections (100 microns total) should be cut and submitted in a cryovial similar to how 

 
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fixed tissue would be submitted for a PCR-based clonality assay. When fresh tissue is available at diagnosis 
for banking, at least one square centimeter of snap frozen tumor is requested in addition to the material 
required for central review (described in Section 14.5). If more than 1 gram is available, cut tissue into 1 
gram aliquots. Wrap each aliquot of tissue in a piece of foil and snap freeze in vapor phase liquid nitrogen 
(do not submerge the tissue in the liquid nitrogen) or on dry ice. Place frozen tissue in zip lock bag. Using 
a waterproof marker, label the bag with the patient’s BPC number, specimen type and date obtained. Store 
specimens at -70°C or colder until shipped. Include a transmittal form with each shipment of specimens. If 
tumor tissue is obtained at the time of relapse for clinical purposes, additional material (as described above 
for diagnosis) is requested for banking and subsequent biologic studies. The Biopathology Center (BPC) 
will bank the tissue for future distribution and use including the studies listed above. 
 
14.8.1 Specimen Shipping Instructions 
Specimen Procurement Kits for shipping frozen tumor tissue to the BPC for AALL0932 are provided upon 
request. To request a Specimen Procurement Kit,access the BPC Kit Management system: 
https://ricapps.nationwidechildrens.org/KitManagement/ Specimen procurement kits must be shipped to 
the BPC, Monday through Thursday for delivery Tuesday through Friday. 
 
1. Before the frozen tissue is placed into the Specimen Procurement Kit, it must first be placed in 
3 separate layers of packaging: 
a. Place the tissue in a zip lock bag. 
b. Place the zip lock bag in the plastic watertight biohazard diagnostic envelope and seal the 
envelope securely. 
c. Place the clear plastic biohazard diagnostic envelope inside the pressure-proof Tyvek 
diagnostic envelope and seal securely. 
 
2. Place the tissue inside the kit compartment with dry ice. Layer the bottom of the compartment with 
dry ice until it is approximately one-third full. Place the frozen specimens on top of the dry ice. 
Cover the specimens with the dry ice until the compartment is almost completely full. 
 
3. Place the transmittal form inside the compartment. 
 
4. Place the Styrofoam lid on top to secure specimens during shipment. 
 
5. Close the outer lid of the Specimen Procurement Kit and tape with filament or other durable sealing 
tape. 
 
6. Access the BPC Kit Management system at: 
 
https://ricapps.nationwidechildrens.org/KitManagement/ 
 
Print a Federal Express shipping label. A blank adhesive label is provided in the Specimen 
Procurement Kit to use when printing the shipping label. Attach the shipping label to the top of the 
kit. Complete the dry ice label (UN 1845). Stick the dry ice and Exempt Human Specimen labels 
to the side of the kit. Arrange for Federal Express pick-up per your usual institutional procedure or 
by calling 1(800) 238-5355. 
 
Ship specimens to: 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 

 
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Phone: (614) 722-2865 
 
* The room number is required. Packages not listing the room number could be denied and returned to 
sender. 
 
14.9 
Optional Studies of Genomic Variation 
 
14.9.1 Sample Collection 
A blood sample at Day 29 is being requested specifically for the purpose of providing constitutional 
(germline) DNA from each B-LLy patient. Whenever possible, an aliquot of diagnostic BM or PB will also 
be set aside for extraction of somatic tumor DNA. In some cases, RNA may be used as the starting material. 
 
Peripheral Blood Collection Procedures for Reference Laboratories for B-LLy: 
a. For studies of genomic variation, 5 mL of PB on Day 29 should be placed in plastic, purple, EDTA 
tubes. DO NOT SHIP SYRINGES. 
 
Specimen 
Study 
Laboratory 
Peripheral blood 5 mL 
Studies of Genomic Variation 
Molecular Reference Laboratory 
 
14.9.2 Sample Shipping 
B-LLy peripheral blood samples will be shipped to the Molecular reference laboratory. 
 
Molecular Laboratory 
Julie Gastier-Foster, PhD 
COG ALL Reference Laboratory 
Nationwide Children’s Hospital 
700 Children's Drive, C1961 
Columbus, OH 43205 
Contact Person: Yvonne Moyer 
Phone: (614) 722-2866 
Fax: (614) 722-2887 
Email: Julie.Gastier-Foster@nationwidechildrens.org 
 
FOR SAMPLES THAT ARE EXPECTED TO BE DELAYED FOR MORE THAN 48 HOURS - 
PLACE A COLD PACK (NOT ICE PACK) IN SHIPMENT. ALL TUBES SHOULD BE LABELED 
WITH AT LEAST THREE PATIENT IDENTIFIERS, INCLUDING THE NAME, DATE OF 
BIRTH, AND THE COG NUMBER. IN ADDITION, A SPECIMEN TRANSMITTAL FORM 
AVAILABLE ON THE RDE SHOULD ALWAYS BE SUBMITTED WITH EACH SAMPLE. 
 
Call Reference Laboratory only when shipping a sample to be delivered on Saturday.  
 
Samples for the Molecular Reference Laboratory should be mailed by FEDERAL EXPRESS PRIORITY 
(DELIVERY BEFORE 10 AM) using the COG Federal Express account number available at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf  
 
 
 
15.0 
THE PATIENT LEUKEMIA EXPERIENCE ANCILLARY STUDY:  
ASSESSMENT OF BURDEN OF THERAPY FOR CHILDREN WITH AVERAGE RISK 
ACUTE LYMPHOBLASTIC LEUKEMIA (AR B-ALL) ENROLLED IN COG AALL0932 AS 
MEASURED BY, PATIENT QUALITY OF LIFE, MISSED SCHOOL/WORK, AND PARENT’S 

 
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PERCEPTION OF HEALTH VULNERABILITY, PHYSICAL FUNCTIONING, AND 
EMOTIONAL DISTRESS  
 
15.1 
Correlative Study Design: 
As of April 19, 2013, the PLES has met accrual goals and is closed to new patient enrollment. 
However, institutions are required to continue data collection at remaining evaluation time points, 
for patients already enrolled on this study. 
 
15.1.1 Eligibility Criteria:  
1. 
Enrolled on AR B-ALL post-Induction arm of AALL0932. 
2. 
At least one parent must have speaking and writing knowledge of English (because of instrument 
availability). 
3. 
Age ≥ 4 years at time of study consent (validated age ranges of instruments). 
4. 
No history of pre-leukemia diagnosis of neurodevelopmental disorder (i.e. Down syndrome, 
autism, seizure disorder). 
 
15.1.2 Consent 
This Patient Leukemia Experience (PLE) ancillary study is embedded in the AR arm of AALL0932. 
Consent for this study is incorporated into the consent for the AR arm, which occurs at the conclusion of 
Induction therapy. Patients who enroll on the AR arm of AALL0932 can elect to enroll on this ancillary 
study as an option, not a requirement. 
 
15.1.3 Data Collection 
The required observations for enrollees on the Patient Leukemia Experience ancillary study are included 
on AALL0932 roadmaps. At the scheduled time points (described below), the study surveys are completed 
by parents. The surveys are administered at the time of the clinic visit in hard copy and completed by the 
end of the clinic visit. Institutions receive these survey tools by email upon enrollment to this correlative 
study. In addition, the gender-specific survey instruments are located in the Data Collection/Specimens 
section of the AALL0932 protocol webpage. To insure data fidelity, except for the BASC-2 PRS, data will 
be entered systematically by the clinical research associates (CRAs) via the RDE system. The BASC-2 PRS 
data forms will be sent to COG via DocuSam by the CRA’s at which time the researchers at the Yale site 
will enter the data. For any issues related to the ancillary study, contact may be made to Moira Whitley 
(moira.whitley@yale.edu) or the Patient Leukemia Ancillary Study Chair, Dr. Kadan-Lottick (nina.kadan-
lottick@yale.edu) 
 
The total time needed to complete the assessments will be about 25 - 35 minutes for each of the first four 
time points and about 60 minutes for the last time point, which is a similar length of time in the currently 
successful AALL0331 ancillary study. The instruments were selected based on extensive validation in 
children with cancer and/or life-threatening illness, sensitivity to treatment related burdens relevant to the 
proposed therapies, ease of administration by ancillary staff and brevity: 
 
1) Baseline Demographic/Family Survey (~10 minutes) (PLE Demographics Questionnaire): 
Questions related to education, family income, and family structure; are completed by 
parent. 
 
2) Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) (< 4 minutes): 
(PLE Form A) 23 items with responses on 5 point Likert scale. This instrument measures 
the child’s quality of life, yielding separate scales for physical, emotional, social, and 
school functioning. The Parent Version (validated for ages ≥ 2 years) is administered for 
all participants.98 
 

 
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3) Family life with Leukemia Survey (10 minutes): (PLE Form B) Asks the parents questions 
regarding the family’s school and work status. 
 
4) The Family Assessment Device (FAD) - General Functioning Subscale (~5 minutes): (PLE 
Form C) This is an extensively used questionnaire to assess family functioning, including 
that of hospitalized children experiencing chronic illness.99 Parents rate the extent to which 
each statement describes their family on a 4 point scale ranging from 1 (strongly agree) to 
4 (strongly disagree). Cutoff points for unhealthy family functioning100,101 and reliability 
has been established.102 The General Functioning Subscale relies on 12 questions. 
 
