A Phase III Randomized Trial Investigating Bortezomib (NSC# 681239) on a Modified Augmented BFM (ABFM) Backbone in Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LLy)
Phase: PHASE3
Conditions: Adult T Acute Lymphoblastic Leukemia, Ann Arbor Stage II Adult Lymphoblastic Lymphoma, Ann Arbor Stage II Childhood Lymphoblastic Lymphoma, Ann Arbor Stage III Adult Lymphoblastic Lymphoma, Ann Arbor Stage III Childhood Lymphoblastic Lymphoma, Ann Arbor Stage IV Adult Lymphoblastic Lymphoma, Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma, Childhood T Acute Lymphoblastic Leukemia
Sponsor: National Cancer Institute (NCI)

  
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
May 29, 2019 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office 
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #6 to protocol AALL1231, A Phase III Randomized Trial 
Investigating Bortezomib (NSC# 681239; IND# 58443) on a Modified Augmented BFM (ABFM) 
Backbone in Newly Diagnosed T- Lymphoblastic Leukemia (T-ALL) and T- Lymphoblastic 
Lymphoma (T-LLy), for CTEP review. 
 
This amendment is being submitted in response to a Request for Amendment (RRA) from Dr. John 
Wright, dated April 16th 2019. In this amendment, the revised CAEPR for Bortezomib, (Version 2.7, 
March 25, 2019) has been inserted in the protocol and the associated risk information in the 
informed consent document has been revised accordingly. In addition an update has been made to 
reflect CTCAE V5 for CTEP-AERS reporting. Language has also been added regarding permanent 
closure to accrual as of 5/24/19. Revisions to the protocol and consent are detailed in the pages 
below.  
 
The AALL1231 study team looks forward to approval of this amendment. Please let me know if we 
can offer further information. 
 
 
Sincerely, 
 
Arshi Reyaz, MS, Protocol Coordinator (on behalf of) 
 
David Teachey, M.D., Study Chair, AALL1231 
Elizabeth Ann Raetz, M.D., Study Vice Chair, AALL1231 
Meenakshi Devidas, Ph.D., Study Statistician, AALL1231 
Mignon Loh, M.D., ALL Committee Chair 
Peter Adamson, Group Chair, Children’s Oncology Group 
 
 
 

 
AALL1231 SUMMARY OF CHANGES 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. Additions 
are in boldfaced font and deletions in strikethrough font. 
 
Section 
Page 
Comments 
Title Page 
1 
Protocol version date and amendment number have been updated and the closure date was 
added. 
Table of 
Contents 
2-6 
Table of contents has been updated to account for repagination. 
Study 
Committee 
7 
The address for Meenakshi Devidas has been updated.  
6.1 
93-98 
The revised CAEPR for Bortezomib (Version 2.7, March 25, 2019) has been inserted. This 
CAEPR, which was previously in CTCAE 4.0 language (version 2.6), has been migrated to 
CTCAE 5.0 language (version 2.7). There is no new or modified risk information for 
Bortezomib.   
9.3.1.1 
137 
Language added regarding permanent closure to accrual as of 5/24/19. 
11.0 
146-150 
Language was updated to reflect the use of CTCAE V5 throughout.  
 
 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENTS  
(CHANGES BELOW APPLY TO BOTH STUDY CONSENTS) 
In accordance with the above discussion, the following specific revisions have been made to the protocol. Additions 
are in boldfaced font and deletions in strikethrough font. 
Section 
Page 
Comments 
Throughout 
Throughout 
The version date has been updated. 
What side effects or 
risks can I expect from 
being in the study? 
11-12 
The term “muscle spasms” was removed. This risk is captured as part of “pain” under 
Occasional. “Velcade” has been added. Dehydration and weight loss have been 
combined. Additional minor administrative updates have been added. 
 

 
 
AALL1231 
 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 1 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
AALL1231 
 
 
A Phase III Randomized Trial Investigating Bortezomib (NSC# 681239; IND# 58443) on a Modified 
Augmented BFM (ABFM) Backbone in Newly Diagnosed T- Lymphoblastic Leukemia (T-ALL) 
and T- Lymphoblastic Lymphoma (T-LLy) 
 
 
A Groupwide Phase III Study 
 
NCI Supplied Agent: Bortezomib (NSC# 681239; IND# 58443) 
 
Sponsor: CTEP, NCI, DCTD 
Protocol IND: 58443 
 
 
 
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 
 
Name: 
David T. Teachey 
Address: 
The Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard, CTRB 3008 
Philadelphia, PA 19104 
Phone: 
(267) 426-5802 
Fax: 
(215) 590-3770 
E-mail: 
teacheyd@email.chop.edu 
Activated: 
09/29/14 
Version Date:  
05/29/19 
Closed:  
05/24/19 
Amendment  
#6 

 
 
 
AALL1231 
 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 2 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
AALL1231 
1 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
7 
ABSTRACT 
11 
EXPERIMENTAL DESIGN SCHEMA: T-ALL 
12 
EXPERIMENTAL DESIGN SCHEMA: T-LLY (STAGES II-IV) 
13 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
14 
1.1 
Primary Aims 
14 
1.2 
Secondary Aims 
14 
1.3 
Correlative Aims 
14 
2.0 
BACKGROUND 
15 
2.1 
Trial Rationale 
15 
2.2 
Early T cell Precursor ALL (ETP ALL) 
23 
2.3 
Impact 
24 
2.4 
Relevant Pre-clinical Data on Bortezomib 
24 
2.5 
Clinical Experience with Bortezomib 
26 
2.6 
Developmental Plans 
30 
2.7 
Correlative Biology Studies 
31 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
32 
3.1 
Study Enrollment 
32 
3.2 
Patient Eligibility Criteria 
34 
3.3 
DEFINITIONS 
36 
3.4 
RISK STRATIFICATION 
37 
3.5 
PHILADELPHIA CHROMOSOME POSITIVE (Ph+) 
38 
4.0 
TREATMENT PLAN 
39 
4.1 
Overview of Treatment Plan 
39 
4.2 
Concomitant Therapy Restrictions 
40 
4.3 
General Guidelines 
42 
4.4 
INDUCTION ARM A (without bortezomib) 
43 
4.5 
INDUCTION ARM B (with bortezomib) 
45 
4.6 
CONSOLIDATION-All Patients 
48 
4.7 
INTERIM MAINTENANCE with CMTX- – All Patients 
51 
4.8 
DELAYED INTENSIFICATION- Arm A (without bortezomib) 
53 
4.9 
DELAYED INTENSIFICATION Arm B (with bortezomib) 
56 
4.10 
INTERIM MAINTENANCE #1 with HD MTX- ALL INTERMEDIATE RISK 
SUBJECTS 
59 
4.11 
INTENSIFICATION BLOCK 1 (HR1)- ALL VERY HIGH RISK SUBJECTS 
62 
4.12 
INTENSIFICATION BLOCK 2- ALL VERY HIGH RISK SUBJECTS 
65 

 
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4.13 
INTENSIFICATION BLOCK 3 (HR3) ALL VERY HIGH RISK SUBJECTS 
68 
4.14 
MAINTENANCE - All Patients 
71 
5.0 
DOSE MODIFICATION FOR TOXICITIES 
74 
5.1 
Asparaginase [E.coli, Pegaspargase (PEG-Asparaginase) or Erwinia] 
74 
5.2 
Bortezomib Related Toxicities 
76 
5.3 
Cyclophosphamide 
79 
5.4 
Cytarabine (ARAC) 
79 
5.5 
Daunorubicin and Doxorubicin 
80 
5.6 
Etoposide 
80 
5.7 
Ifosfamide 
81 
5.8 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
81 
5.9 
High-Dose Methotrexate (HDMTX) and Leucovorin Rescue 
82 
5.10 
Capizzi Methotrexate Regimens 
86 
5.11 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
87 
5.12 
Steroids (Dexamethasone and Prednisone) 
89 
5.13 
PO 6-Thioguanine (TG) 
90 
5.14 
Vincristine 
90 
6.0 
DRUG INFORMATION 
92 
6.1 
BORTEZOMIB 
93 
6.2 
CYCLOPHOSPHAMIDE - INJECTION 
99 
6.3 
CYTARABINE - ALL ROUTES 
101 
6.4 
DAUNORUBICIN 
103 
6.5 
DEXAMETHASONE 
104 
6.6 
DOXORUBICIN 
106 
6.7 
ETOPOSIDE - INJECTION 
107 
6.8 
FILGRASTIM 
110 
6.9 
HYDROCORTISONE – INTRATHECAL 
111 
6.10 
INTRATHECAL TRIPLES (Methotrexate/Hydrocortisone/Cytarabine, IT-3) 
113 
6.11 
IFOSFAMIDE 
114 
6.12 
LEUCOVORIN CALCIUM 
116 
6.13 
MERCAPTOPURINE 
117 
6.14 
MESNA - INJECTION 
119 
6.15 
METHOTREXATE - All Routes 
120 
6.16 
PEGASPARGASE 
124 
6.17 
THIOGUANINE 
126 
6.18 
VINCRISTINE SULFATE 
127 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
130 
7.1 
Required & Optional Clinical, Laboratory and Disease Evaluations: 
Diagnosis, Induction, Consolidation Arm A and Arm B: T-ALL ONLY 
130 
7.2 
Required & Optional Clinical, Laboratory and Disease Evaluations: 
Diagnosis, Induction, Consolidation: Arm A and Arm B: T-LLy ONLY 
131 
7.3 
Required Clinical, Laboratory and Disease Evaluations Post-Consolidation Therapy: 
Arm A-SR and Arm B-SR (T-ALL and T-LLy) 
132 

 
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7.4 
Required Clinical, Laboratory and Disease Evaluations Post-Consolidation Therapy: 
Arm A-IR and Arm B-IR (T-ALL and T-LLy) 
133 
7.5 
Required & Optional Clinical, Laboratory and Disease Evaluations 
for Arm A-VHR and Arm B-VHR (T-ALL and T-LLy) 
134 
7.6 
Studies Suggested to be Obtained After Stopping Therapy (T-ALL Patients) 
135 
7.7 
Studies Suggested to be Obtained After Stopping Therapy (T-LLy Patients) 
135 
7.8 
At Relapse 
135 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
136 
8.1 
Criteria for Removal from Protocol Therapy 
136 
8.2 
Off Study Criteria 
136 
9.0 
STATISTICAL CONSIDERATIONS 
136 
9.1 
Statistical Design and Endpoints 
136 
9.2 
Patient Accrual and Expected Duration of Trial 
137 
9.3 
Statistical Analysis Methods 
137 
9.4 
Gender and Minority Accrual Estimates 
141 
9.5 
Correlative Studies 
141 
10.0 
EVALUATION CRITERIA 
143 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
143 
10.2 
T-ALL and T-LLy: Relapse 
143 
10.3 
T-ALL: Response 
143 
10.4 
T-LLy: Response 
143 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
145 
11.1 
Purpose 
145 
11.2 
Determination of Reporting Requirements 
145 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
145 
11.4 
Special Situations for Expedited Reporting 
146 
11.5 
Reporting Requirements for Specialized AEs 
148 
11.6 
Exceptions to Expedited Reporting 
149 
11.7 
Reporting Requirements - Investigator Responsibility 
149 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
149 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
150 
11.10 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
151 
11.11 Routine Adverse Event Reporting 
152 
12.0 
RECORDS AND REPORTING 
152 
12.1 
CDUS 
152 
12.2 
CTA/CRADA 
153 
13.0 
PATHOLOGY GUIDELINES FOR T-LLY 
154 
13.1 
Pathology Goals 
154 
13.2 
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
154 
13.3 
Immunophenotyping Recommendations for Primary Institutions 
155 
13.4 
Pathology Staging Criteria 
156 