5) Child Vulnerability Scale (~ 5 minutes): (PLE Form D) The parent completes the Child 
Vulnerability Scale103, which assesses parent’s perceptions of children’s general 
vulnerability to health problems. This 8 item scale uses a 4 point Likert scale ranging from 
0 (Definitely False) to 3 (Definitely True). A sample item includes “I often think about 
calling the doctor about my child.” The scale is scored by summing responses and higher 
scores reflect greater perceived vulnerability. The Child Vulnerability Scale has an internal 
consistency alpha of 0.74103 and a test-retest reliability coefficient of 0.84.104 
 
6 
Behavior Assessment Scales of Children – Second Edition, Parent Rating Scale (BASC-2 
PRS) (~10-20 minutes): (PLE Form E) The parent completes the BASC-2 PRS29, a 
questionnaire that assesses the emotional (e.g. anxiety, depression, somatization), 
behavioral (e.g. hyperactivity, aggression, withdrawal), and adaptive functioning (e.g. 
social skills, functional communication, adaptability) of children and adolescents. The 
BASC-2 PRS contains 134 - 160 items and uses a 4 choice response format. Scores are 
scaled so that a T-score greater than or equal to 70 is clinically significant and a T-score 
between 60 and 69 falls within the at risk range. For the Adaptive Scale a T-score under 30 
is clinically significant. Assessment with this tool will be performed only at the last data 
collection point – i) Eighteen months after the beginning of Maintenance (off therapy time 
point for girls, ii) Thirty months after the beginning of Maintenance (off therapy time point 
for boys; girls will not be evaluated at this time point). 
 
15.1.4 Evaluation Schedule 
 
There will be 5 time points for collection of data (4 for girls; 5 for boys): 
1. End of Consolidation (~ 2 months after diagnosis): sometime between Day 15 of 
Consolidation and prior to Day 1 of Interim Maintenance I  
2. End of first month of Maintenance (~ 8 months after diagnosis - Day 29 of Maintenance 
Cycle #1) 
3. Ten months after beginning of Maintenance (Day 29 of Maintenance Cycle #4) 
4. Eighteen months after beginning of Maintenance (off-therapy time point for girls; Day 29 
of Maintenance Cycle #7 for boys) 
5. Thirty months after beginning of Maintenance (off-therapy time point for boys; girls 
will not be evaluated at this time point) 
 
The end-Consolidation is the first feasible time point to get a baseline evaluation because average risk status 
will not be determined until the end of Induction. The first time point may be completed as early as Day 15 
of Consolidation to as late as Day 29 of Consolidation/Day 1 of Interim Maintenance I so all patients are at 
least 2 weeks after the previous dose of vincristine and at least 3 weeks after completion of the 
dexamethasone pulse. For the other time points, there will be a 1 month grace period to collect the data, i.e. 
data must be collected at the designated time point or within 1 month after that time point. If the evaluation 
day also includes intrathecal chemotherapy, the evaluation will be done prior to the procedure. 

 
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Table 15.1.4.1 
 
Demographic 
Questionnaire 
 
(PLE 
Demographics 
questionnaire) 
PedsQL 
 
 
 
(PLE Form A) 
Family Life 
with Leukemia 
 
 
(PLE Form B) 
Family 
Assessment 
Device 
 
(PLE Form C) 
Child 
Vulnerability 
Scale 
 
(PLE Form D) 
BASC- 2 PRS 
 
 
 
(PLE Form E) 
End of Consolidation  
(After Day 15, but 
before start of IM#I) 
X 
X 
X 
X 
X 
 
End of first month of 
Maintenance (Day 29 of 
Maintenance Cycle #1). 
 
X 
X 
X 
X 
 
Day 29 of Maintenance 
Cycle #4 
 
X 
X 
X 
X 
 
Day 29 of Maintenance 
Cycle #7 (boys)/End of 
therapy (girls) 
 
X 
X 
X 
X 
X 
(girls only) 
End of therapy (boys) 
 
X 
X 
X 
X 
X 
 
 
15.2 
Specific Hypotheses 
The treatment of pediatric cancer poses a significant burden to the child and their family. We propose to 
assess this burden by quantifying the following elements related to care: 1) patient quality of life, including 
emotional distress and physical functioning, 2) missed days of school/daycare by patients and work by 
parents, and 3) parent perception of the child’s health vulnerability. 
 
A child’s physical, emotional, school, and peer functioning can all be disrupted by the acute toxicities of 
specific therapeutic agents as well as the need to miss school and interaction with peers which treatment 
demands. Certain chemotherapy agents have been shown to adversely affect emotional and physical 
functioning, aspects of the child’s quality of life. Specifically, dexamethasone and vincristine are associated 
with pain from myopathy19 and peripheral neuropathy, respectively.20 Further, dexamethasone is also 
associated with emotional liability, aggressive behaviors, and depression.105 Dexamethasone therapy has 
been associated with depression and anxiety in the clinically distressing range during therapy in about 30% 
- 45% of ALL patients.26,105 About 45% of children enrolled on the HRQOL component of AALL0331 have 
depression symptoms in the at-risk/clinical range at the beginning of Maintenance, several weeks after the 
last dexamethasone pulse (Kadan-Lottick, 2009, unpublished data). 
 
Rates of absenteeism are 4 times higher for children with cancer as compared to the general school-age 
population, missing 21 to 45 days of school per year.106-108 Intermittent and prolonged absences from school 
are disruptive to the child’s academic progress and social relationships, particularly for those children who 
had learning or social vulnerabilities prior to the cancer diagnosis.109-111 While some medical professionals 
may urge parents to maintain normalcy by keeping their child in school and participating in social activities, 
parents have expressed the considerable difficulty in doing so given hospital visits, changes in mobility and 
the need to manage symptoms and painful procedures.112 
 
Children with serious illnesses such as leukemia are at increased risk of being viewed as abnormally 
susceptible to illness or death, even after they are fully recovered.103,104 The term vulnerable child describes 
a child who is perceived in this way by his/her parents. Continued parental fears can result in abnormal 
interactions between the parents and their child that in turn adversely affect normal child development.27 
For example, children who are perceived as vulnerable have been shown to avoid school and have more 

 
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internalizing problems, including separation and social anxiety.110,111,113,114 Studies in premature infants, 
children hospitalized for infectious illnesses, and infants with congenital abnormalities suggest that it is the 
parents’ understanding and beliefs about the problems that determines perceptions of vulnerability, not 
what is understood by the physician. Parents whose children are randomized to less intensive therapy during 
Maintenance may be more reassured that their child is on a positive trajectory to recovery. 
 
The nonmedical burden of illness to families of children with cancer can be substantial.31,115,116 Many 
families experience lost income or productivity associated with providing care to the child.31 In one United 
States study of 70 families of children with cancer, over half of the families experienced financial hardship 
amounting to more than 20% of the weekly family income.117 Many parents, mainly mothers, will resign or 
reduce outside employment in order to care for their child.30,116  
 
In assessing average risk patients, overall, we will generate needed data that will inform future intervention 
studies to provide supportive care in the domains most affected for patients and their family. Specifically, 
we will learn the optimal timing of interventions for the non-survival outcomes that are most impacted. 
 
15.3 
Specific Aims 
Specific Aim 1: To assess prospectively the burden of AR B-ALL therapy in children enrolled in COG 
AALL0932 compared to published normative data, with respect to the following: 
1. Child’s quality of life as reported by parent 
2. Missed days of school/daycare/work by patients and their parents  
3. Parental perception of the child’s health vulnerability 
4. Physical functioning in daily age-appropriate activities 
5. Emotional functioning 
 
Specific Aim 2: To compare the relative burden of AR B-ALL therapy in children randomized to every 
4 week (Arm A and B) vs. every 12 week (Arm C and D) dexamethasone/vincristine pulses during 
Maintenance on COG AALL0932 as measured by the child’s quality of life, missed days of 
school/daycare/work by patients and their parents, parental perception of the child’s health vulnerability, 
physical functioning, and emotional functioning, standardized to published normative data on validated 
instruments. 
 
 

 
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15.4 
Statistical Design  
 
Specific Aim 1 
The first specific aim is to evaluate whether or not children treated for Average Risk B-ALL have clinically 
significant impairment in the child’s quality of life (measured by PedsQL), missed days of 
school/daycare/work by patients and their parents, parental perception of the child’s health vulnerability 
(assessed by Child Vulnerability Scale), and emotional functioning (measured by the BASC-2 PRS). The 
primary data analysis will be of PedsQL scores. Standardized scores for the sub-scales of the PedsQL 4.0 
will be calculated using age and gender specific normative data. Values will be age and, where appropriate, 
gender standardized, and compared between the children with ALL and the population normative values 
with a one-sample t-test.118 If the data are not normally distributed, a non-parametric equivalent will be 
used.119 To achieve over 90% power with a two sided alpha level of 0.001 (adjusted for multiple 
comparisons); we require a sample size of 169 children to detect a 0.3 standard deviation difference between 
the children with ALL and the published normative values on each of the sub-scales at each of the time 
points. 
 
Specific Aim 2 
The second specific aim seeks to determine how child quality of life measures in children with Average 
Risk B-ALL vary as a function of randomization to every 12 weeks or every 4 weeks DEX/VCR pulses 
during Maintenance. The overall objective is to identify (1) if every 12 weeks DEX/VCR pulses results in 
enhanced quality of life compared to every 4 weeks DEX/VCR pulses at 2 (girls) or 3 (boys) time points 
during Maintenance and at the end of therapy. Assessments of the child will be completed beginning with 
a baseline prior to the start of Maintenance therapy at the end of the Interim Maintenance II phase of therapy. 
The first time point will be used as a baseline to confirm that functioning in the 2 therapy groups is similar 
prior to the start of Maintenance therapy; data from the subsequent 3 time points will be the outcomes of 
interest. We will compare differences in means (of the continuous measures) between the 2 randomization 
groups with 2 sample t-tests. Values will be normalized for age and gender prior to comparison. If the 
continuous data are not normally distributed, a non-parametric statistical measure will be used. 
 