 
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13.5 
Retrospective Central Pathology Review 
156 
13.6 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse- for T-LLy 
patients not enrolled on Project: Evey Child (APEC14B1) 
158 
14.0 
MRD ANALYSIS GUIDELINES AND REQUIREMENTS 
159 
14.1 
Minimal Residual Disease- Required and Optional Specimens: T-ALL patients 
159 
14.2 
Minimal Residual Disease- Required and Optional Specimens: T-LLy Only 
159 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
159 
15.1 
Evaluating Mechanisms of Bortezomib Response and Resistance in T-ALL and 
Identifying 
160 
15.2 
OPTIONAL TISSUE BANKING 
160 
16.0 
RADIATION THERAPY GUIDELINES 
161 
16.1 
Cranial Radiation Therapy 
161 
16.2 
Testicular Radiation 
163 
16.3 
Quality Assurance Documentation 
164 
16.4 
Definitions of Deviation in Protocol Performance 
165 
APPENDIX I: 
THERAPY DELIVERY MAPS – ARM A (T-ALL AND T-LLY) 
166 
THERAPY DELIVERY MAPS – ARM A-SR  (T-ALL and T-LLy) 
170 
THERAPY DELIVERY MAPS – ARM A-IR  (T-ALL and T-LLy) 
174 
THERAPY DELIVERY MAPS – ARM A-VHR (T-ALL and T-LLy) 
179 
THERAPY DELIVERY MAP – MAINTENANCE ARM A  (T-ALL and T-LLy) 
187 
APPENDIX II: 
THERAPY DELIVERY MAPS – ARM B  (T-ALL AND T-LLY) 
189 
THERAPY DELIVERY MAPS – ARM B-SR  (T-ALL and T-LLy) 
194 
THERAPY DELIVERY MAPS – ARM B-IR  (T-ALL and T-LLy) 
198 
THERAPY DELIVERY MAPS – ARM B-VHR (T-ALL and T-LLy) 
203 
THERAPY DELIVERY MAP – MAINTENANCE ARM B  (T-ALL and T-LLy) 
212 
APPENDIX III: YOUTH INFORMATION SHEETS 
214 
APPENDIX IV: HIGH-DOSE METHOTREXATE FLOWCHART 
218 
APPENDIX V: CYP3A4/5 INHIBITORS AND INDUCERS 
219 
APPENDIX VI: MERCAPTOPURING DOSING TABLE 
219 
APPENDIX VII: THIOGUANINE DOSING TABLE 
222 
APPENDIX VIII: STAGING CLASSIFICATION OF CHILDHOOD NON-HODGKIN 
LYMPHOMA 
228 
APPENDIX IX: MINIMAL RESIDUAL DISEASE-SAMPLE SHIPPING REQUIREMENTS 
229 
APPENDIX X: EVALUATING MECHANISMS OF BORTEZOMIB RESPONSE AND 
RESISTANCE IN T-ALL AND IDENTIFYING BIOMARKERS AND MECHANISMS 
OF CHEMOTHERAPY RESISTANCE AND RESPONSE IN T-ALL, FOCUSING ON 
ETP ALL 
231 
APPENDIX XI: MINIMAL RESIDUAL DISEASE (MRD): DESCRIPTION AND 
CHARACTERIZATION OF ASSAY 
234 

 
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APPENDIX XII: ADDITIONAL INFORMATION FOR PROPOSED BIOLOGY STUDIES: 
STUDIES OF PROTEASOME ACTIVITY, PROTEOMICS, AND SIGNAL 
TRANSDUCTION 
239 
APPENDIX XIII:  CTEP AND CTSU REGISTRATION PROCEDURES 
264 
APPENDIX XIV POSSIBLE DRUG INTERACTIONS 
266 
REFERENCES 
274 
 
 
 

 
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
David T. Teachey, MD 
Keith Jason August, MD MSc 
Hematology/Oncology 
Hematology/Oncology 
The Children’s Hospital of Philadelphia 
Children's Mercy Hospitals and Clinics 
3615 Civic Center Boulevard, ARC902 
Philadelphia, PA 19104 
2401 Gillham Road  
Kansas City, MO 64108 
Phone: (267) 426-5802  
Phone: (816) 302-6808  
Fax: 
(215) 590-3770 
Fax: 
(816) 302-9894 
E-mail: teacheyd@email.chop.edu 
E-mail: kjaugust@cmh.edu 
 
 
STUDY VICE CHAIR 
Steve Yoon-Ho Cho, MD 
Elizabeth Ann Raetz, MD 
Diagnostic  
Hematology/Oncology 
Wisconsin Institute for Medical Research  
Primary Children’s Hospital 
1111 Highland Ave 
100 N Mario Capecchi Drive 
Madison, WI 53705 
Salt Lake City, UT 
Phone: (608) 263-5084 
Phone: (801) 662-4700  
Fax: 
(608) 265-7390 
Fax: 
(801) 662-4707 
E-mail: scho@uwhealth.org 
E-mail: elizabeth.raetz@hci.utah.edu   
 
 
Robert J. Hayashi, MD 
STUDY STATISTICIAN 
Hematology/Oncology 
Meenakshi Devidas, PhD 
Washington University School of Medicine 
Director, Global Analytics Unit 
One Children’s Place  
St. Jude Children’s Research Hospital 
St. Louis, MO 63110 
262 Danny Thomas Place, Mail Stop 721 
Phone: (314) 454-2041   
Memphis, TN 38105-3678 
Fax: 
(314) 454-2780    
Phone: (901) 595-1764  
E-mail: hayashi_r@kids.wustl.edu       
Fax: 
(901) 595-5319 
 
E-mail: mini.devidas@stjude.org      
Stephen P. Hunger, MD 
 
Hematology/Oncology 
STUDY COMMITTEE MEMBERS 
Children’s Hospital Philadelphia 
Robert D. Annett, PhD 
Colket Translational Research Building 
Behavioral Science 
3501 Civic Center Blvd 
University of Mississippi Medical Center 
Philadelphia, PA 19104 
2500 N. State Street 
Phone: 267 425-0197  
Jackson, MS 39216 
E-mail: hungers@email.chop.edu 
Phone: (601) 984-5863     
 
Fax: 
(601) 984-5857    
Brent Lee Wood, MD PhD 
E-mail: rdannett@umc.edu      
Pathology 
 
Seattle Children's Hospital 
 
Seattle Cancer Care Alliance G7-800 
Barbara L. Asselin, MD 
Seattle, WA 98109-1028 
Hematology/Oncology 
Phone: (206) 288-7060     
University of Rochester 
Fax: 
(206) 288-7127    
601 Elmwood Avenue, Box 777 
E-mail: woodbl@u.washington.edu 
Rochester, NY 14642 
 
Phone: (585) 275-2981     
 
Fax: 
(585) 275-1039    
 
E-mail: barbara_asselin@urmc.rochester.edu 
 
 
 
 
 
 
 
 
 

 
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STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Alok I. Jaju, MD 
Eric Stephen Schafer, MD 
Diagnostic Imaging 
Hematology/Oncology 
225 E Chicago Avenue, Box #9 
Chicago, IL 60614 
Phone: (312) 227-3513 
Fax : 
(312) 227-9786 
E-mail: ajaju@luriechildrens.org 
Baylor College of Medicine  
1102 Bates Avenue, Suite 1590. 
Houston, TX 77030 
Phone: (832) 824-4241     
Fax: 
(832) 825-4170     
 
E-mail: esschafe@txch.org 
Allison Lam, PharmD, BCPS 
 
Pharmacy 
Tal Tova Schechter-Finkelstein, MD 
Miller Children's and Women’s Hospital Long Beach 
Stem Cell Transplantation 
2801 Atlantic Avenue 
Hospital for Sick Children 
Long Beach. CA 90806 
555 University Avenue 
Phone: (562) 833-8161      
Toronto, ON M5G1X8 
Fax: 
(562) 933-8337    
Phone: (416) 813-4505  
E-mail: alam@memorialcare.org 
Fax: 
(416) 813-5372 
 
E-mail: tal.schechter-finkelstein@sickkids.ca 
Mignon Lee-Cheun Loh, MD 
 
Hematology/Oncology 
Kristin Ammon Shimano, MD 
Helen Diller Family Comprehensive Cancer Center  
Hematology/Oncology 
1450 3rd St HD284 
UCSF Medical Center-Mission Bay 
San Francisco, CA 94158-3112 
550 16th Street, Box 0434 
Phone: (415) 514-9389     
San Francisco, CA 94158 
Fax: 
(415) 353-2657    
Phone: (415) 476-3831      
E-mail: Mignon.Loh@ucsf.edu      
Fax: 
(415) 353-2657     
 
E-mail: ShimanoK@peds.ucsf.edu 
 
 
Yoav H. Messinger, MD 
Amii Corbisiero Steele, PhD 
Hematology/Oncology 
Behavioral Science 
Children's Hospitals and Clinics of Minnesota - 
Minneapolis 
Carolinas Medical Center/Levine Cancer Institute 
1001 Blythe Blvd, MCP Suite 601 
2525 Chicago Ave S CSC-175 
Charlotte, NC 28232 
Minneapolis, MN 55404 
Phone: (704) 381-9966      
Phone: (612) 813-5940     
E-mail: amii.steele@carolinashealthcare.org 
Fax: 
(612) 813-6325    
 
E-mail: Yoav.Messinger@childrensmn.org       
Stuart Sheldon Winter, MD 
 
Hematology/Oncology 
Samir I Patel, MD  
University of New Mexico 
Radiation Oncology 
1 University of New Mexico, MSC 10-5590 
University of Alberta- Stollery Children’s Hospital 
Albuquerque, NM 87131-0001 
11560 University Avenue 
Phone: (505) 272-4461      
Edmonton, AB T6G1Z2 
Fax: 
(505) 272-8699     
Phone: (780) 432-8518     
E-mail: swinter@salud.unm.edu 
Fax: 
(780) 432-8380    
 
E-mail: samir.patel2@albertahealthservices.ca 
Patrick A. Zweidler-McKay, MD PhD 
 
Hematology/Oncology 
Kathleen W. Rao, PhD 
M D Anderson Cancer Center 
Cytogenetics 
1515 Holcombe Blvd. Box 853 
University of North Carolina at Chapel Hill 
Houston, TX 77030 
Room 1071, 1st Floor Memorial Hospital 
Phone: (713) 563-5395      
Chapel Hill, NC 27599-7220 
Fax: 
(713) 563-5407     
Phone: (919) 966-1595     
E-mail: pzweidler@mdanderson.org 
Fax: 
(919) 966-1411    
 
E-mail: krao@med.unc.edu 
 
 
 

 
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STUDY COMMITTEE MEMBERS 
Maki Okada, RN, CPNP 
Michelle Hermiston, MD PhD 
Nursing 
Hematology/Oncology 
Miller Children’s & Women’s Hospital Long Beach 
UCSF Medical Center – Mission Bay 
2801 Atlantic Ave 
550 16th Street, Box 0434 
Long Beach, CA 90806 
San Francisco, CA 94158-3112 
Phone: (562) 728-5000 
Phone: (415) 476-3831     
Fax: 
(562) 933-1815 
Fax: 
(415) 353-2657    
E-mail: mokada@memorialcare.org 
E-mail: Michelle.Hermiston@ucsf.edu 
 
 
Neelam Singh, PhD 
Terzah M. Horton, MD PhD 
Clinical Research Associate 
Hematology/Oncology 
Michigan State University Clinical Center 
Baylor College of Medicine 
Sparrow Professional Building Suite 145 
1102 Bates Avenue, Suite 750 
1200 East Michigan Avenue  
Houston TX, 77030 
Lansing, MI 48912 
Phone: (832) 824-4269     
Phone: (517) 364-5591 
Fax: 
(832) 824-1206    
Email: neelam.singh@hc.msu.edu  
E-mail: tmhorton@txch.org 
 
 
COG RESEARCH COORDINATOR 
Kimberly Panter Dunsmore, MD 
Charlotte Wood, CCRP 
Hematology/Oncology 
Children's Oncology Group - Data Center (Gaines) 
University of Virginia Cancer Center 
6011 NW 1st Place 
Box 800386 
Gainesville, FL 32607 
Charlottesville, VA 22908 
Phone: (352) 273-0573     
Phone: (434) 924-5105     
Fax: 
(352) 392-8162     
Fax: 
(434) 982-1927    
E-mail: cwood@cog.ufl.edu 
E-mail: kpd6u@virginia.edu 
 
 
Jason Lawrence Freedman, MD 
Brian Thomas Fisher, DO MSCE 
Hematology/Oncology 
Pediatrics, Division of Infectious Diseases 
The Children’s Hospital of Philadelphia 
The Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard, CTRB 10405 
34th Street and Civic Center Boulevard 
Philadelphia, PA 19104 
Philadelphia, PA 19104 
Phone: (215) 906-7885 
Phone: (267) 426-7110 
E-mail: feedmanj@email.chop.edu 
Fax: 
(215) 590-2017 
 
E-mail: fisherbria@email.chop.edu 
COG PROTOCOL COORDINATOR 
 
Sarah L. Vargas, Ph.D. 
Paul John Galardy, MD 
Children's Oncology Group - Operations Center 
Hematology/Oncology 
222 E Huntington Drive Suite 100 
Mayo Clinic 
Monrovia, CA 91016 
200 First Street SW 
Phone:  (626) 241-5116 
Rochester, MN 55906 
Fax:  
(626) 445-4334 
Phone: (507) 284-2695     
Email:  svargas@childrensoncologygroup.org 
galardy.paul@mayo.edu 
 
 
Maria Luisa Sulis, MD 
Rodney R. Miles, MD PhD 
Hematology/Oncology 
Pathology 
Columbia University Medical Center 
Primary Children's Hospital 
161 Fort Washington Ave -IP7 
15 N. Medical Dr. East JMRB Rm 2100 
New York, NY 10032 
Salt Lake City, UT 84112-0565 
Phone: (212) 305-5808   
Phone: (801) 213-3448    
Fax:       (212) 305-5848   
Email: rodney.miles@path.utah.edu 
Email: mls95@columbia.edu 
 
 
 
 
 
 
 
 

 
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Page 10 
 
CTEP Supplied Agent: Bortezomib, NSC# 681239 
IND# 58443 
 
(IND Sponsor: CTEP) 
 
Cyclophosphamide, NSC# 026271, Commercial 
 
Cytarabine, NSC# 063878, Commercial 
 
Daunorubicin, NSC# 082151, Commercial 
 
Dexamethasone, NSC# 034521, Commercial 
 
Doxorubicin, NSC# 123127, Commercial 
 
Etoposide, NSC# 141540, Commercial 
 
Filgrastim, NSC# 614629, Commercial 
 
Hydrocortisone, NSC# 010483, Commercial 
 
Ifosfamide, NSC# 109724, Commercial 
 
Leucovorin, NSC# 003590, Commercial 
 
6-Mercaptopurine, NSC# 000755, Commercial 
 
Mesna, NSC# 113891, Commercial 
 
Methotrexate, NSC# 000740, Commercial 
 
Pegaspargase, NSC# 624239, Commercial 
 
6-Thioguanine, NSC# 000752, Commercial 
 
Vincristine, NSC# 675574, Commercial 
 
 
 
 
 
 
 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
ABSTRACT 
AALL1231 is a COG group-wide Phase III study for patients between 1-30 years of age with newly 
diagnosed T- lymphoblastic leukemia (T-ALL) or T-Lymphoblastic Lymphoma (T-LLy) that will assess 
whether the addition of bortezomib (PS-341) to a modified augmented BFM backbone will decrease relapse 
risk and improve event-free survival (EFS) and overall survival (OS). Although EFS and OS continue to 
increase for children and young adults with T-ALL and T-LLy, patients who relapse have a dismal 
prognosis. These patients are extremely difficult to salvage as they tend to relapse early and with 
chemotherapy-refractory disease. There is strong biological rationale for introducing bortezomib early in 
treatment to prevent relapse. Bortezomib has been shown to have a favorable synergistic interaction with 
backbone chemotherapy drugs and the potential to reverse both innate and acquired steroid resistance. In 
addition, early phase clinical trials suggest bortezomib is a therapeutically active agent in T-ALL and T-
LLy. 
 
Patients will be randomized to receive backbone therapy with or without bortezomib during Induction and 
Delayed Intensification. T-ALL patients will be stratified into standard risk (SR), intermediate risk (IR), or 
very high risk (VHR) groups based on assessments minimal residual disease (MRD) at Day 29 and End of 
Consolidation (EOC). T-LLy patients will be risk stratified into the same groups, based on percentage 
disease in marrow at diagnosis and radiographic disease response at end of Induction.  
 
The augmented BFM backbone will be modified in this trial to include dexamethasone as the sole 
corticosteroid throughout therapy and to increase the exposure to pegaspargase, based on the success of this 
approach in the recently completed UKALL 2003 trial. This trial also aims to establish whether prophylactic 
cranial radiation therapy (CRT) can be safely eliminated from the treatment in the vast majority (~90%) of 
children with T-ALL and to determine if intensification of chemotherapy in VHR T-ALL and T-LLy 
patients will prevent relapse. Finally, this trial aims to determine whether a response assessment after 
Intensification therapy in VHR patients (T-ALL and T-LLy) can identify patients who are chemotherapy 
refractory and who may potentially benefit from novel agents and/or stem cell transplant.  
 
Amendment 3 includes the correction to an error in the date of administration of PEG-Aspargase during 
Delayed Intensification, and emphasizes supportive care guidelines to remind clinicians of the potential 
and expected risk of Invasive Fungal Infections, especially during Induction and periods of prolonged 
neutropenia. 
 
Amendment 4 revises the eligibility criteria for T-cell Lymphoblastic Lymphoma (T-LLy) patients, and 
clarifies classification study enrollment for T-cell Acute Lymphoblastic Leukemia (T-ALL) patients. 
 

 
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EXPERIMENTAL DESIGN SCHEMA: T-ALL 
 
 
 
 
 
 
 
 
 
AALL08B1 or 
Project: 
EveryChild 
APEC14B1 (if 
available for 
ALL patients) 
T-ALL 
RANDOMIZATION
T-ALL: T-Lymphoblastic Leukemia MRD: Minimal Residual Disease 
HR: High Risk SR: Standard Risk  IR: Intermediate Risk  
 
VHR: Very High Risk  
 
IM: Interim Maintenance   
DI: Delayed Intensification  
CMTX: Capizzi Methotrexate  
 
 
 
HDMTX: High Dose Methotrexate   $Undetectable MRD 
 
 @Detectible MRD 
#See Section 3.4 for definitions. OF NOTE, subjects who are CNS2, CNS3, or have testicular disease, or were steroid pre-treated CANNOT be SR. 
†See Section 3.5 for details            ^ T-ALL:  all VHR subjects regardless of CNS status, and IR subjects with CNS3 disease will receive cranial radiation
therapy (CRT). See Section 16.1 for details. 
‡ Patients with persistent testicular disease at end-Induction should receive radiation to the testes during Consolidation. A testicular biopsy should be 
performed if the clinical findings are equivocal. See Section 16.2 for details. 
*Induction failures are treated as VHR regardless of MRD status 
 
 
 
 
On study  
(AALL1231) 
ARM A 
MRD EVALUATION (DAY 29) 
Induction  
Consolidation‡ 
MRD* 
<0.01%# 
≥0.01%# 
ARM A-SR# 
ARM B 
Induction + Bortezomib 
MRD EVALUATION (DAY 29) 
Consolidation‡ 
MRD*
<0.01%# 
≥0.01%# 
ARM B-SR# 
ARM B-IR# 
<0.1% 
≥0.1% 
ARM B-VHR# 
DI + 
Bortezomib 
IM CMTX 
Maintenance 
<0.1% 
Intensification 
 HR blocks (x3) 
≥0.1% 
Arm A-VHR# 
ARM A-IR# 
Maintenance 
IM CMTX 
DI  
Maintenance^ 
IM#1 HDMTX 
DI + 
Bortezomib 
IM#2 CMTX 
Intensification 
 HR blocks (x3) 
EVALUATION
Off 
Protocol 
Therapy 
DI + 
Bortezomib 
MRD  
-ve$ 
MRD 
+ive@ 
IM CMTX 
Maintenance^ 
†PH+ 
Removed 
from 
Protocol 
Therapy 
IM#1 HDMTX 
DI  
IM#2 CMTX 
Maintenance^ 
EVALUATION
Off 
Protocol 
Therapy 
DI  
IM CMTX 
Maintenance^ 
MRD 
+ive@ 
MRD  
-ve$ 

  
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EXPERIMENTAL DESIGN SCHEMA: T-LLy (Stages II-IV) 
T-LLy (Stage II-IV) 
On study 
(AALL1231) 
RANDOMIZATION
T-LLy: T-Lymphoblastic Lymphoma 
MRD: Minimal Residual Disease 
HR: High Risk SR: Standard Risk   
IR: Intermediate Risk 
  
 
VHR: Very High Risk 
IM: Interim Maintenance   
 
DI: Delayed Intensification  
CMTX: Capizzi Methotrexate  
 
HDMTX: High Dose Methotrexate  
CR: complete response  
 
 
PR: Partial Response  
#See Section 3.4  for definitions. OF NOTE, subjects who are CNS2, CNS3, have testicular disease, or were steroid pre-treated, CANNOT be SR. 
†See Section 3.5 for details 
^ T-LLy subjects with CNS3 disease receive cranial radiation therapy (CRT). See Section 16.1 for details 
*Patients who are in a radiographic PR at the end of the 3 Intensification HR blocks should be re-biopsied. If the biopsy finds residual disease, the 
patient comes off protocol therapy. If the biopsy does not demonstrate active disease, the patient continues on therapy at DI 
‡ Patients with persistent testicular disease at end-Induction should receive radiation to the testes during Consolidation. A testicular biopsy 
 should be performed if the clinical findings are equivocal. See Section 16.2 for details.                                                 &See Section 10.4 for details 
ARM A 
DISEASE EVALUATION (Day 29) 
Induction  
ARM A-SR#
ARM A-IR#
ARM A-VHR# 
ARM B 
Induction + Bortezomib 
DISEASE EVALUATION (Day 29) 
Project: 
EveryChild 
APEC14B1 
(OPTIONAL) 
†PH+ 
Removed 
from 
Protocol 
Therapy 
IM CMTX 
IM CMTX 
DI  
Maintenance 
Intensification 
 HR blocks (x3) 
EVALUATION
Off 
Protocol 
Therapy 
DI  
IM CMTX 
Maintenance^ 
IM#1 HDMTX 
DI  
IM#2 CMTX 
Maintenance^ 
DI + 
Bortezomib 
Maintenance 
Intensification 
 HR blocks (x3) 
EVALUATION
Off 
Protocol 
Therapy 
DI + 
Bortezomib 
IM CMTX 
Maintenance^ 
Radiographic 
PR*/CR&
NR/ 
SD/PD& 
IM#1 HDMTX 
DI + 
Bortezomib 
IM#2 CMTX 
Maintenance^ 
Radiographic 
PR*/CR&
Consolidation‡ 
ARM B-IR# 
ARM B-SR#
Consolidation‡ 
ARM B-VHR# 
NR/ 
SD/PD& 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To compare EFS in patients with newly diagnosed T-ALL and T-LLy who are 
randomized to a modified ABFM backbone versus bortezomib plus the modified 
ABFM backbone. 
 
1.2 
Secondary Aims  
 
1.2.1 
To determine the safety and feasibility of modifying standard therapy for T-ALL 
and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-
based Induction, additional doses of pegaspargase (PEG-ASP) during Induction 
and Delayed Intensification (DI), and dexamethasone pulses during Maintenance 
therapy 
 
1.2.2 
To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) 
can be safely and effectively eliminated in the 85-90% of T-ALL patients classified 
as standard or intermediate risk. 
 