The primary data analysis will be of Pediatric Quality of Life Instrument scores. Standardized scores for 
the sub-scales of the Pediatric Quality of Life Instrument will be calculated using age and gender specific 
normative data. The primary analysis will consist of comparing scaled outcomes in the 4 separate domains 
of emotional, physical, school, and social functioning at the 3 repeated measures, adjusted for age, gender, 
and family income. Sample size calculations based on a 2-sided alpha level of 0.01 (to adjust for the multiple 
comparisons of 4 sub-scales of quality of life) to achieve 90% power. A minimum sample of 240 patients 
in each of the post-Induction groups is needed in a design with 3 repeated measurements having a 
Compound Symmetry covariance structure when the standard deviation is 1, the correlation between 
observations on the same subject is 0.5, and the alpha level is 0.01, to detect group differences of 0.3 
standard deviations. This difference is validated as being in the small to moderate effect size range.98  
 
Data analysis will also be done to compare missed days of school/daycare by patients and work by parent, 
family functioning, measured by the FAD, parent perception of child vulnerability (measured by the Child 
Vulnerability Scale), and emotional symptoms (measured by the BASC-2 PRS), adjusting for age, gender, 
and family income.  
 
It is not a specific aim to examine quality of life outcomes in patients randomized to the different 
methotrexate doses. Methotrexate was not associated with physical or emotional impairment at the higher 
40 mg/m2/week oral dose during continuation therapy in a study of 243 children with ALL enrolled in the 
Dallas-Fort worth protocol, except for largely self-limited sub-clinical transaminitis11 Oral methotrexate 
has been associated with subtle changes in the attentional and executive functioning domains of 
neurocognitive functioning, but typically these changes develop years after diagnosis and require 

 
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standardized performance-based neuropsychological instruments for detection.71,120 We would not expect 
any detectable differences during therapy and with a self-reported instrument. To verify that oral 
methotrexate is not associated with the measured quality of life outcomes, we will perform post-hoc 
analyses comparing the 20 mg/m2 (groups A and C) and 40 mg/m2 (groups B and D) oral methotrexate 
groups. 
 
Patient Accrual: 
Based on recently observed attrition rates of about 25% on the HRQOL component of COG AALL0331 
due to relapse, death, and study withdrawal, 276 patients in each of the two randomization groups (600 
overall) will be required to adequately assess Specific Aim 2 and is more than adequate for Specific Aim 
1. As stated above in the description of the therapeutic study, a total of 2996 AR patients will be accrued 
over 4.9 years. Based on past studies, we estimate that 90% are English speaking and 90% are at least 4 
years of age, yielding 1,747 potentially eligible participants (364 per year) for the AR B-ALL ancillary 
study. Assuming 75% participation on this ancillary study, the needed 600 patients will be enrolled in 
approximately 20 months corresponding to a 30 patient/month enrollment rate. 
 
15.5 
Significance 
Cancer treatment is a burden to children and their families in terms of the parents’ perception of their child’s 
vulnerability, the child’s general quality of life including emotional distress and physical functioning, and 
the disruption to the child and family. This includes school and work absenteeism, which has implications 
for academic progress and adequate socialization for the child, as well as economic loss for the parent and 
family. These concepts have been understudied among those children undergoing average risk treatment 
for ALL. Quantifying the extent to which these areas are affected in children and their families will directly 
inform the development of interventions designed to ameliorate their impact, including their timing and 
focus. 
 
In addition, we will have the data to compare severity of these issues between patients on a 
dexamethasone/vincristine pulse schedule of every 4 weeks versus every 12 weeks. This comparison will 
be especially useful to inform future clinical trials if event free survival does not differ significantly between 
the two arms, but the burden of therapy is worse in one or the other arm. Because we will have standardized, 
informative data regarding the burden of therapy, we will have sufficient data to plan future intervention 
studies to ameliorate functional outcomes regardless of which regimen moves forward in subsequent 
therapeutic studies. 
 
 

 
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16.0 
THE LEUKEMIA PHYSICAL FUNCTIONING STUDY: 
LONGITUDINAL ASSESSMENT OF PERIPHERAL NEUROPATHY AND MOTOR 
FUNCTION IN CHILDREN TREATED FOR AVERAGE RISK ACUTE LYMPHOBLASTIC 
LEUKEMIA (AR B-ALL)  
 
16.1 
Correlative Study Design: 
As of March 15, 2013, the LPFS has met accrual goals and is closed to new patient enrollment. 
However, institutions are required to continue data collection at remaining evaluation time points, 
for patients already enrolled on this study. 
 
16.1.1 Eligibility Criteria:  
1. 
Enrolled on the Average Risk arm of AALL0932 at one of the limited participating sites 
(available on the AALL0932 protocol webpage) within the Children’s Oncology Group 
2. 
At least 1 parent must have speaking and writing knowledge of English or Spanish 
3. 
Age ≥ 3 years at time of study consent (age ranges of instruments used in validation or 
other studies) 
4. 
No history of neurodevelopmental disorder prior to leukemia diagnosis (i.e. Down 
syndrome, autism, seizure disorder) 
 
16.1.2 Consent 
This Leukemia Physical Functioning ancillary study is embedded in the AR arm of the AALL0932 
therapeutic study. Consent for this study is attached in an amendment into the consent for enrollment on 
the AR Arm, which occurs at the conclusion of Induction therapy. Patients who enroll on the average risk 
arm of AALL0932 can elect to enroll on this ancillary study as an option, not a requirement.  
 
16.1.3 Data Collection 
The required observations for enrollees on the neuropathy ancillary study are included on AALL0932 
roadmaps. At the scheduled time points (described below in 16.1.4), which coincide with regularly 
scheduled clinic visits, participants will undergo an approximately 45 minute functional and parent-report 
evaluation by a pediatric physical therapist or occupational therapist. All measures are widely-used, non-
invasive assessments that would be within the scope of practice of any licensed physical therapist or 
occupational therapist that assesses children in the clinical setting. The assessments were chosen to measure 
all of the key elements of chemotherapy associated neuropathy in a valid fashion, but without redundancy. 
We included complementary assessments of actual day to day functioning by performance tests and parent 
report. Institutions receive the data tools by email upon enrollment to this correlative study. In addition, the 
gender specific survey instruments are located on the Data Collection/Specimens section of the AALL0932 
protocol webpage. Data entry occurs via eRDES. For issues related to the ancillary study, contact may be 
made to Moira Whitley (moira.whitley@yale.edu) or the Leukemia Physical Functioning Study Chair, Dr. 
Nina Kadan-Lottick (nina.kadan-lottick@yale.edu). 
 
The following table displays the evaluation of standardized measures that will be completed at each of the 
4 time points:  

 
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Table 16.1.3.1. Assessment of Peripheral Neuropathy and Motor Function 
Parameter Assessed 
Test/method 
Time to Complete 
(minutes) 
Peripheral Sensation in the upper 
and lower extremities 
Peripheral assessment using the Semmes 
Weinstein monofilaments (SWM) 
5 
Peripheral vibratory perception in 
the upper and lower extremities 
Vibration using a 128 Hz Rydel-Seiffer tuning 
fork 
3-5 
Peripheral motor functioning in 
the upper extremities  
Handgrip strength assessed by a dynamometer 
(exclude if < 4 years at evaluation time point) 
2 
Peripheral motor functioning in 
the lower extremities 
Isometric ankle dorsiflexion strength assessed 
by a myometer 
10 
Flexibility in the lower 
extremities 
Active and passive ankle range of motion 
assessed by a goniometer 
5 
Proximal motor functioning  
Sit-ups and push-ups  
(if ≥ 4 years at evaluation time point) 
 
Manual assessment of proximal muscle strength 
(if 3 - 3.9 years at evaluation time point) 
3 - 5 
Fine motor dexterity in the upper 
extremities 
Purdue Pegboard 
5 
Lower extremity daily function 
6 Minute Walk with timer. 
10 
Child report of child’s pain and 
other sensory symptoms 
Sensory Symptoms question from the Pediatric-
Modified Total Neuropathy Scale 
3 
Parent report of child daily 
physical functioning 
Pediatric Outcome Data Collection (PODCI) 
Instrument 
15  
(completed by parent) 
Parent report of child’s quality of 
life 
Pediatric Quality of Life Inventory (PedsQL) 
instrument 
5  
(completed by parent) 
Total duration: ~ 45 minute functional evaluation  
(with 25 minute concurrent parent surveys) 
 
The approximately 45 minute evaluation will be done in the order described in the table above to ensure 
reliability across examiners, patients, and time points. For Spanish speaking patients, the hands-on 
evaluation will be done with translation by an interpreter. The 2 parent report instruments are validated in 
Spanish, as well as English. The parent report instruments will not extend the time of the evaluation because 
they will be completed by the parent concurrently while the child is undergoing the functional evaluation. 
 
The physical therapists will complete a brief clinical research form at the time of each evaluation recording 
the history of physical therapy and occupational therapy since the last evaluation (or since diagnosis at the 
first time point) including the indications, frequency, and duration.  
 
Different aspects of actual day to day functioning are assessed with a combination of performance-based 
and parent report measures: the Purdue Pegboard, the 6 Minute Walk, the PODCI parent-report instrument, 
and the PedsQL parent-report instrument. The Purdue Pegboard is a measure of fine motor dexterity which 
is needed in many activities of daily functioning such as buttoning, dressing, and playing with small 
objects.121 Walking is an essential lower extremity motor activity of individuals of all ages > 2 years. Parent 
report of specific age-appropriate activities and quality of life provide insights that may not be elicited 
during the physical therapy evaluation, but which reflect meaningful impairment.  
 