1.2.3 
To determine the proportion of EOC MRD ≥ 0.1% T-ALL patients who become 
MRD negative (undetectable by flow cytometry) after intensification of 
chemotherapy, using three high risk (HR) BFM blocks, and to compare EFS 
between the patients who become MRD negative after the three HR BFM blocks 
and continue on chemotherapy with those who continue to have detectable MRD 
and are eligible for other treatment strategies, including hematopoietic stem cell 
transplant (HSCT). Similarly, to compare the EFS between very high risk 
(Induction failure) T-LLy patients treated with HR BFM intensification blocks 
who have partial or complete response (PR or CR) with those who do not respond 
(NR). 
 
1.3 
Correlative Aims 
1.3.1 
To investigate the prognostic significance of Day 29 BM MRD in T-LLy patients. 
 
1.3.2 
To determine if protein expression patterns can predict bortezomib response and 
drug resistance in T-ALL 
 
1.3.3 
To analyze and target relevant signaling pathways in T-ALL blasts, focusing on 
Early T cell Precursor (ETP) ALL 
 
 
 
 

  
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2.0 
BACKGROUND 
 
2.1 
Trial Rationale  
T-cell lymphoid malignancies have distinct biochemical, immunologic and clinical features which 
set them apart from non-T lymphoid malignancies.1,2 Historically, the diagnosis of T-
Lymphoblastic Leukemia (T-ALL) portended a worse prognosis than other forms of non-T 
childhood ALL.3,4 Over the past three decades, the introduction of intensive, high-dose, multi-agent 
pulse chemotherapy has improved the EFS for patients with T-ALL from 15%-20% to 50%-85%. 
The outcomes for T-ALL are now comparable to those of children with high risk B Lymphoblastic 
Leukemia (B-ALL).5-8 Lymphoblastic Lymphoma (LL) accounts for approximately 25% of all 
pediatric non-Hodgkin lymphoma (NHL) cases. The history of the treatment for LL over the past 
3 decades reflects the evolution of treatment from conventional lymphoma-based treatment to 
ALL-based treatment. With current therapies for T-LLy (~90% of pediatric LL), the majority of 
patients, including those with advanced stage disease, can expect a likelihood of 80%-85% EFS 
utilizing regimens modified from those used to treat ALL.9-11 
 
Despite these significant advances, relapsed T-ALL and T-LLy have a dismal prognosis with 
reported 3-year EFS rates of <15%.12,13.14 These patients are extremely difficult to salvage as most 
have chemotherapy-refractory disease. Accordingly, the primary goal in this trial is to prevent 
relapse. AALL1231 will test two major strategies to meet this goal: (1) to modify the existing 
chemotherapy platform to mirror the most efficacious backbone that has been tested in Phase 3 
trials; and, (2) to randomize patients to receive/not receive a novel agent (bortezomib), with strong 
biologic rationale, introduced early into therapy in a safe and feasible manner to determine if this 
will improve EFS and OS. 
 
2.1.1 
Rationale for Incorporating Bortezomib 
AALL1231 is a Phase 3 randomized trial with the primary objective of testing the safety 
and efficacy of adding bortezomib (PS-341) to a modified ABFM backbone in patients 
with newly diagnosed T-ALL and T-LLy. Bortezomib has been studied extensively in 
preclinical models of T-ALL. The pediatric preclinical testing program (PPTP) tested 
bortezomib in vitro in T-ALL cell lines finding single agent activity and in vivo using 
xenografted NOD-SCID mice and found a 100% response rate in T-ALL (2 of 2 samples) 
compared with a 40% (2 of 5 samples) response rate in pre-B ALL.15 These data are not 
surprising as T-ALL blasts often have considerable activation of the NF-kappa B pathway, 
frequently as a consequence of activated Notch1.16 
 
In order to move a new agent into a complex chemotherapy backbone, it is important to 
investigate the activity of the novel agent with conventional cytotoxics in preclinical 
models. Bortezomib has a favorable additive or synergistic interaction against T-ALL 
when combined with a number of cytotoxic agents, including dexamethasone (DEX), 
cytarabine, doxorubicin, asparaginase, vincristine, and etoposide in vitro (Table 1).17 One 
benefit of targeting the proteasome with bortezomib is the potential to overcome 
chemotherapy resistance. Bortezomib has been shown to overcome chemotherapy 
resistance to anthracyclines, alkylators, and corticosteroids in a number of malignancies.18-
22 Preclinical data suggest that bortezomib may sensitize steroid resistant T-ALL cells to 
corticosteroids.23 As corticosteroid resistance is correlated with a particularly poor 
prognosis in T-ALL, the possibility of overcoming steroid resistance is quite attractive. 
The plan to treat subjects with bortezomib during Induction and Delayed Intensification 
(DI) gives the potential to reverse both innate and acquired steroid resistance as well as 
take advantage of the synergistic interaction between DEX and bortezomib. Finally, 
preclinical data suggest that proteasome inhibition may also reverse anthracycline 
resistance in T-ALL.24 

  
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Bortezomib has been studied in early phase trials in adults and children and has an 
acceptable toxicity profile. Dose limiting toxicities (DLTs) in early phase trials in adults 
with hematologic malignancies included thrombocytopenia, hyponatremia, fluid retention, 
diarrhea, hypokalemia, fatigue, and malaise.25,26 A Phase 1 study in children with refractory 
leukemia (ADVL0317) demonstrated a maximum tolerated dose (MTD) of 1.3 mg/m2 
given twice weekly for 2 weeks as a single agent, followed by a 10-day rest.27 DLTs were 
febrile neutropenia with hypotension and azotemia. Early data also suggest that bortezomib 
may be active against T-cell lymphomas in adults when given as a single agent or in 
combination with chemotherapy.28-32 
 
Bortezomib was safely incorporated into an intensive ALL re-induction backbone (TACL 
2005-003) and is currently under investigation in the COG AALL07P1 first relapse ALL 
trial.33 AALL07P1 incorporates bortezomib into the AALL01P2 backbone. AALL07P1 
recently successfully completed the second stage of the Simon 2-stage design. Sixty-one 
eligible evaluable B-ALL patients were accrued, including 28 with early (<18 months) and 
33 with intermediate (18-36 months) relapse. Forty-two CRs were observed in this phase, 
resulting in exceeding the efficacy boundary, and bortezomib was deemed worthy of 
further investigation in pediatric ALL.34 AALL07P1 also enrolled T-ALL and T-LLy 
patients with descriptive statistics regarding response. Thus far, 17 eligible, evaluable T-
ALL patients have been treated on AALL07P1 and 11 of 17 (65%) have obtained CR2 at 
the end of Block 1. This is in contrast to AALL01P2, in which only 1 of 7 (17%) T-ALL 
patients attained CR2 at the end of the first block of re-induction therapy (Block 1). While 
patient numbers are small, the response to chemotherapy plus bortezomib is extremely 
encouraging, as the CR2 rate is very similar to that of B-ALL patients with early relapse 
(64%). Relapsed B-ALL patients have also been treated with bortezomib in combination 
with re-induction chemotherapy on the TACL study (2005-003) with a highly promising 
80% objective response rate (ORR) (CR +CRp).34 The preclinical data strongly suggest T-
ALL/T-LLy should be at least as sensitive to bortezomib as B-ALL. Together the response 
rates of relapsed B- and T-ALL on AALL07P1 in conjunction with published TACL data 
in B-ALL support testing bortezomib in patients with newly diagnosed ALL. Bortezomib 
has also been shown to be active as a single agent and in combination with chemotherapy 
in multiple studies in adults with advanced T-cell lymphomas.28,29,35 More detailed data 
describing the use of bortezomib in clinical trials is included in the relevant data (Section 
2.4) below. 
 
Based on these data, all patients with T-ALL and T-LLy will be randomized to receive or 
not receive 8 doses of bortezomib 1.3 mg/m2/dose (4 doses in Induction on Days 1, 4, 8, 
and 11 and 4 doses in Delayed Intensification (DI) on Days 1, 4, 15, and 18). These 
schedules of bortezomib are designed to optimize the co-administration of bortezomib and 
DEX. 
 
2.1.2 
Rationale for Updating Risk Stratification 
MRD is the single most powerful prognostic factor in childhood ALL.36-38 A number of 
large studies have investigated the sensitivity and specificity of MRD at different time 
points on a variety of treatment protocols, using either flow- or PCR-based technologies.39 
While the majority of data suggest that end Induction MRD assessment is the best predictor 
of outcome in B-ALL, recent data from AIEOP-BFM ALL 2000 strongly suggest that EOC 
MRD is a better predictor of adverse outcome in T-ALL.38 These data are based on 
European studies that measure MRD using molecular techniques. In COG T-ALL studies, 
MRD is measured by flow cytometry. While the MRD cutoffs that predict outcome using 
flow-based MRD are not as clearly defined, several studies have shown that flow cytometry 

  
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and PCR amplification of antigen-receptor genes yield remarkably concordant 
measurements if MRD is present at a ≥ 0.01% level.40-42 On AIEOP-BFM ALL 2000, 
patients were stratified into 3 risk groups based on MRD and early prednisone response. 
Patients with a prednisone good response who were MRD <0.01% at end Induction and 
EOC were standard risk. Patients who had an EOC MRD ≥ 0.1% or were prednisone poor 
responders were considered high risk. All others were classified as intermediate risk. The 
same MRD cutoffs will be used on AALL1231. 
 
A recent review of data from children enrolled on AALL0434 (the current open COG trial 
for newly diagnosed T-ALL and T-LLy) validated the prognostic value of these MRD 
cutoffs for patients with T-ALL (unpublished and DMSC protected confidential data). 
 
On AALL1231, T-ALL patients will be stratified into 3 risk groups based on MRD: 
Standard Risk (SR) - Day 29 M1 marrow, Day 29 BM MRD < 0.01%, CNS 1, no testicular 
disease, no pre-treatment with corticosteroids; Intermediate Risk (IR) - Day 29 M1 or M2 
marrow, Day 29 marrow MRD ≥ 0.01%, EOC MRD < 0.1%, any CNS and testicular 
disease status; and, Very High Risk (VHR) - EOC MRD ≥ 0.1% or Induction failure (M3 
marrow), any CNS or testicular disease status. This stratification is estimated to allocate 
subjects as follows: SR T-ALL: 40%-50% of T-ALL patients; IR T-ALL: 35%-50% of 
patients; VHR T-ALL: 10%-15% of patients.  
 
T-ALL subjects enrolled on AALL1231 will receive a modified ABFM backbone based 
on the data from UKALL 2003 (described below) and will be randomized to receive or not 
receive bortezomib during Induction and the re-Induction portion of DI. Modifications 
from the COG ABFM backbone include the use of DEX 6 mg/m2/day x 28 days during 
Induction, administration of 2 rather than 1 dose of pegaspargase during Induction and the 
re-Induction portion of Delayed Intensification, and the use of DEX rather than prednisone 
pulses during Maintenance therapy. 
 
After Induction, the three risk groups will be treated differently. SR subjects will receive 1 
Interim Maintenance (IM) phase with Capizzi methotrexate (CMTX) and PEG-ASP. They 
will not receive prophylactic cranial radiation therapy (CRT). IR subjects will receive 2 IM 
phases: the first with high dose methotrexate (HD MTX) and the second with CMTX and 
PEG-ASP. They will not receive prophylactic CRT. Patients with CNS disease (CNS3) 
will receive 1800 cGy CRT during the first Maintenance cycle. VHR subjects will receive 
3 HR BFM blocks in lieu of IM #1. If they become MRD negative (undetectable) at end of 
HR3, then they will remain on study and receive DI (± bortezomib as randomized) and IM 
#2 with CMTX and PEG-ASP. During the first cycle of maintenance therapy they will 
either receive 1200 cGy CRT (CNS1 or CNS2) or 1800 cGy CRT (CNS3). Subjects who 
remain MRD positive (any level of detectable MRD) at the end of HR3 will go off study 
and presumably most will undergo HSCT. 
 