To help distinguish between corticosteroid-associated myopathy and vincristine-associated neuropathy, we 
will assess the patient’s ability to do sit-ups and push-ups for patients ≥ 4 years, for which there are 
normative data. These tasks rely almost entirely on proximal strength functioning and are impaired in 
steroid-associated myopathy. For patients 3.0 - 3.9 years of age, proximal strength in the upper and lower 
extremities will be assessed manually and rated from zero (no movement) to five (normal power). 
Myopathy is characteristically symmetric proximal weakness that may or may not be associated with 

 
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muscle pain and cramps.122 In contrast, vincristine associated neuropathy is usually peripheral in 
distribution and would more likely affect fine motor functioning, handgrip strength, ankle strength, and 
ankle range of motion. In terms of discomfort, vincristine associated neuropathy typically presents as 
paresthesias in the distal extremities, and rarely pain.123 We will ask the children to report on their sensory 
symptoms with a short question from the Pediatric-Modified Total Neuropathy Scale that asks if “any parts 
of your body are tingly, numb (can hardly feel), or hurt” and the location of symptoms reported.124 Because 
the definitive tests of nerve and muscle biopsy would be too invasive,122 we will rely on the pattern of 
deficits to help distinguish neuropathy from myopathy. Impairment in proximal strength without peripheral 
involvement will be categorized as myopathy. Impairment in peripheral strength without proximal 
involvement will be categorized as neuropathy. Concomitant proximal and peripheral impairment will be 
categorized as indeterminate with likely contributions by both myopathy and neuropathy. 
 
The sit-ups/push-ups and handgrip measures only have normative data for children ≥ 4 years (see further 
details about each measure below). These 2 measures will be excluded for patients who are not yet 4 years 
at the evaluation time point. As discussed above, for patients 3.0 to 3.9 years of age, proximal strength in 
the upper and lower extremities will be assesses manually and rated from zero (no movement) to five 
(normal power). This will only affect children enrolled at the age of 3.0 to 3.9 years for the first, and possibly 
the second, time point(s). 
 
Measures included in the focused evaluation have established validity in young children with peripheral 
neuropathy, availability of standardized normative data, a history of successful administration in both the 
research and clinical settings, and, when available, past studies in children with cancer and/or life-
threatening illness.  
 
16.1.4 Evaluation Schedule 
There will be 4 time points for collection of data  
1) Between Day 15 of Consolidation Phase and prior to Day 1 of Interim Maintenance I  
2) End of first month of Maintenance Phase ( Day 29 of Maintenance Cycle #1) 
3) 18 months after starting the Maintenance Phase (Day 29 of Maintenance Cycle #7 for boys and 
end of therapy for girls) 
4) 12 months after end of therapy (both boys and girls) 
 
The beginning of Consolidation is the first feasible time point to get an evaluation because average risk 
status will not be determined until the end of Induction. The first time point will measure the effects of the 
first 5 almost weekly vincristine doses. Time point 2 will assess the effect of 14 doses of vincristine during 
the 24 weeks of Interim Maintenance I, Delayed Intensification I, and Interim Maintenance II, and the first 
4 weeks of Maintenance. By specifying Day 29 of Cycle #1 of Maintenance (i.e. time point 2), all patients 
will be approximately 4 weeks after the last dose of vincristine and will not be scheduled for a procedure 
that day. Time points 3 will indicate how functioning varies during monthly vs. every 3 month vincristine 
therapy. Time point 4 will represent the 12 month off-therapy evaluation for girls and boys to measure 
whether any impairment is persistent in the immediate off-therapy period. 
 
The first time point may be completed as early as Day 15 of Consolidation but prior to Day 1 of Interim 
Maintenance so all patients are at least 2 weeks after the previous dose of vincristine and at least 3 weeks 
after completion of the dexamethasone pulse. In extraordinary circumstances, a one week grace period can 
be allowed for the collection of first time point data after obtaining LPFS Study Chair approval (nina.kadan-
lottick@yale.edu). For the other time points, there will be a 1 month grace period to collect the data, i.e. 
data must be collected at the designated time point or within 1 month after that time point. If the evaluation 
day also includes intrathecal chemotherapy, the evaluation will be done prior to the procedure. 
 

 
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16.1.4.1 Table of measures administered at specific time points: 
 
Physical 
Therapist/Occupational 
Therapist Intake Form   
Sensory  and 
Motor 
Symptoms  
Assessment 
 
 
 
(LPFS Form A) 
Physical 
Functioning 
Therapy 
Assessments 
 
 
 
(LPFS Form B) 
(PODCI) 
 
 
 
 
 
 
(LPFS Form C) 
PedsQL 
 
 
 
 
 
 
(LPFS Form D) 
End of Consolidation  
(After Day 15 but before 
start of IM#I) 
X 
 
X 
X 
X 
X 
End of first month of 
Maintenance (Day 29 of 
Maintenance Cycle #1). 
X 
X 
X 
X 
X 
~18 months after starting 
Maintenance (Day 29 of 
Maintenance Cycle #7 
for boys) 
End of therapy for girls 
X 
X 
X 
X 
X 
12 months after end of 
therapy for both boys 
and girls 
X 
X 
X 
X 
X 
 
16.1.5 Strategies to Enhance Feasibility and Data Fidelity 
Limited institutions within the COG were chosen to participate in this study primarily based on the 
availability of physical therapists who are expert in assessing chemotherapy-associated peripheral 
neuropathy and success with previous ancillary studies of non-survival outcomes.  
 
We conservatively estimate that 75% of patients who enroll on the average risk component of the 
therapeutic study at centers participating in this HRQOL study will also consent to the neuropathy 
ancillary study. An ongoing, multi-site interventional study of neuropathy in children undergoing therapy 
for acute lymphoblastic leukemia has enrolled 27 of the 28 eligible patients to date (RO1CA129384 [Ness- 
Co-Investigator], Dr. Kirsten Ness, personal communication, May 10, 2010). Also, for the current standard 
risk ALL therapeutic study in COG, AALL0331, almost 90% of eligible patients have enrolled on the 
embedded health related quality of life ancillary study (Buchanan et al., Abstract presented at American 
Society of Clinical Oncology in Chicago, IL, 2008). Therefore, we believe that our projections are 
reasonable and our study is feasible. 
 
Site principal investigators at the selected institutions are oncology or nursing investigators known to be 
committed to enrolling patients on studies of physical functioning outcomes in cancer patients. Sites were 
not considered if they had competing research protocols that would potentially influence the development 
of peripheral neuropathy in ALL patients (e.g. neuropathy intervention studies), or if they did not have 
adequate clinic time and/or space to do the required study observations.  
 
At the beginning of the study, the responsible physical therapist or occupational therapist from each 
participating site will review a DVD explaining study procedures that will be prepared by Dr. Ness. In this 
DVD, Dr. Ness will demonstrate all the study assessments on a model patient and explain how to handle 
frequently handled challenges. In the DVD, overall education regarding study procedures and quality 
control of data will be described. The physical therapist (or occupational therapist) at each site will be 
required to achieve 90% proficiency on a written test of study procedures after reviewing the DVD. Dr. 

 
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Ness will communicate individually with therapists who require additional assistance to achieve the target 
proficiency goal.  
 
A comprehensive manual describing the step-by-step procedures used to collect, record, store, transmit and 
manage data will be provided for each site. The physical therapists will also undergo yearly performance 
reviews on their proficiency with the study procedures. As stated above, all measures are routinely used 
assessments that would be within the scope of practice of any licensed physical therapist or occupational 
therapist who evaluates children for movement disorders in the clinical setting. To maintain data fidelity, 
therapists will participate in quarterly conference calls to discuss study progress and challenges. 
 
16.2 
Background and Specific Hypotheses 
 
16.2.1  Background 
Recent COG trials data project that children with Average Risk Acute Lymphoblastic Leukemia (ALL) will 
have 5 year event free survival rates of 90% - 95%. Because most patients are anticipated to be long-term 
survivors, optimal care includes the identification and clinical management of the toxic effects of 
chemotherapy severe enough to negatively quality of life. A 2009 review of 28 studies evaluating physical 
activity and exercise during childhood cancer treatment found considerably reduced physical activity during 
and after treatment.125 This review emphasized the need for exploration into the pathology underlying these 
deficits.  
 
Vincristine is an established and integral component of therapy for childhood ALL. Unfortunately, 
vincristine is also associated with acute and long term peripheral neuropathy that can adversely affect the 
fine motor skills needed in learning18 and gross motor abilities important to mobility.32,126 Although 
peripheral neuropathy can adversely affect function, oncologists and nurses typically do not have the skills 
needed to accurately assess and grade this toxicity. Performance data obtained by physical therapists who 
are expert in the evaluation of movement are needed to characterize the severity (grade), latency, and 
persistence of vincristine associated toxicity. This information will inform the timing and scope of 
subsequent screening and intervention trials. 
 
Pathophysiology of Vincristine Toxicity 
Vincristine, a vinca alkaloid, binds with tubulin and blocks polymerization into microtubules, resulting in 
arrest of mitosis in metaphase. This mechanism also affects axonal transport.127 Structural changes in the 
cytoskeleton of large myelinated axons and accumulation of neurofilaments in dorsal sensory ganglion 
neurons have been documented in animal studies.128 Reports also indicate that vincristine can unmask 
underlying hereditary neuropathies129 and that a drug interaction between vincristine and antifungal azoles 
may exacerbate a mild neuropathy.32,130-132 Animal and human studies indicate that the rate of vincristine 
clearance is associated with age, perhaps accounting for higher rates of vincristine neurotoxicity among 
adolescents and young adults.133,134  
 
Vincristine Is Associated With both Acute and Long Term Neuropathy 
Acute axonal peripheral neuropathy has been documented in children during ALL treatment and is likely 
associated with vincristine administration. This distal polyneuropathy can be initially uncomfortable, 
affecting both sensory and motor functions. Bed rest and immobility during neuropathy contribute to muscle 
wasting and can be accompanied by a loss in ankle and wrist dorsiflexion range of motion. Reinders-
Messelink et al135 reported mild deficits in vibratory perception, reduced amplitude of action potentials in 
median, ulnar and fibular sensory nerves, and mild muscle weakness in 11 children after receiving 8 doses 
of vincristine at 1.5 mg/m2 per dose for remission induction and intensification therapy.  
 