All other components of therapy will remain the same for all three risk groups. The 
rationale for these differences is described in the Section 2.1.3 below describing the 
backbone modifications and plans to eliminate prophylactic CRT in most patients. 
 
On AALL0434, T-LLy patients were risk stratified into SR, HR, or Induction failure based 
on the disease burden in their marrow at diagnosis and by disease response, measured 
radiographically and by bone marrow morphology at the end of Induction. T-LLy patients 
with < 1% disease in the marrow at diagnosis will continue to be classified as SR on this 
study and those with ≥ 1% marrow disease at diagnosis or pre-treated with corticosteroids 
will be classified as IR. Patients who fail to achieve at least a radiographic partial response 

  
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(PR) or who do not achieve morphological marrow remission at the end of Induction will 
be designated VHR (Induction failures). In addition, similar to patients with T-ALL, Day 
29 marrow MRD may be obtained. Patients who have identifiable marrow disease at 
diagnosis by morphology will need a repeat bone marrow at Day 29. Patients who do not 
have identifiable marrow disease by morphology at diagnosis have the option of a Day 29 
marrow for correlative studies. MRD at diagnosis will be used in T-LLy risk stratification. 
Day 29 MRD will not be used for risk stratification but will be important for correlative 
endpoints. Response definitions for T-LLy patients are provided in Section 9.0. SR T-LLy 
subjects will receive 1 IM phase with CMTX and PEG-ASP, IR subjects will receive 2 IM 
phases (the first with HD MTX and second with CMTX and PEG-ASP), and VHR subjects 
will receive 3 HR BFM blocks; the same as the treatment strategy for T-ALL. If VHR 
patients achieve a CR/PR at end of HR3, then they will remain on study and receive DI (± 
bortezomib as randomized) and IM #2 with CMTX and PEG-ASP. They will either receive 
1800 cGy CRT if CNS3. No T-LLy patient will receive prophylactic CRT. The rationale 
for these differences is described below. 
 
2.1.3 
Rationale for Modifying Backbone. 
Rationale for steroid modifications 
UKALL 2003 is a recently completed Phase 3 clinical trial that tested whether treatment 
can be safely and effectively stratified using MRD in patients with B- and T-ALL.43 
UKALL 2003 utilized a modified COG ABFM regimen that included Capizzi MTX with 
PEG-ASP, rather than HD MTX during IM. Even though only CNS3 patients received 
CRT, T-ALL patients treated on this trial had an 84% 5yr EFS, a rate superior to any 
published results from a multi-center trial in newly diagnosed T-ALL.44-46 In addition, T-
ALL patients had markedly improved survival when compared to the preceding trial, 
UKALL 97/99 (86% vs. 73% 3yr EFS; 90% vs. 78% 3 yr. OS).45,46 The most significant 
protocol changes were a transition to PEG-ASP from native E. Coli asparaginase and the 
use of DEX as the only corticosteroid for all patients. The UKALL 2003 Induction included 
DEX 6 mg/m2/day x 28 days with the same dose of DEX given for 5 days every 4 weeks 
during Maintenance therapy. They also found that rapid responder (RER) T-ALL subjects 
with NCI HR features had a 5yr EFS and OS of 86.7% and 91.2%, respectively.46 This was 
in contrast to RER T-ALL subjects with NCI SR features who had a worse outcome (80.1% 
EFS and 85.6% 5 year OS). One major difference between the two groups was that the 
RER NCI SR subjects received a three-drug DEX based Induction and a 4-week oral 6-MP 
based Consolidation, while the RER NCI HR subjects received a four-drug DEX-based 
Induction and a BFM style Consolidation, confirming the importance of a 4-drug Induction 
and early intensive therapy in T-ALL. All T-ALL subjects on the recently opened successor 
trial, UKALL 2011, will receive a 4-drug Induction with DEX and the intensified PEG-
ASP with either a standard BFM consolidation or an ABFM style consolidation based on 
Day 29 MRD, as given in UKALL 2003. 
 
The UKALL 2003 regimen was well tolerated with acceptable rates of toxicity, including 
Induction mortality and osteonecrosis.43,46 The Induction mortality rate on UKALL 2003 
was 2% for ALL patients treated with the anthracycline containing Induction, DEX at 
6mg/m2/day, and an extra dose of PEG-ASP on day 18. 43 This TRM rate is quite similar 
to that seen in other recent studies using a 4-drug Induction regimen, including AIEOP-
BFM ALL 2000 and COG AALL0232 (2.16% for AYA patients vs. 1.67% for younger 
patients).47 The vast majority of studies that encountered excess toxicity with DEX-based 
4-drug Inductions used higher doses of 10 mg/m2/day, as opposed to the 6 mg/m2/day 
schedule proposed in AALL1231. The rate of symptomatic osteonecrosis in patients over 
10 years of age treated on UKALL 2003 was lower than the rate found in the prednisone 
arm of AALL0232 (12% vs 15%).43,46,48 Two older studies did include DEX in Induction 

  
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at 6 mg/m2/day for 28 days. DFCI 91-01 found a higher rate of infectious toxicity, using 
DEX at 6mg/m2/day in Induction as compared with prednisone; however, this trial also 
included high dose MTX (4gm/m2) on day 2-3 of Induction.49 POG 9905/6 initially 
included DEX at 6mg/m2/day for 28 days in a four-drug Induction regimen.50 DEX was 
changed to prednisone after 2 infectious deaths occurred among the first 32 treated 
subjects. Nevertheless, on the UKALL2003 trial over 1000 patients were treated with a 4-
drug Induction regimen, including DEX at 6mg/m2/day, and it was a safe and well-tolerated 
regimen with modern supportive care guidelines. 
 
The current AIEOP-BFM ALL 2009 trial uses 7 days of prednisone at 60 mg/m2/day 
followed by 21 days of DEX at 10 mg/m2/day (plus taper) for prednisone good responder 
T-ALL patients. The AIEOP-BFM ALL 2000 trial compared this DEX-based Induction 
with a prednisone-based Induction. On that trial the Induction treatment-related mortality 
(TRM) was higher in the DEX arm (2% vs 0.9%); however, the EFS/OS for T-ALL patients 
was superior in the DEX arm with a threefold reduction in the cumulative incidence of 
relapse (6% vs. 20%, p =0.003), leading to the continued use of DEX for T-ALL patients 
with a good prednisone response in the successor AIEOP-BFM ALL 2009 trial.46,51 No 
difference was seen in the overall rate of symptomatic osteonecrosis, comparing the two 
arms.52 
 
The DFCI ALL Protocol 00-01 randomized patients to receive DEX or prednisone pulses 
every 3 weeks for 104 weeks of Intensification and Maintenance.53 T-ALL patients and all 
patients 10+ years old were classified as high-risk patients, and they were treated with 
120 mg/m2/day of prednisone vs. 18 mg/m2/day of DEX, during a 30-week intensification 
phase and with 40 mg/m2/day of prednisone vs. 6 mg/m2/day of DEX, during a 72-week 
consolidation phase. They found a higher rate of symptomatic ON in children over 10 years 
of age treated with DEX. They also found a significant 5-year EFS advantage for DEX 
among all patients (90% vs. 81%; p = 0.01). While the number of T-ALL patients was 
relatively small (n=39), the advantage for DEX was particularly striking in this group with 
5-year EFS 96% vs. 65%. Accordingly, the Dana Farber Cancer Institute (DFCI) is also 
continuing to use DEX in all adolescents based on the improved survival. Of note, the 
Maintenance pulses of DEX proposed on AALL1231 are every 4 weeks, not every 3 weeks, 
as used in the DFCI, and the DFCI regimen contained 10 pulses of DEX at doses 3-fold 
higher than those used by the COG. 
 
The MRC and BFM recently opened Phase 3 ALL trials (AIEOP-BFM ALL 2009 and 
UKALL 2011) and in both of these trials T-ALL patients are treated with a DEX, regardless 
of age, based on its superior efficacy in T-ALL. SJCRH also uses DEX during 
maintenance/continuation for teenagers. 
 
The 6mg/m2/day DEX schedule has the potential to provide the enhanced efficacy of DEX 
over prednisone without the toxicity found in the 10 mg/m2/day regimens. In addition, 
infectious toxicity on AALL07P1 (bortezomib plus backbone) during Block 1 therapy is 
similar to AALL01P2 (backbone alone) and ADVL04P2 (backbone plus epratuzumab). 
Each of these relapsed ALL trials have a 45% Grade 3-5 infection rate in Block 1. 
Accordingly, it is not anticipated that bortezomib will add significant infectious risk 
(Horton, Rheingold, and Raetz, personal communications). 
 
Rationale for additional Asparaginase therapy 
Based on these promising results, all patients enrolled in the current trial will be treated 
with the same DEX-based Induction and DEX will be used as the sole steroid in other 
blocks, mirroring UKALL 2003. In addition, a number of studies suggest additional ASP 

  
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may improve outcome in T-ALL (UKALL 2003, POG 8704, DFCI (85-01, 87-01, 91-01), 
and St. Jude Total Therapy XV).6,8,54 Accordingly, this trial will non-randomly include a 
modest increase in the number of doses of PEG-ASP, as compared to AALL0434, with 
one additional dose during Induction and during DI. UKALL 2003 only included one 
additional dose during Induction. Additionally, two doses will be included in the second 
Capizzi IM Phase. The vast majority of subjects on this trial therefore will receive 9 doses 
of PEG-ASP as compared with 5 or 7 doses on AALL0434. Subjects on the high-risk 
stratum of UKALL 2003 received 12 well-tolerated doses of PEG-ASP delivered during 
the first 6 courses of therapy. NCI HR patients on the Capizzi MTX arm of AALL0232 
received 2 Capizzi IM and 2 DI phases with a total of 11 doses of PEG ASP with acceptable 
toxicity. 
 
2.1.4 
Rationale for Eliminating Prophylactic CRT in the Majority of Patients  
Regardless of treatment modality, between 3%-8% of children treated for de novo ALL 
ultimately have a CNS relapse.55 A significant majority of patients with T-ALL treated on 
COG and POG trials have traditionally received prophylactic CRT in order to reduce CNS 
relapse, though RER non-CNS3 T-ALL patients did not receive CRT on CCG 1961.56 RER 
non-CNS T-ALL patients (who did not receive CRT) had a higher incidence (7.9%) of 
CNS relapse than slow early responder (SER) non-CNS T-ALL patients (0.8%, who did 
receive 1200cGy CRT) on CCG 1961, leading to increased use of CRT in T-ALL in 
subsequent COG trials.57 AALL0434 is non-randomly investigating whether CRT can be 
safely eliminated from low-risk T-ALL patients, but this population includes only ~10% 
of patients. While effective, the usefulness of CRT may be offset by substantial long-term 
adverse effects, including second cancers, irreversible endocrinopathies, neurocognitive, 
and neurotoxic effects. Pui et al. showed that previous irradiation in 10-year event-free 
survivors of childhood ALL was associated with a 20.9% cumulative risk of second 
neoplasms at 20 years (30 years from remission Induction), a higher mortality rate than the 
general population, and an increased unemployment rate.58  
 
Partly, in an effort to reduce these events, between 1983-1989, the European Organization 
for the Research and Treatment of Cancer (EORTC) treated medium and high risk ALL 
patients on studies 58831 and 58832 with early, frequent IT MTX, systemic HD MTX, 
increased doses of ASNase and a DI phase while randomizing patients to receive or not to 
receive standard prophylactic CRT. While patients with overt CNS disease at diagnosis 
were not eligible for 58831 or 58832, there was no statistically significant difference in 6-
year DFS (66%-68%), isolated CNS relapse rate (7%) or total CNS relapse rate (9%-15%) 
in the two study arms.59 T-ALL patients were enrolled and randomized to receive or not 
receive prophylactic radiation on 58831 or 58832; however, immunophenotypic data was 
not systematically collected, precluding analysis of T-ALL specific outcomes. Based on 
these results, several subsequent studies have continued to intensify systemic and 
intrathecal therapy and non-randomly omit CRT for a majority of ALL patients. EORTC 
58881 and 58951, the follow-up studies to 58831 and 58832, eliminated CRT for all de 
novo ALL patients, including those with CNS manifestations at diagnosis (CNS3), while 
further intensifying systemic and intrathecal therapies. Both studies included multiple 
courses of HD MTX and triple (MTX, hydrocortisone and ARAC) intrathecal 
chemotherapy (ITT), and 58951 included an intensified Induction. In 58881, the 8 year 
isolated and overall CNS relapse incidences in T-ALL patients decreased to 6.8% and 
10.9% respectively, and these decreased further in T-ALL patients to 5.3% and 8.5% 
respectively in 58951.59,60 
 
St. Jude Total Therapy trials have also eliminated CRT for all patients with de novo ALL. 
In Total Therapy XV, patients received systemic chemotherapy with DEX as the Induction 

  
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and post-Induction steroid, HD MTX, intensified ASNase and an intensified regimen of 
ITT and with no prophylactic CRT. Isolated CNS relapse occurred in 7.7% of T-ALL 
patients.54 This showed relative equivalence to the study’s predecessor, Total Therapy 
XIIIB which showed a 7% isolated CNS relapse rate despite utilizing prophylactic CRT in 
patients with either CNS3 disease at diagnosis or T-ALL presenting with a WBC count of 
≥50,000/µL.61 In addition, all Total Therapy XV patients with isolated CNS relapse were 
successfully salvaged after additional chemotherapy plus CRT.54 The Dutch Childhood 
Oncology Group (DCOG) eliminated CRT from all ALL patients in protocol ALL-9. While 
T-ALL specific outcomes have not been published, the 5-year isolated CNS relapse rate 
was reported to be only 2.6% and providing evidence of decreased toxicities with 
elimination of CRT, only 2 second malignancies, neither of them in the brain, were noted 
during follow-up.62 The Israeli National Studies 89 and 98 (INS89/98) used BFM-90 based 
therapy with intensified ITT to eliminate CRT from 76% of T-ALL patients; the remaining 
24% of patients received prophylactic cCRT secondary to high risk disease, defined as 
patients presenting with CNS3 disease or WBC ≥100 000/L and/or a poor response to the 
prednisone prophase. With this strategy, INS 89 had a cumulative incidence of any CNS 
relapse of 7.1% while INS 98 reduced the incidence to 1.7%.63 
 
Finally, the United Kingdom Medical Research Council (UK MRC) eliminated CRT in all 
T-ALL patients except those with CNS3 disease at presentation in UKALL 97, 97/99, and 
2003. The UKALL 97 and 97/99 trials randomized subjects to prednisone at 40 mg/m2 vs 
DEX at 6.5 mg/m2. The results of the trial showed an overall improvement in EFS in the 
DEX arm across all risk groups; in particular, patients with T-ALL had only a 3.8% risk of 
isolated CNS relapse. Notably, there was no difference in Induction deaths or deaths during 
complete remission between the two arms. In UKALL 2003, using DEX as the Induction 
and Maintenance steroid for all patients, extra doses of PEG-ASP, no HD MTX, and 
intrathecal methotrexate rather than ITT, the current actuarial incidence of isolated CNS 
and overall CNS relapse is 3% and 4%, respectively.45 
 
Together, these studies support the elimination of CRT from the majority of T-ALL 
patients without significantly increasing CNS relapse rates or compromising survival.54,62-
64 In these trials, a number of interventions were incorporated into existing backbones to 
compensate for the removal of CRT, including HD MTX, intensified ASP, DEX as the 
corticosteroid, and triple intrathecal chemotherapy (ITT). Not all of these interventions 
were used in each of the above trials, none of which were designed to prove if any single 
intervention could reduce the rate of CNS relapse. AALL1231 will eliminate CRT from 
the majority of patients with T-ALL (all SR and IR) by incorporating the interventions that 
were used successfully to eliminate CRT in UKALL 2003 (and are retained in UKALL 
2011) in to a modified ABFM backbone. AIEOP-BFM ALL 2000 recently demonstrated 
that T-ALL patients with EOC MRD >0.1% had an isolated CNS relapse rate of 7.2% and 
a cumulative extramedullary relapse rate of 18.6% despite the use of DEX, intensified 
ASNase, IT MTX, systemic HD MTX and prophylactic CRT.38 Accordingly, VHR patients 
on AALL1231 will continue to receive 1200 cGy prophylactic CRT. 
 
No IR patients with CNS1 or 2 disease or SR T-ALL or T-LLy patients will receive 
prophylactic radiation therapy. HR T-LLy patients who are CNS1 or 2 will not receive 
prophylactic radiation therapy. IR and VHR T-ALL and T-LLy patients who are CNS3 
will receive CRT during first cycle of Maintenance (1800 cGy). VHR T-ALL patients who 
are CNS1 or 2 disease will receive 1200 cGy CRT during the first cycle of Maintenance.  
 
Additional backbone modifications based on UKALL 2003 and the elimination of CRT in 
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The AALL1231 backbone is based on the UKALL 2003 backbone. On UKALL2003, 231 
patients with more favorable disease characteristics were treated with 1 IM phase and 100 
patients with less favorable disease characteristics were treated with 2 IM phases (both 
Capizzi MTX with PEG-ASP).  
 
SR patients on AALL1231 will receive a single IM phase using Capizzi MTX with PEG-
ASP. This will mirror the standard arm of AALL0434 and the practice at COG institutions 
for over 10 years. If AALL0434 finds HD MTX is superior to Capizzi MTX, AALL1231 
may be amended to change to HD MTX. A subset of T-ALL patients in this arm would 
have received prophylactic CRT on AALL0434. Nevertheless, this is a favorable risk group 
and favorable risk patients on UKALL 2003 who did not receive prophylactic CRT, 
received 1 IM, and had excellent outcomes. 
 
IR patients on AALL1231 will receive 2 IM phases, the first with HD MTX and the second 
with Capizzi. These patients would have received prophylactic CRT on AALL0434. On 
UKALL 2003 less favorable patients received 2 IM phases. The rationale to use HD MTX 
as one of the IM phases instead of two Capizzi IM phases is there are numerous other 
studies demonstrating a reduced risk of CNS relapse with HD MTX.54,59,60 The combination 
will intensify both ASNase and MTX in an effort to reduce the risk of recurrence and 
improve outcomes. This is identical to the approach used for VHR B-cell precursor ALL 
patients on COG AALL1131. 
 
2.1.5 
Rationale for Intensification of Therapy for Patients with EOC BM MRD ≥ 0.1% 
T-ALL patients with EOC MRD ≥ 0.1% and T-ALL patients who fail Induction (M3 
marrow at day 29) have a poor prognosis.38,65 Intensification of therapy in order to achieve 
an MRD-negative remission may improve outcome. AALL1231 will non-randomly assign 
T-ALL patients who fail Induction or have persistent MRD ≥ 0.1% at the EOC to receive 
3 additional intensive multi-agent blocks of therapy in lieu of the HD MTX IM phase. The 
blocks that will be used in this study are the BFM High Risk (HR) Blocks 1-3, which have 
been used for over 15 years in Europe in AIEOP and BFM cooperative group trials in 
patients with high risk B-LL and T-ALL.38,66,67 These HR blocks were non-randomly 
incorporated into treatment in ALL-BFM 95 and AIEOP-ALL95.66,67 In both studies, the 
HR blocks were well tolerated and survival was improved when compared with 
predecessor trials. The blocks subsequently became standard of care for high-risk patients 
in AIEOP and BFM trials. These blocks are also included in the backbone therapy for 
patients in the COG AALL1122 Ph+ ALL trial. 
 
It is hypothesized that most patients with T-ALL who have EOC MRD ≥ 0.1% will become 
MRD negative (undetectable by flow cytometry) after these blocks of relatively intensive 
therapy. It is anticipated that the patients who become MRD negative will have improved 
survival as compared to those that have detectable MRD present at end HR Block 3; and, 
therefore, they will continue on study at DI with or without bortezomib (as randomized) 
followed by an IM phase with Capizzi MTX with PEG-ASP. The patients who remain 
MRD positive at end HR Block 3 are unlikely to be cured with chemotherapy alone and 
will be removed from protocol therapy and eligible to participate in COG HSCT trials. This 
approach, which is analogous to that used in AIEOP-BFM ALL 2009 and COG 
AALL1122, is designed to capture T-ALL subjects who are very high risk, yet may benefit 
from intensification, using established drugs. This approach also establishes a possible 
framework for future collaborative international trials, where a novel agent or novel 
combination may be studied in these high-risk EOC MRD ≥ 0.1% T-ALL patients. 
Similarly, HR T-LLy patients have a poor prognosis and will be treated by these HR BFM 
blocks.64 T-LLy patients who are in a PR or better at the end of these blocks can resume 

  
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protocol therapy at DI with or without bortezomib (as randomized) followed by an IM 
phase with Capizzi MTX with PEG-ASP. T-LLy patients who are not in a PR will be 
removed from protocol therapy. HD MTX is included in the 3 HR blocks. VHR T-ALL 
and T-LLy patients who resume protocol therapy after the 3 HR blocks will receive CRT 
in the 1st cycle (1st four weeks) of maintenance (1200cGy non-CNS3; 1800cGy CNS3). 
 
2.1.6  Rationale for Supportive Care Guidelines for Invasive Fungal Infections.  
AALL1231 amendment #3 incorporates the use of dexamethasone throughout the 
Induction phase of chemotherapy for all patients based on promising results from the 
UKALL2003 and AIEOP BFM ALL 2000 studies. These studies showed improvements in 
event-free survival (EFS) with the use of dexamethasone vs. prednisone during Induction 
in patients with T-ALL. For example, the results of the AIEOP BMF 2000 trial were 
recently published and demonstrated a significant improvement in overall survival (OS) 
from 83% to 91% in children with T-ALL and a prednisone good response when treated 
with dexamethasone in Induction instead of prednisone).68 
 
IFIs are an expected complication on any ALL protocol, and other studies demonstrate the 
use of dexamethasone may increase that risk of IFIs over prednisone-based backbones. In 
the UKALL2003 trial the incidence of Invasive Fungal Infection was 2%, 6% and 3% in 
the standard, intermediate and high risk groups, respectively.69 In the AIEOP BFM ALL 
2000, the reported incidence of IFI on the dexamethasone arm was 1.6% during Induction. 
Direct comparisons between trials is challenging based on the level of details (e.g. 
pathogen) provided and different monitoring and reporting requirements. While IFIs have 
been seen on AALL1231, the current IFI rate for AALL1231 has not exceeded overall 
reported rates of IFIs with other dexamethasone–based induction regimens and the 
induction mortality (from all causes) on the trial has been low and within expected rates 
(<1.5%). 
 