While some previous reports have dismissed this acute effect of chemotherapy as transient, recent findings 
indicate that many survivors have long-term neuropathy.136 Harila-Saari et al 137evaluated motor evoked 

 
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potentials (MEPs) in 32 children upon completing treatment for ALL and found prolonged latencies in both 
upper and lower extremity axons when responses were compared to an age, gender and height matched 
control group. Wright et al.138 reported 10 degree differences in ankle dorsiflexion range of motion when 
they compared ALL survivors at least 1 year off therapy to age and gender matched normal controls. Harila-
Saari et al57 utilized somatosensory evoked potentials (SEP) to evaluate central and peripheral axonal 
integrity in 31 childhood ALL survivors who were at least 2 years off therapy. When compared to age and 
gender matched controls, median nerve stimulation in ALL survivors demonstrated prolonged SEP 
latencies at the level of the brachial plexus and spinal cord, as well as prolonged latencies at the level of 
spinal cord and cortex with tibial nerve stimulation at the knee. Lehtinen et al139 showed that peripheral 
neuropathy persisted as long as 5 years off-therapy as measured by MEPs in 27 children treated for ALL.  
 
Impact on Daily Life 
Hand function is necessary for all aspects of daily life. Sensation, dexterity and strength are required for 
object manipulation during play, during eating, during dressing and bathing, and keyboarding and 
manipulating electronic devices as the child ages and eventually reaches adulthood and starts work. Hands 
are used to touch, to assist with communication and to help convey emotion. A child with a painful, 
insensate or weak hand will not be able to participate in day to day activities consistent with his or her role 
as a child. 
 
Several studies have documented that peripheral neuropathy in children treated for ALL often manifests as 
handwriting problems. Reinders-Messelink et al135 reported that ALL patients draw slower with longer 
pauses and increased drawing pressure. A separate report showed that handwriting difficulties persisted 
2 years after completing therapy.140 Handwriting is felt to be important by educators because it is essential 
to school success. Children spend 31% - 60% of their school hours in handwriting and other fine motor 
activities.141 Even in the current computer age, difficulties can impede other higher order skills such as 
spelling, essay composition, note-taking, and expression of ideas.142 Fine motor skills are needed for self-
care skills such as dressing with buttons and zippers as well as using standard and small keyboards (e.g. 
calculator, cell phones). 
 
Many ALL survivors report physical disability that adversely affects their daily life. Physical performance 
limitations were documented in 14.6% of adult ALL survivors in the Childhood Cancer Survivor Study 
cohort, impacting their ability to attend work or school and their participation in recreational physical 
activity.143 Among adult survivors of ALL, only 42.9% self-report regular participation in physical activity 
compared to 51.3% of siblings (p < 0.05).144 Small changes in muscular strength correspond to large change 
in function in other populations.145  
 
Dose-Related Vincristine Toxicity 
Previous investigators found no association between motor performance and vincristine dose among a 
heterogeneous sample of childhood cancer survivors.146 However, we recently evaluated 321 adult 
survivors of childhood ALL treated with vincristine at St. Jude Children’s Research Hospital and 
documented problems with ankle range of motion in 36.3%, sensation in 4.7%, vibration in 12.0%, deep 
tendon reflexes in 14.7% and ankle dorsiflexion strength in 21.2% of these young adults.144 Ankle range of 
motion limitations were associated with reduced balance, mobility and ambulation skills in this 20+ year 
survivor population. After adjusting for both cranial radiation and methotrexate doses, total cumulative 
vincristine doses above 32 mg/m2 were associated with ankle active dorsiflexion less than 5 degrees. 
Children enrolled on the standard regimen of the AR arm of AALL0932 are scheduled to receive 39 mg/m2 
(girls) to 57 mg/m2 (boys). 
 
Vincristine Toxicity is Amenable to Intervention 
Early identification of children at risk for peripheral neuropathy is important because there are interventions 
to ameliorate physical impairments so that the child will not experience long term functional loss. Wright 

 
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et al 147 studied 40 children who received an individualized stretching and bracing program during treatment 
for ALL, measuring range of motion at multiple times during the course of disease therapy and then after 
therapy was completed. When compared to a historical control group, among whom 33% of age and sex-
matched children with ALL had passive dorsiflexion range of motion less than 10 degrees, none of the 
children who participated in the individualized stretching and bracing program lost dorsiflexion range of 
motion. 
 
Intervention is necessary because children with impaired motion and strength are at risk for injury and less 
than optimal participation in daily activities. Tabrizi et al148 documented an association between frequent 
ankle injury and decreased ankle range of motion in healthy children. Full ankle range of motion is 
necessary for normal walking speed149 and for complex upright tasks, like stair climbing150 and participation 
in sports.151-153  
 
Limitations with Current COG Resources 
Currently, COG clinical trials only ascertain peripheral neuropathy outcomes in a limited fashion based on 
the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) categorization 
from assessment by pediatric oncology physicians. There are at least 2 major challenges in relying on 
CTCAE reporting. First, CTCAE categories are too broad and insensitive for clinically meaningful 
differences. Second, in clinical practice, physicians do not routinely ask about and test for peripheral 
neuropathy. Most physicians lack the expertise and time to accurately and comprehensively measure 
peripheral neuropathy. Therefore, physicians under-report the incidence and severity of chemotherapy 
associated peripheral neuropathy.154,155 Neuropathy assessment is ideally done by a pediatric physical 
therapist trained in chemotherapy associated neuropathy. Most institutions do not have the resources to 
provide physical therapists at oncology clinic visits and COG per case reimbursement does not provide 
funds for this purpose. Thus, it would be impossible to conduct this research in the setting of the usual COG 
ALL protocols. 
 
The CTCAE data are not adequate to inform clinical management of symptoms and the timing of 
interventions that can limit patients’ participation in developmentally appropriate physical activity and 
learning. Critical data are needed regarding the timing, progression, and severity of peripheral neuropathy 
in ALL patients. The current study sample is particularly informative because we will have the data to 
compare the severity of neuropathy associated with monthly vs. every 3 month vincristine dosing. Because 
we will have high quality peripheral neuropathy data for both vincristine schedules, we will have sufficient 
data to plan future intervention studies to ameliorate functional outcomes regardless of which regimen 
moves forward in subsequent therapeutic studies. 
 
Summary 
Peripheral neuropathy is a toxicity that was previously under appreciated, and is only recently understood 
to impact long term functioning and quality of life in cancer patients. Children with ALL are at risk for both 
neurosensory and neuromotor impairments as a result of vincristine induced peripheral neuropathy. These 
impairments interfere with touch and vibration perception, ankle motion, ankle and hand strength, fine 
motor skill, balance and visual motor integration. In turn, these functional limitations impact normal 
movement (i.e. walking, running, jumping) and the normal developmental activities of childhood. 
Interventions are available to address these impairments, and if implemented early may ameliorate long 
term functional loss. Increased understanding of the pathophysiology causing these impairments is crucial 
to developing early intervention programs to prevent these deficits in the future. 
 
The current practice of reporting peripheral neuropathy based on patient self-report and physician 
assessment through the CTCAE system results is too crude to accurately assess the incidence and severity 
of this toxicity and does not allow for accurate assessment of the effect of treatment interventions. 
Functional assessments by a trained physical therapist are needed to determine the timing, progression, and 

 
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severity of peripheral neuropathy in ALL patients. The selected tests are feasible, focused, and objective, 
but are too expensive to be funded by usual clinical trial consortium or cancer control resources. The current 
study will yield important data on the incidence, severity, and natural history of vincristine induced 
peripheral neuropathy in childhood ALL and is a critical first step needed in order to plan future intervention 
trials. 
 
Knowledge of the onset and progression of peripheral neuropathy in children during treatment for ALL will 
inform screening guidelines and allow intervention to be implemented at the right time during the course 
of therapy. Early attention to small sensory and motor loss will prevent large losses in function as the child 
progresses through the course of therapy. Data from this study will also be informative for children at risk 
for vincristine associated neuropathy in other cancers. For example, treatment regimens for Wilm’s tumor, 
rhabdomyosarcoma, and many central nervous system tumors include significant doses of vincristine that 
often lead to clinical neuropathies. This study thus represents a unique opportunity to understand the natural 
history of peripheral neuropathy in oncology patients.  
 
16.2.2. Specific Aims and Hypotheses:  
Specific Aim 1: To characterize the onset, severity, and natural history of vincristine-associated neuropathy 
by physical therapists in children undergoing therapy for Average Risk Acute Lymphoblastic Leukemia. 
We hypothesize the following: 
 
Hypothesis 1: Children treated for Average Risk ALL will have clinically significant neurosensory 
impairments and functional loss at both 1) the end of consolidation therapy after 5 doses of vincristine, and 
2) the end of Interim Maintenance II/Beginning of Maintenance immediately after receiving an additional 
13 doses of vincristine over approximately 24 weeks.  
 
Hypothesis 2: Children will have improved, but still sub-normal, neurosensory integrity and function during 
Maintenance therapy, as assessed 18 months after beginning the Maintenance phase of therapy. 
 