2.2 
Early T cell Precursor ALL (ETP ALL) 
Early T cell Precursor (ETP) ALL is a recently identified type of T-ALL that may carry a poor 
prognosis.70 ETP ALL blasts are defined by a unique immunophenotype, expressing T-lineage 
markers and myeloid/early progenitor markers; however, ETP ALL is not ambiguous-lineage 
leukemia. Despite their T cell origin, very recent work suggests ETP ALL blasts have a gene 
expression profile more similar to myeloid/early progenitor leukemia than lymphoid leukemia.70,71 
ETP ALL blasts also frequently have mutations more commonly found in myeloid leukemia, 
including mutations in histone-modifying proteins and in genes that regulate Ras and cytokine 
receptor signaling.71 
 
Data from St. Jude Children’s Research Hospital (SJCRH) and older AIEOP trials suggested ETP 
ALL patients respond poorly to current chemotherapeutic approaches, but this report included only 
31 ETP patients.70,72 More recent data from AIEOP-BFM ALL 2000 and UK ALL 2003 suggest 
not all of these patients do poorly. 387 T-ALL patients were treated on UKALL 2003. Of these, 
239 had immunophenotypic data allowing for classification as non-ETP, definitive/probable ETP, 
or possible ETP with the definitive, probable, and possible having similar outcome.73 ETP ALL 
patients were less likely to be MRD low risk at the end of induction (4% vs 27%; p = 0.008). They 
also found the ETP ALL patients had a non-statistically significant inferior 5-year EFS (76% vs 
84.6%; p =0.2) and 5-year OS (84.1% vs 90.9%); p = 0.08). The data from UKALL 2003 thus argue 
against stem cell transplant in CR1 for ETP ALL. AIEOP-BFM ALL 2000 demonstrated that ETP 
ALL patients can be classified based on response to chemotherapy, e.g., the majority of patients 
who do poorly are already designated high risk based on prednisone response, end Induction 
morphologic response, and end Induction and EOC MRD38 This study had data on ETP status for 

  
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only 19 patients, with 9/19 remaining in CR1. Fourteen were classified as high risk based on MRD 
alone (10), Induction failure (2), or prednisone poor response (2) with 7/14 relapsing and 2 deaths 
in CR after transplantation in first remission. Five ETP patients were classified as either standard 
(1) or intermediate (4) risk, with 4/5 remaining in CR with chemotherapy alone. 
 
Over 100 patients with ETP ALL have been identified to date on AALL0434, and we project that 
approximately 150 ETP ALL patients will eventually be identified on AALL0434. Once 
AALL0434 data mature, this experience will allow us to assess whether or not ETP ALL is an 
independent predictor of poor risk regardless of MRD response. Based on the conflicting results 
between UKALL 2003, AIEOP-BFM ALL 2000, and SJCRH and the lack of mature outcome data 
from COG AALL0434, it is currently not justified to use ETP as an independent risk factor on 
AALL1231. UKALL 2003 is the largest of these studies and provides the most data in ETP ALL 
and is the backbone of therapy for AALL1231. 
 
2.3 
Impact 
Relapsed T-ALL and T-LLy have a dismal prognosis with the majority of patients relapsing early 
in therapy with chemotherapy refractory disease. This study will test whether the addition of 
bortezomib, which is a very promising agent based on responses seen in relapsed B-ALL and T-
ALL, to an ABFM backbone will decrease relapse risk, improving EFS and OS in children, 
adolescents and young adults with T-ALL and T-LLy. It is anticipated the modifications in the 
chemotherapy backbone will also decrease relapse risk. This trial will also establish if prophylactic 
CRT can be safely eliminated from the treatment in the vast majority (~90%) of pediatric patients 
with T-ALL. We also expect to determine if intensification of chemotherapy in VHR T-ALL and 
T-LLy will prevent relapse in these patients and further identify patients who are chemotherapy 
refractory and require novel agents and/or HSCT for cure. This model could potentially be used for 
future international collaborative trials in VHR patients. Finally, it is anticipated that this trial will 
answer a number of important correlative biologic aims, improving the understanding of the 
biology of T-ALL and T-LLy, which may translate into better therapies in the future. 
 
2.4 
Relevant Pre-clinical Data on Bortezomib 
2.4.1 
Biologic Rationale for Bortezomib  
Bortezomib, a dipeptidyl boronic acid, is a selective inhibitor of the ubiquitin proteasome 
pathway (UPP), which is essential for the degradation of most short-lived and many long 
lived intracellular proteins in eukaryotic cells.74 Bortezomib specifically inhibits the 26S 
proteasome, an ATP-dependent multi-subunit protein that degrades ubiquitinated proteins 
involved in multiple cellular processes, including cell cycle regulation, transcription factor 
activation, apoptosis, and cell trafficking.75,76 Proteasome inhibition stabilizes many cell 
cycle-regulatory proteins that are overexpressed in leukemia cells.77 Previous studies have 
shown that proteasome inhibition may sensitize malignant hematologic cells to apoptosis 
induced by both radiation and chemotherapy.78-80 Apoptosis following proteasome 
inhibition is seen in leukemia cells lines17,81,82 as well as in primary ALL lymphoblasts17 
but not in normal hematopoietic progenitors.83,84 Important regulatory proteins affected by 
inhibition of the UPP system include NF-B, p53, Bax and other cell cycle regulatory 
proteins such as the cyclin-dependent kinase inhibitors p27 and p21.85 It is believed that 
proteasome inhibition alters the ratio of pro-apoptotic and anti-apoptotic proteins within a 
cell, resulting in an increased sensitivity to apoptosis.86 
 
2.4.2 
NF-B Alterations in Hematopoietic Malignancies 
In non-proliferative cells, the inhibitor protein IB sequesters NF-B in the cytoplasm.87 
Cellular stress results in ubiquitination and the subsequent proteasomal degradation of 
IB.87 NF-B dimerizes and rapidly translocates into the nucleus, is phosphorylated, and 
activates the promoter regions of numerous genes, including genes encoding several anti-

  
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apoptotic proteins such as Bcl-2, X-linked inhibitor of apoptosis protein (XIAP), and c-Jun 
N-terminal kinase (JNK).88 Inhibiting proteasomal degradation of IB inhibits NF-B 
nuclear translocation and binding of NF-B to NF-B response elements; this may prevent 
anti-apoptotic responses induced by chemotherapy.87 
 
Studies have shown constitutive activation of NF-B in many hematologic malignancies,80 
including primary ALL,89 acute myeloid leukemia (AML),81 and numerous leukemia cell 
lines.90,91 Constitutive activation of NF-B occurs through a variety of mechanisms, 
including NF-B gene amplification, NF-B chromosomal rearrangements, IB 
mutations, induction of IB kinase (IKK), and the induction of upstream regulators of NF-
B.88 Constitutive NF-B activation has been observed in Philadelphia chromosome 
positive (Ph+) ALL91 and in primary T-cell leukemia.92 Amplification and chromosomal 
rearrangements of NF-B subunits have also been found in adult T-ALL.93 Abnormal 
signaling through Notch1 and PI3K/Akt/mTOR is very common in pediatric T-ALL, and 
one or both of these pathways are dysregulated in the majority of T-ALL blasts.94 NF-B 
was recently demonstrated to be one of the major mediators of Notch1-induced 
transformation in T-ALL.16 Constitutively activated Notch1 activates NF-B through IKK, 
and inhibiting the proteasome is very effective in preclinical models of Notch1-driven 
cancers.16 NF-B can also be activated as a consequence of activated Akt in T cells.95 
Accordingly, proteasome inhibition with bortezomib has the potential to target two of the 
major dysregulated signaling pathways in T-ALL. 
 
Confounding the understanding of the mechanism of action of proteasome inhibition in 
malignancies are recent reports suggesting proteasome inhibitors, including bortezomib, 
may induce NF-B despite degrading IKK in vivo.96-98 Similar to drugs that inhibit other 
biologic and signaling pathways, in vivo assessment of biomarkers can be difficult to 
interpret. Targeting pathways with biologic agents can lead to compensatory feedback 
inhibition, making it difficult to determine the best biomarkers to measure and the 
appropriate time to measure them in vivo, in order to assess pathway activation and 
response to target inhibition. Nevertheless, multiple studies suggest proteasome inhibitors 
are very active in tumors with activated NF-B, including T-ALL.15,99-102 
 
2.4.3 
Proteasome Inhibition Results in Increased Sensitivity to Chemotherapeutic Agents and 
May Overcome Chemotherapy Resistance 
Several studies have shown that inhibition of NF-B can enhance leukemia cell sensitivity 
to chemotherapeutic agents.82,103,104 Both lymphoid and myeloid malignancies show 
enhanced sensitivity to doxorubicin after transient over-expression of mutant IB or 
proteasome inhibition.24,87 Leukemia cells are more sensitive to anthracyclines, etoposide 
and cytarabine in the presence of proteasome inhibitors such as bortezomib.17,83,105-107 
Bortezomib potentiation of anthracyclines and cytarabine in leukemia cells appears to be 
independent of p53 status and multi-drug resistance mechanisms.107,108 Bortezomib also 
enhances doxorubicin and cytarabine apoptosis in vitro in T-cell lymphomas and human 
T-lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia.109,110 Bortezomib 
has been shown to overcome chemotherapy resistance to anthracyclines, alkylators, and 
corticosteroids in a number of malignancies.18-22 Preclinical data suggest that bortezomib 
may sensitize steroid resistant T-ALL cells to corticosteroids.23 Preclinical data also 
suggest that proteasome inhibition may reverse anthracycline resistance in T-ALL.24 
Finally, recent work suggests bortezomib may help overcome chemotherapy resistance in 
leukemic cells by down-regulation of mdr1 and reduction of p-glycoprotein (p-gp) 
expression.98 
 

  
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2.4.4 
Proteasome Inhibition Alters Expression of P53 and Other Regulatory Cell Cycle 
Proteins 
Many short-lived regulatory proteins are degraded by the UPP system in addition to IB, 
and apoptosis following proteasome inhibition may not be exclusively dependent on NF-
B activation.85 Evidence for this has been provided by a murine AML xenograft model111 
and a phase 1 clinical trial.27 Several other regulatory cell cycle proteins are ubiquitinated 
and degraded by the 26S proteasome and could contribute to proteasome-induced 
apoptosis. p53, an ubiquitin-regulated cell cycle checkpoint protein and tumor suppressor, 
accumulates after proteasome inhibition.90 The cyclin-dependent kinase inhibitors p21 and 
p27 are also ubiquitinated and alterations in p21 accumulate in many relapsed 
hematopoietic malignancies.112 
 
2.4.5 
Preclinical Studies Using Bortezomib in T-ALL 
The anti-leukemia activity of bortezomib has been tested in both cell culture and 
xenotransplantation systems. Houghton et al. tested bortezomib as part of the NIH-
sponsored CTEP pediatric preclinical testing program (PPTP).15 Potent bortezomib activity 
was noted in vitro and bortezomib demonstrated significant in vivo activity in murine 
leukemia ALL xenografts, finding a 100% response rate against T-ALL (2 of 2 samples) 
as compared with a 40% (2 of 5 samples) response rate in pre-B ALL.15 Work in the Horton 
lab has shown that bortezomib and DEX have synergistic anti-leukemia interactions in 
vitro.17 Bortezomib also had additive anti-leukemia effects when combined with 
asparaginase, vincristine, doxorubicin or cytarabine.17 Preliminary data indicate that 
bortezomib and etoposide also appear to have at least additive interactions in vitro when 
drug-drug interactions are analyzed using the stringent universal response surface approach 
(URSA)17,113 (Table 1) 
 
Table 1: Drug Interaction Summary: Strength of in vitro bortezomib drug interactions with 
chemotherapy agents using the URSA modeling method. 
 