Hypothesis 3: Children will not demonstrate complete recovery of neurosensory integrity and function 
12 months after completing therapy. 
 
Specific Aim 2: To compare the severity of vincristine associated neuropathy in children with Average Risk 
Acute Lymphoblastic Leukemia randomized to every 4 week vs. every 12 week vincristine therapy during 
Maintenance. 
 
Hypothesis 4: Children randomized to every 4 week vincristine pulses during Maintenance will have more 
severe neurosensory impairments and functional losses than those randomized to every 12 week vincristine 
pulses. 
 
 

 
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16.3 
Statistical Design 
 
16.3.1 Analysis of Aim 1 to characterize the onset, severity, and natural history of vincristine-associated 
neuropathy by physical therapists in children undergoing therapy for Average Risk Acute Lymphoblastic 
Leukemia. 
 
Because healthy children perform differently on tests of neuromotor performance based on their age, body 
weight, height, and sometimes sex, we will calculate for comparison, a set of expected mean values for 
each measure of performance (based on published normative data) that matches the distribution of our 
population. Strength in the ankle dorsiflexors is the primary outcome for the sample size calculations; we 
then calculate the minimal detectable difference for the other outcome measures based on the calculated 
sample size (displayed in Table 16.3.1.1 below). For example, a healthy 4 year old boy, on average, can 
generate 71 ± 22 Newtons of isometric force with his ankle dorsiflexors. A healthy 4 year old girl, on 
average can generate 75 ± 20 Newtons of force with her ankle dorsiflexors. If our population includes 
70 boys and 60 girls who are all (hypothetically) 4 years of age, then our population comparison mean and 
standard deviation for dorsiflexion strength would be: 
 
(70*71) + (60*75))/130 ± ((70*22) + (60*20))/130 = 72.8 ± 21.1 Newtons. 
 
This value will be compared at the first time point to our measured value with a 2 sample t-test using the 
formula: 
 
  x1      -   x2 
√s12      s22 
  n1        n2 
 
Using the ankle dorsiflexion strength measure as our primary outcome, with 130 children enrolled on the 
study and a 2-sided alpha level set at 0.0055 for the 9 different performance measures (0.05 divided by 9, 
Bonferroni adjustment), we have 90% power to detect 10.6 Newtons or a 0.5 standard deviation between 
the measured values and the expected values. At the second, third and fourth time points, the measured 
performance outcomes will be compared to expected performance outcomes (expected normative values 
will represent baseline time) using repeated measures analysis of variance (time as the dependent variable) 
in order to account for within participant correlation between measures. 
 
Table 16.3.1.1 below demonstrates expected values and minimally detectable differences between expected 
and measured values on each of our performance measures. On the measures where a threshold of 
performance indicates an abnormality (sensation, vibration) the outcome is binomial. In those cases we will 
utilize a 2 sided binomial test to detect differences between the population expected and the measured 
proportions of children with ALL who have disordered function and generalized linear mixed models to 
allow for within person correlation when evaluating each outcome over time.   
+

 
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Table 16.3.1.1 
Measure 
Published Mean or 
Threshold for 
abnormality 
Published 
Standard 
Deviation 
Minimally 
detectable 
difference 
Reference 
source 
 
Mechanical 
pressure 
1.36 Newton 
meters (log 
transformed) 
0.35 Newton 
meters (log 
transformed) 
0.18 Newton 
meters (log 
transformed) 
156 
Vibration  
7.62 x/8 
0.42 x/8 
0.21 x/8 
156 
Handgrip strength  
47.5 Newtons 
12.3 Newtons 
6.2 Newtons 
157 
Isometric ankle 
dorsiflexion 
strength  
72.8 Newtons 
21.1 Newtons 
10.6 Newtons 
158 
Ankle dorsiflexion 
18.1 degrees 
6.9 degrees 
3.5 degrees 
150,159 
Sit-ups and push-
ups  
6 repetitions 
3 repetitions 
3 repetitions 
2 repetitions 
1.5 repetitions 
1 repetition 
160 
Purdue Pegboard 
9.33 seconds 
1.81 seconds 
0.91 seconds 
121 
Six minute walk 
519.2 Meters 
92.9 Meters 
46.5 Meters 
161 
 
To gain further insights regarding the burden of peripheral neuropathy, we plan to analyze associations 
between quality of life outcomes from the PedsQL and 1) participation in age appropriate activities on the 
PODCI, and 2) performance on the Purdue Pegboard and 6 Minute Walk. 
 
16.3.2 Analysis of Aim 2 to compare the severity of vincristine associated neuropathy in children with 
Average Risk Acute Lymphoblastic Leukemia randomized to every 4 week vs. every 12 week vincristine 
therapy during Maintenance. 
 
We will test the hypothesis that children randomized to every 4 week vincristine pulses during Maintenance 
will have more severe neurosensory impairments and functional losses than those randomized to every 12 
week vincristine pulses. Both boys and girls will be evaluated and compared 18 months after starting 
maintenance. Differences in performance on between the two groups of patients on the tests of motor 
performance will also be evaluated with 2 sample t-tests. With 65 participants per group and a 2-sided alpha 
value of 0.0055 (allowing for multiple comparisons, we have 80% power to detect a 0.63 standard deviation 
difference between the 2 groups at the end of treatment. 
 
16.3.3 Patient Accrual 
We project that 75% of patients enrolled on the therapeutic study will be eligible and also enroll on the 
neuropathy study annually at select participating centers. The total annual accrual on the Average Risk ALL 
therapeutic study will be ~89 patients annually at the COG sites selected for the current ancillary neuropathy 
study based on past COG logs. Overall, we will enroll about 67 patients, estimated as 75% of 89 patients, 
per year at the participating sites. This corresponds to about 5 - 6 patients per month for a total of 24 months 
to meet our accrual goals. 
 
16.4 
Significance 
Peripheral neuropathy is a toxicity that was previously under appreciated, but is now understood to impact 
long term functioning and quality of life in cancer patients. Children with ALL are at risk for both 
neurosensory and neuromotor impairments as a result of vincristine induced peripheral neuropathy. These 
impairments interfere with touch and vibration perception, ankle motion, ankle and hand strength, fine 
motor skill, balance and visual motor integration. These functional limitations impact daily activities and 
eventually, academic performance. Interventions are available to address these impairments, and if 

 
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implemented early may ameliorate long term functional loss. This project will generate needed data that 
could not be supported through the usual COG consortium mechanism.  
 
An increased understanding of the pathophysiology causing these impairments is crucial to the design of 
future clinical trials that test early intervention programs designed to prevent and/or ameliorate these 
deficits. In addition, we will have the data to compare severity and progression of peripheral neuropathy 
between a vincristine schedule of every 4 weeks versus a vincristine schedule of every 12 weeks. This 
comparison would be useful to inform future clinical trials if event free survival does not differ between 
the 2 arms, but the incidence and severity of peripheral neuropathy is worse in one or the other arm. This 
may be particularly relevant because the therapeutic study is powered to detect a 3% difference between 
the treatment arms. Because we will have high quality peripheral neuropathy data for both vincristine 
schedules, we will have sufficient data to plan future intervention studies to ameliorate functional outcomes 
regardless of which regimen moves forward in subsequent therapeutic studies. 
 
Generalizing beyond ALL, vincristine is used extensively in multiple other pediatric cancer conditions, 
including rhabdomyosarcoma, neuroblastoma, central nervous system tumors, and lymphoma. AALL0932 
provides the opportunity to characterize the incidence and natural history of peripheral neuropathy in a 
population that is not confounded by administration of other drugs associated with peripheral neuropathy 
(e.g. cisplatinum) or nervous system deficits often present in patients with brain tumors. This population 
allows an opportunity to evaluate the potential contributions of vincristine toxicity to neurosensory 
outcomes in these other populations. Data from this study will thus inform other disease group monitoring 
or interventions in the future. 
 
 
 

 
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APPENDIX I: MERCAPTOPURINE DOSING GUIDELINES 
 
 
MERCAPTOPURINE 75 mg/m2  
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 
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 

 
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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 II: THIOGUANINE DOSING GUIDELINES 
 
THIOGUANINE 60 mg/m2 
Body Surface 
Area (m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 40 mg) 
Cumulative 
Weekly Dose 
0.31 - 0.35 
½ tab / d x 7 
140 mg/wk 
0.36 - 0.40 
½ tab / d x 6; 1 tab / d x 1 
160 mg/wk 
0.41 - 0.45 
½ tab / d x 5; 1 tab / d x 2 
180 mg/wk 
0.46 - 0.49 
½ tab / d x 4; 1 tab / d x 3 
200 mg/wk 
0.50 - 0.54 
1 tab / d x 4; ½ tab / d x 3 
220 mg/wk 
0.55 - 0.59 
1 tab / d x 5; ½ tab / d x 2 
240 mg/wk 
0.60 - 0.64 
1 tab/ d x 6; ½ tab / d x 1 
260 mg/wk 
0.65 - 0.69 
1 tab / day 
280 mg/wk 
0.70 - 0.73 
1 tab / d x 6; 1½ tab / d x 1 
300 mg/wk 
0.74 - 0.78 
1 tab / d x 5; 1½ tab / d x 2 
320 mg/wk 
0.79 - 0.83 
1 tab/ d x 4; 1½ tab / d x 3 
340 mg/wk 
0.84 - 0.88 
1½ tab / d x 4; 1 tab / d x 3 
360 mg/wk 
0.89 - 0.92 
1½ tab / d x 5; 1 tab /d x 2 
380 mg/wk 
0.93 - 0.97 
1½ tab / d x 6; 1 tab / d x 1 
400 mg/wk 
0.98 - 1.02 
1½ tab /day 
420 mg/wk 
1.03 - 1.07 
1½ tab / d x 6; 2 tab / d x 1 
440 mg/wk 
1.08 - 1.11 
1½ tab / d x 5; 2 tab / d x 2 
460 mg/wk 
1.12 - 1.16 
1½ tab / d x 4; 2 tab / d x 3 
480 mg/wk 
1.17 - 1.21 
2 tab / d x 4; 1½ tab / d x 3 
500 mg/wk 
1.22 - 1.26 
2 tab / d x 5; 1½ tab / d x 2 
520 mg/wk 
1.27 - 1.30 
2 tab / d x 6; 1½ tab / d x 1 
540 mg/wk 
1.31 - 1.35 
2 tab / day 
560 mg/wk 
1.36 - 1.40 
2 tab / d x 6; 2½ tab / d x 1 
580 mg/wk 
1.41 - 1.45 
2 tab / d x 5; 2½ tab / d x 2 
600 mg/wk 
1.46 - 1.49 
2 tab / d x 4; 2½ tab / d x 3 
620 mg/wk 
1.50 - 1.54 
2½ tab / d x 4; 2 tab / d x 3 
640 mg/wk 
1.55 - 1.59 
2½ tab / d x 5; 2 tab / d x 2 
660 mg/wk 
1.60 - 1.64 
2½ tab / d x 6; 2 tab / d x 1 
680 mg/wk 
1.65 - 1.69 
2½ tab / d 
700 mg/wk 
1.70 - 1.73 
2½ tab / d x 6; 3 tab / d x 1 
720 mg/wk 
1.74 - 1.78 
2½ tab / d x 5; 3 tab / d x 2 
740 mg/wk 
1.79 - 1.83 
2½ tab / d x 4; 3 tab / d x 3 
760 mg/wk 
1.84 - 1.88 
3 tab / d x 4; 2½ tab / d x 3 
780 mg/wk 
1.89 - 1.92 
3 tab / d x 5; 2½ tab / d x 2 
800 mg/wk 
1.93 - 1.97 
3 tab / d x 6; 2½ tab / d x 1 
820 mg/wk 
1.98 - 2.02 
3 tab / d x 7 
840 mg/wk 
2.03 - 2.07 
3 tab / d x 6; 3½ tab / d x 1 
860 mg/wk 
2.08 - 2.11 
3 tab / d x 5; 3½ tab / d x 2 
880 mg/wk 
2.12 - 2.16 
3 tab / d x 4; 3½ tab / d x 3 
900 mg/wk 
2.17 - 2.21 
3½ tab / d x 4; 3 tab / d x 3 
920 mg/wk 
2.22 - 2.26 
3½ tab / d x 5; 3 tab / d x 2 
940 mg/wk 
2.27 – 2.30 
3½ tab / d x 6; 3 tab / d x 1 
960 mg/wk 
2.31 – 2.35 
3½ tab / d x 7 
980 mg/wk 

 
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200 
2.36 – 2.40 
3½  tab / d x 6; 4 tab / d x 1 
1000 mg/wk 
2.41 – 2.45 
3½  tab / d x 5; 4 tab / d x 2 
1020 mg/wk 
2.46 – 2.49 
3½ tab / d x 4; 4 tab / d x 3 
1040 mg/wk 
2.50 – 2.54 
4 tab / d x 4; 3½  tab / d x 3 
1060 mg/wk 
2.55 – 2.59 
4 tab / d x 5; 3½  tab / d x 2 
1080 mg/wk 
2.60 – 2.64 
4 tab / d x 6; 3½  tab / d x 1 
1100 mg/wk 
2.65 – 2.69 
4 tab / d x 7 
1120 mg/wk 
2.70 – 2.73 
4  tab / d x 6; 4½ tab / d x 1 
1140 mg/wk 
2.74 – 2.78 
4  tab / d x 5; 4½ tab / d x 2 
1160 mg/wk 
2.79 – 2.83 
4 tab / d x 4; 4½ tab / d x 3 
1180 mg/wk 
2.84 – 2.88 
4½ tab / d x 4; 4  tab / d x 3 
1200 mg/wk 
2.89 – 2.92 
4½ tab / d x 5; 4  tab / d x 2 
1220 mg/wk 
2.93 – 2.97 
4½ tab / d x 6; 4  tab / d x 1 
1240 mg/wk 
2.98 – 3.00 
4½ tab / d x 7 
1260 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their TG doses calculated on 
actual BSA with no maximum dose. 
  
 

 
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APPENDIX III: MERCAPTOPURINE DOSING GUIDELINES 
 
MERCAPTOPURINE 50 mg/m2 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly 
Dose 
0.33 - 0.39 
½ tab / d x 5 
125 mg/wk 
0.40 - 0.46 
½ tab / d x 6 
150 mg/wk 
0.47 - 0.53 
½ tab / d x 7 
175 mg/wk 
0.54 - 0.60 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.61 - 0.67 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.68- 0.74 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.75 - 0.82 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.83 - 0.89 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.90 - 0.96 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.97 - 1.03 
1 tab / d x 7 
350 mg/wk 
1.04 – 1.10 
1 tab / d x 6; 1½ tab / d x 1 
375 mg/wk 
1.11 - 1.17 
1 tab / d x 5; 1½ tab / d x 2 
400 mg/wk 
1.18 - 1.24 
1 tab / d x 4; 1½ tab / d x 3 
425 mg/wk 
1.25 - 1.32 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
1.33 - 1.39 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
1.40 - 1.46 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
1.47 - 1.53 
1½ tab / d x 7 
525 mg/wk 
1.54 - 1.60 
1½ tab / d x 6; 2 tab / d x 1 
550 mg/wk 
1.61 - 1.67 
1½ tab / d x 5; 2 tab / d x 2 
575 mg/wk 
1.68 - 1.74 
1½ tab / d x 4; 2 tab / d x 3 
600 mg/wk 
1.75 - 1.82 
2 tab / d x 4; 1½ tab / d x 3 
625 mg/wk 
1.83 - 1.89 
2 tab / d x 5; 1½ tab / d x 2 
650 mg/wk 
1.90 - 1.96 
2 tab / d x 6; 1½ tab / d x 1 
675 mg/wk 
1.97 - 2.03 
2 tab / d x 7 
700 mg/wk 
2.04 – 2.10 
2 tab / d x 6; 2½ tab / d x 1 
725 mg/wk 
2.11 – 2.17 
2 tab / d x 5; 2½ tab / d x 2 
750 mg/wk 
2.18 – 2.24 
2 tab / d x 4; 2½ tab / d x 3 
775 mg/wk 
2.25 – 2.32 
2½ tab / d x 4; 2 tab / d x 3 
800 mg/wk 
2.33 – 2.39 
2½ tab / d x 5; 2 tab / d x 2 
825 mg/wk 
2.40 – 2.46 
2½ tab / d x 6; 2 tab / d x 1 
850 mg/wk 
2.47 – 2.53 
2½ tab / d x 7 
875 mg/wk 
2.54 – 2.60 
2½ tab / d x 6; 3 tab / d x 1 
900 mg/wk 

 
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2.61 – 2.67 
2½ tab / d x 5; 3 tab / d x 2 
925 mg/wk 
2.68 – 2.74 
2½ tab / d x 4; 3 tab / d x 3 
950 mg/wk 
2.75 – 2.82 
3 tab / d x 4; 2½ tab / d x 3 
975 mg/wk 
2.83 – 2.89 
3 tab / d x 5; 2½ tab / d x 2 
1000 mg/wk 
2.90 – 2.96 
3 tab / d x 6; 2½ tab / d x 1 
1025 mg/wk 
2.97 – 3.00 
3 tab / d x 7 
1050 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated on 
  
 

 
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APPENDIX IV: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL0932 
(for children from 7 through 12 years of age) 
 
Standard Risk B-Lymphoblastic Leukemia 
 
1 
We have been talking with you about Acute Lymphoblastic Leukemia or ALL. ALL is a type of cancer 
that grows in the bone marrow. The bone marrow is inside your bones. It is where your blood is made. 
After doing tests, we have found that you have this type of cancer. 
 
2 
We are asking you to take part in a research study because you have Standard Risk ALL. A research 
study is when doctors work together to try out new ways to help people who are sick. In this study, we 
want to learn more about how to treat ALL and reduce the bad effects of the anticancer drugs. We will 
do this by trying different ways to treat ALL and seeing which one works better. We don’t know which 
way is better. That is why we are doing this study. 
 
3 
Children who are part of this study will receive a treatment called chemotherapy. Chemotherapy is 
medicine that kills cancer. Children who are part of this study will get the usual treatment doctors use 
for ALL. Some of the children will get extra chemotherapy and some will get less chemotherapy. You 
will also have regular blood tests and several bone marrow tests and spinal taps during your treatment. 
These tests help doctors in deciding the most appropriate treatment for your ALL. The bone marrow 
tests and spinal taps may hurt some, but medicines will be given to keep it from hurting too much. 
 
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 getting rid of the cancer 
for as long as possible, and with fewer bad effects; 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 increased toxicities that can cause infections or make 
it harder for a patient to fight off infections, loss of healthy blood cells and damage to bones or joints. 
Steroid drugs, such as dexamethasone, are known causes of a disease called “osteonecrosis” (ON). 
Osteonecrosis results from the temporary or permanent loss of the blood supply to the bones. Without 
blood, the bone tissue dies and causes the bone to breakdown. ON is most commonly seen in the hip 
joint. If the bones near a joint breakdown it can cause the joint to collapse. The exact reason why 
corticosteroids cause ON is not known. We hope that a reduced exposure to steroids such as 
dexamethasone will reduce the likelihood of some of the risks associated with treatment for ALL. We 
do not know this for sure which is why we are doing this study. 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. 
   
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY AALL0932 
(for children from 7 through 12 years of age) 
 
Localized B-Lymphoblastic Lymphoma 
 
1 
We have been talking with you about localized B-lymphoblastic lymphoma or B-LLy. B-LLy is a 
type of cancer that can grow in the lymph system that is made up of lymph nodes and other tissue 
throughout the body, helping to fight infections and keep the body healthy. Lymph nodes are 
located all over your body. After doing tests, we have found that you have this type of cancer and 
it is only located in one particular area in the body. 
 
2 
We are asking you to take part in a research study because you have localized B-LLy. A research 
study is when doctors work together to try out new ways to help people who are sick. In this study, 
we want to learn more about how to treat B-LLy and reduce the bad effects of the anticancer drugs. 
All patients with B-LLy on this study will receive the same treatment but we would like to learn 
more of how these patients are doing and whether we can find out which patients are doing better 
or worse. That is why we are doing this study. 
 
3 
Children who are part of this study will receive a treatment called chemotherapy. Chemotherapy is 
medicine that kills cancer. Children who are part of this study will get the treatment similar to that 
for children with B-ALL, a similar kind of cancer that affects the bone marrow. You will have 
regular blood tests, bone marrow tests, spinal taps and scans during your treatment. These tests help 
doctors in deciding the best treatment for your B-LLy. The bone marrow tests and spinal taps may 
hurt some, but medicines will be given to keep it from hurting too much. 
 
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 getting rid of the 
cancer for as long as possible, and with fewer bad effects; 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 increased bad effects that can cause infections 
or make it harder for a patient to fight off infections, loss of healthy blood cells and damage to 
bones or joints. Steroid drugs, such as dexamethasone, are known causes of a condition called 
“osteonecrosis” (ON). Osteonecrosis results from the temporary or permanent loss of the blood 
supply to the bones. Without blood, the bone tissue dies and causes the bone to breakdown. ON is 
most commonly seen in the hip joint. The exact reason why corticosteroids cause ON is not known. 
We do not know for sure why these bad effects happen, which is why we are doing this study. 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, as well as to use some tumor tissue to 
perform some special studies. These studies will help us better understand B-LLy. These samples 
would be taken when other standard tests are being performed. You can still be treated on this study 
even if you don't want to take part in these special studies.  

 
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INFORMATION SHEET REGARDING RESEARCH STUDY AALL0932 
(for children from 13 through 17 years of age) 
 
Localized B-Lymphoblastic Lymphoma 
1 
We have been talking with you about localized B-lymphoblastic lymphoma or B-LLy. B-LLy 
is a type of cancer that occurs in the lymph system, which is made up of the lymph nodes and 
other lymph tissue throughout the body. Lymph tissue makes and stores infection-fighting 
white blood cells called lymphocytes. These cells begin to grow in a disorderly fashion and no 
longer perform their usual function when a subject has lymphoma. After doing tests, we have 
found that you have this type of cancer and it is only located in a restricted area (localized). 
 
2 
We are asking you to take part in a research study because you have localized B-LLy. A 
research study is when doctors work together to try out new ways to help people who are sick. 
In this study, we want to learn more about how to treat B-LLy and reduce the bad effects of the 
anticancer drugs. All patients with B-LLy on this study will receive the same treatment but we 
would like to learn more of how these patients are doing and whether we can find out which 
patients are doing better or worse. We do not know these things, which is why we are doing 
this study. 
 
3 
Children who are part of this study will receive a treatment called chemotherapy. 
Chemotherapy is medicine that kills cancer. Children who are part of this study will get the 
same treatment given to children with B-ALL (a similar kind of cancer that affects the bone 
marrow), but with one difference during the phase of therapy called Maintenance - you will 
have the same duration of Maintenance therapy whether you are male or female, unlike 
Maintenance for B-ALL, where male patients get treatment for longer. If you have Down 
syndrome and B-LLy (DS B-LLy), you will get exactly the same treatment given to patients 
with DS B-ALL. You will have regular blood tests and several bone marrow tests and spinal 
taps during your treatment. You will also have scans performed to make sure the B-LLy is 
responding to treatment. These tests help doctors in deciding the most appropriate treatment 
for your B-LLy. The bone marrow tests and spinal taps may hurt some, but medicines will be 
given to keep it from hurting too much. 
 
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 getting 
rid of the cancer for as long as possible, and with fewer bad effects; 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 increased toxicities that can cause 
infections or make it harder for a patient to fight off infections, loss of healthy blood cells and 
damage to bones or joints. Steroid drugs, such as dexamethasone, are known causes of a disease 
called “osteonecrosis” (ON). Osteonecrosis results from the temporary or permanent loss of 
the blood supply to the bones. Without blood, the bone tissue dies and causes the bone to 
breakdown. ON is most commonly seen in the hip joint. If the bones near a joint breakdown it 
can cause the joint to collapse. The exact reason why corticosteroids cause ON is not known. 
We do not know for sure why these toxicities and side effects occur, which is why we are doing 
this study. 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. 

 
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7 
We are asking your permission to collect additional blood, as well as to use some left over 
tumor tissue to perform some special studies. These studies will help us better understand B-
LLy. Some of the studies involve studying the lymphoma cells using special tests to help us 
understand better, why some patients may responds differently to treatment given for 
lymphoma. These samples would be taken when other standard tests are being done, so there 
will be no extra procedures performed. You can still be treated on this study even if you don't 
want to take part in these special studies.  
 
 
 

 
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APPENDIX V: STAGING CLASSIFICATION OF CHILDHOOD NON-HODGKIN 
LYMPHOMA 
 
 
 

 
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APPENDIX VI:  CTEP REGISTRATION PROCEDURES 
 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
investigators participating in any NCI-sponsored clinical trial to register and to renew their registration 
annually. 
 
Registration requires the submission of: 
 
 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
 
a current Curriculum Vitae (CV) 
 
a completed and signed Supplemental Investigator Data Form (IDF) 
 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please contact 
the CTEP Investigator Registration Help Desk by email at <pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a 
web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of 
NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator 
Registration Procedures above for information on registering with CTEP as an Investigator, which must be 
completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact the CTEP 
Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
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 1100 
      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. 
 
 

 
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APPENDIX VII:  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 
 
Chloramphenicol 
 
Cyclosporine 
 
Digoxin  
 
Etanercept  
 
Hydrochlorothiazide 
 
Indomethacin 
 
Nevirapine 
 
Pentostatin  
 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide** 
 
St. John’s Wort 
 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Cytarabine (by vein) 
Drugs that may interact with cytarabine* 
 
Clozapine, digoxin, flucytosine, leflunomide 
 
Food and supplements that may interact with cytarabine** 
 
Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
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  
o Caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 
Arthritis medications  
o Leflunomide, tofacitinib 
 
Anti-rejection medications 

 
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o Cyclosporine, sirolimus, tacrolimus 
 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, 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 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Doxorubicin 
Drugs that may interact with doxorubicin* 
 
Some antiepileptics (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, fosphenytoin) 
 
Some antiretrovirals (stavudine, zidovudine) 
 
Other agents, such as clozapine, cyclosporine, verapamil, and warfarin 
 
Food and supplements that may interact with doxorubicin** 
 
Echinacea 
 
Glucosamine  
 
St. John’s Wort 
 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Leucovorin 
Drugs that may interact with leucovorin* 
 
Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
 
Food and supplements that may interact with leucovorin** 
 
Folic acid 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 

 
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Mercaptopurine 
Drugs that may interact with mercaptopurine* 
 
Artiritis medications: leflunomide, tofacitinib 
 
Other medications, such as allopurinol, azathioprine, clozapine, febuxostat, natalizumab, 
olsalazine, sulfasalazine, warfarin 
 
Food and supplements that may interact with mercaptopurine** 
 
Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Methotrexate (by mouth or by vein) 
Drugs that may interact with methotrexate* 
 
Some antibiotics (amoxicillin, Bactrim, chloramphenicol, ciprofloxacin, penicillin, 
piperacillin, tetracycline) 
 
Some anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, naproxen, ketorolac) 
 
Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole) 
 
Several other specific agents, including the following: amiodarone, clozapine, cyclosporine, 
eltrombopag, leflunomide, phenytoin, pimecrolimus, probenecid, pyrimethamine, retinoids, 
theophylline, warfain 
 
Food and supplements that may interact with methotrexate** 
 
Alcohol 
 
Echinacea 
 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Pegaspargase 
Drugs that may interact with pegaspargase* 
 
Leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with pegaspargase** 
 
Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
 
 

 
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Thioguanine 
Drugs that may interact with thioguanine* 
 
Arthritis medications: leflunomide, tofacitinib 
 
Other medications, such as allopurinol, clozapine, natalizumab, olsalazine, sulfasalazine 
 
Food and supplements that may interact with thioguanine** 
 Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Vincristine 
Drugs that may interact with vincristine* 
 
Antibiotics  
o 
Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
 
Antidepressants and antipsychotics  
o Aripiprazole, nefazodone, trazodone 
 
Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 
Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
 
Anti-rejection medications 
o Cyclosporine, tacrolimus 
 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tenofovir, tipranavir 
 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
 
Heart medications  
o Amiodarone, digoxin, dronedenarone, propranolol, verapamil 
 
Some chemotherapy (be sure to talk to your doctor about this) 
 
Many other drugs, including the following: 
o Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide, 
warfarin  
 
Food and supplements that may interact with vincristine** 
 
Echinacea 
 
St. John’s Wort 
 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
 
 

 
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