*Drug interactions were considered synergistic if the combination interaction parameter, 
, was significantly greater than 0 (i.e., 95% confidence interval of  did not include 
zero).113 
 
2.5 
Clinical Experience with Bortezomib 
2.5.1 
Bortezomib in Adult Clinical Trials: Toxicities in Phase 1 and 2 Clinical Trials  
Bortezomib has been evaluated as a single agent and in combination with 
chemotherapeutics in adults with leukemia, multiple myeloma and non-Hodgkin 
lymphoma (NHL), leading to its FDA approval for use in adults with multiple myeloma 
and relapsed NHL. 25,26,114,115 Adult early phase trials have demonstrated that the maximum 
tolerated dose (MTD) of bortezomib is schedule dependent. When administered twice 
weekly for 2 weeks in a 21-day cycle, the MTD, alone or in combination with 
chemotherapy, is 1.3-1.5 mg/m2.32,116,117 In a compilation of results from early phase studies 
in multiple myeloma, the most commonly reported adverse events were nausea (62%), 
fatigue (54%), diarrhea (48%), constipation (41%), thrombocytopenia (41%), pyrexia 

  
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(36%), peripheral neuropathy (35%), vomiting (34%), and anorexia (30%).118 Similar 
toxicities were also found in early phase trials using bortezomib in adults with other 
hematologic malignancies.25,26,119-121 Additional reported toxicities of bortezomib from 
early phase trials in adults include mild elevation of liver transaminases, hyponatremia, 
hypokalemia, fluid retention, orthostatic hypotension, neutropenia, lymphopenia, 
infection, coagulopathy, and anemia.25,26,119-121 
 
Bortezomib has been safely combined with chemotherapeutics in a number of adult trials 
in hematologic malignancies, including: 1) bortezomib (1.3 mg/m2) combined with 
etoposide/prednisone/vincristine/cyclophosphamide and doxorubicin (EPOCH) in adults 
with diffuse large-cell B lymphoma (DLCBL);122 2) bortezomib (1.5 mg/m2) combined 
with pegylated doxorubicin in adults with refractory hematologic malignancies;32 3) 
bortezomib (1.3 mg/m2) combined with rituximab in NHL;123 4) bortezomib (1.3 mg/m2) 
combined with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone plus 
rituximab) in adults with lymphoma;124 5) bortezomib (1.5 mg/m2) in combination with 
idarubicin/cytarabine for adults with AML;125 6) bortezomib (1.6 mg/m2) in combination 
with bendamustine and rituximab in adults with follicular lymphoma;126 7) bortezomib 
(1.3 mg/m2) combined with fludarabine and rituximab in mantle cell lymphoma;117 and 8) 
bortezomib (1.6 mg/m2) combined with CHOP in adults with T-cell lymphoma.127 In all of 
these studies, bortezomib-related toxicities were similar to those found in single agent 
studies, and primarily consisted of electrolyte abnormalities (hyponatremia, hypokalemia), 
cytopenias (neutropenia, lymphopenia, and thrombocytopenia), neuropathy, fatigue, 
malaise, nausea, vomiting, and diarrhea. 
 
2.5.2 
Bortezomib in Adults with T-cell Lymphomas 
Kim and colleagues performed a Phase 2 trial evaluating bortezomib (Days 1 and 8 at 
1.6 mg/m2) in addition to CHOP chemotherapy every 3 weeks for six cycles in adults 
(median age 51 years) with newly diagnosed stage III/IV peripheral T-cell lymphoma.127 
Forty-six patients were treated and 65% had CR. The ORR was 76%, and 3 year OS and 
PFS were 47% and 35%, respectively. The only Grade 3 or higher toxicities reported in 
over 10% of patients were hematologic cytopenias. This same group had previously 
reported a Phase 1 trial of bortezomib and CHOP in 13 patients with aggressive T-cell 
lymphoma, finding an MTD of 1.6mg/m2/dose of bortezomib and similar rates of response 
(CR rate 62%) and toxicity.28 Zinzani and colleagues reported a Phase 2 trial of bortezomib 
as a single agent (1.3mg/m2, Days 1, 4, 8 and 11) in 15 adults with relapsed or refractory 
cutaneous T-cell lymphoma.29 The ORR rate was 67% with a 17% CR and 50% PR rate. 
Grade 3 toxicities included neutropenia, thrombocytopenia, and sensory neuropathy, each 
seen in 2 patients. No patient had a Grade 4 toxicity. Falchook and colleagues reported a 
Phase 1 trial of bortezomib (Days 1 and 8; escalating dose from 0.7 mg/m2 to 1.3 mg/m2) 
in combination with gemcitabine and liposomal doxorubicin in adults with advanced 
refractory malignancies. Sixty five patients were treated and the best responses were found 
in patients with cutaneous T-cell lymphoma (6 of 7 PR).30 
 
2.5.3 
Single Agent Bortezomib in Pediatric Clinical Trials: DLT and Pharmacokinetics 
Blaney et al. conducted a bortezomib phase 1 study in pediatric patients with 
relapsed/refractory solid tumors.128 Bortezomib was administered twice weekly for 2 
consecutive weeks at either 1.2 mg/m2 or 1.6 mg/m2 followed by a 10-day rest period. In 
the 12 patients evaluable for toxicity, thrombocytopenia was dose-limiting and prevented 
administration of a complete treatment cycle. The average proteasome inhibition 1 hour 
after drug administration on Day 1 was 67% ± 7% at 1.2 mg/m2 and 76% ± 3% at 
1.6 mg/m2. Grade 3 thrombocytopenia was seen in 2 of 5 evaluable patients receiving 
bortezomib at 1.6 mg/m2. A Phase 1 study of bortezomib in patients with 

  
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relapsed/refractory leukemia (ADVL0317) demonstrated a bortezomib MTD of 1.3 
mg/m2.27 DLTs at the 1.7 mg/m2 dose level were altered mental status (n=1) and Grade 4 
hypotension followed by Grade 5 hypoxia in one patient with febrile neutropenia. 
Hypotension and pulmonary toxicity, although rare, have been previously reported in 
adults.116 Pharmacokinetic profiles were similar to those observed in adults. At the 1.3 
mg/m2 dose, bortezomib had an estimated Cmax of 63 ± 16 ng/mL, clearance of 49 ± 13 
L/h with a rapid distribution half life (3.5 ± 1.7 min) and a mean terminal half life of 12 ± 
1.3 h.27 The dose of bortezomib in this study will be 1.3 mg/m2, the MTD determined in 
ADVL0317 and currently being studied in AALL07P1. 
 
2.5.4 
Pediatric Bortezomib Combination Studies in Hematologic Malignancies 
The Therapeutic Advances in Childhood Leukemia (TACL) consortium recently 
completed a Phase 1-2 study of bortezomib (1.3 mg/m2) combined with a 4-drug Re-
Induction chemotherapy regimen (vincristine, DEX, pegylated L-asparaginase, and 
doxorubicin) (TACL 2005-03) in patients with second or greater relapse. In the Phase 1 
portion of the study, 10 patients were treated with 4-drug Re-Induction combined with 
bortezomib.33 Four patients were treated at 1 mg/m2 with no DLT, and 6 were treated at the 
1.3 mg/m2 dose level and this combination was adequately tolerated. One patient with a 
prior history of hypophosphatemia had dose-limiting hypophosphatemia and 
rhabdomyolysis (secondary to hypophosphatemia) after one dose of bortezomib at 1.3 
mg/m2. This patient died from diffuse zygomycosis on Day 17. Five other patients treated 
at 1.3 mg/m2 did not experience a DLT, and 1.3 mg/m2 was the recommended Phase 2 
dose. Of the 9 patients evaluable for bone marrow response, 6 achieved a CR and one had 
a bone marrow CR with persistent CNS leukemia. There was no overall increase in 
peripheral neuropathy. Only 2 patients had mild peripheral neuropathy (Grades 1 and 2). 
Twenty-two patients were treated on the phase 2 portion of the study which closed early 
secondary to reaching a favorable efficacy end-point.129 The CR rate was 64%, the ORR 
was 73% (CR + CRp), and 2 yr. OS was 41%. Only 2 patients with T-ALL were enrolled. 
Both, who were in second relapse, did not respond. All 22 patients completed the 4 doses 
of bortezomib. Ten of 22 subjects had Grade 3 or higher infection and 3 subjects had 
infectious death, leading to the use of prophylactic antimicrobials. Of note, infectious 
toxicities are commonly far greater in relapsed ALL trials (as described below) than in the 
trials in newly diagnosed patients. Two patients developed Grade 3 peripheral neuropathy. 
Other Grade 3 and 4 toxicities were no more common than expected on backbone alone. 
 
AALL07P1 is a Phase 2 trial currently open for patients with ALL in first relapse that 
incorporates bortezomib into the AALL01P2 backbone. Bortezomib (1.3 mg/m2) is given 
on Days 1, 4, 8, and 11 of Block 1 and on Days 1, 4 and 8 of Block 2. AALL07P1 recently 
completed the second stage of the Simon 2-stage design. As described above (Section 
2.1.1), forty-two CRs were observed amongst patients with early and intermediate risk 
relapses; the efficacy boundary was crossed, and bortezomib was deemed worthy of further 
investigation in B-lineage ALL. More patients who achieved CR2 on AALL07P1 were 
MRD <0.1% when compared to similar patients treated on AALL01P2 (backbone alone). 
Sixteen of 39 (41%) B-lineage patients who attained CR2 on AALL01P2 were MRD 
<0.1%, as compared with 25 of 40 (63%) B-lineage patients who attained CR2 on 
AALL07P1 (p = 0.07) AALL07P1 also enrolled T-ALL and T-LLy patients with 
descriptive statistics regarding response. In AALL01P2, only 1 of 7 T-ALL (17%) patients 
attained CR at the end of Block 1. Thus far, 17 evaluable T-ALL patients have been treated 
on AALL07P1 and 11 of 17 (65%) have attained CR at the end of Block 1. While the 
number of T-ALL patients treated is rather small, the observed CR2 rate is very promising 
in comparison to historical control data from patients with T-ALL and BM relapse and the 
CR2 rate observed is similar to that seen in early relapse B-ALL patients (64%). 

  
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In addition, infectious toxicity on AALL07P1 during Block 1 therapy is similar to 
AALL01P2 (backbone alone) and ADVL04P2 (backbone plus epratuzumab). Each of 
these relapsed ALL trials have a 45% Grade 3-5 infection rate with 2-4 infectious deaths 
in Block 1. Accordingly, these data suggest that the addition of bortezomib is unlikely to 
increase infectious toxicity significantly over that observed with the chemotherapy 
platform. As of January 2013, a total of 93 eligible patients have been enrolled on the trial. 
Other than infection, the only Grade 3 or higher non-hematologic toxicities that occurred 
in over 10% of subjects during Block 1 include hypokalemia (12.3%), hyponatremia 
(13.8%), and hypotension (12.3%). One subject developed reversible, Grade 3 sensory 
peripheral neuropathy. 
 
2.5.5 
Other Pediatric Studies 
Two pediatric COG clinical trials testing bortezomib in combination with Re-Induction 
chemotherapy in children with relapsed hematologic malignancies were recently 
completed. AHOD0521 investigated bortezomib (1.2 mg/m2, Days 1, 4, and 8) combined 
with ifosfamide and vinorelbine in pediatric patients and young adults with relapsed 
Hodgkin lymphoma. This study enrolled 25 subjects and closed early for not meeting an 
efficacy end-point based on CT imaging despite a favorable efficacy signal using PET 
imaging.130 There were no Grade 3 or 4 non-hematologic toxicities that occurred in over 
10% of patients. Rare Grade 3 or 4 events that were possibly related to bortezomib included 
hypokalemia, hypophosphatemia, anorexia/vomiting, limb pain, and neuralgia. One 
subject developed Grade 3 peripheral neuropathy early in therapy that did not recur with 
subsequent doses of bortezomib. AAML07P1 was a Phase 1/2 pilot study combining 
bortezomib with either idarubicin/cytarabine (patients with low prior anthracycline 
exposure) or etoposide/cytarabine (patients with high prior anthracycline exposure) in 
pediatric patients with relapsed AML. The study enrolled a total of 52 subjects between 
dose-finding phase and efficacy phases. The study closed early as it did not meet a pre-
determined efficacy threshold, using a Simon 2-stage design. Bortezomib was tolerated at 
1.3 mg/m2 given on Days 1, 4, and 8. There were 4 deaths. This rate of death is comparable 
to the rate found on AALL01P2. Non-hematologic Grade 3 or higher toxicities were no 
more prevalent than expected on the chemotherapy backbone, and included infection, 
hypotension, hypokalemia, transaminitis, esophagitis, mucositis, nausea, vomiting, and 
abdominal pain (AAML07P1, study report March 31, 2012). AAML1031 is an on-going 
Phase 3 trial for children with de novo AML. A primary objective of the trial is to determine 
if bortezomib with cytarabine, daunomycin and etoposide (ADE) increases EFS when 
compared to ADE alone. All patients are randomized to receive or not receive bortezomib 
for 4 cycles of chemotherapy. This study opened to accrual on June 20, 2011. As of January 
15, 2013, 249 patients have enrolled. Grade 3-4 toxicities are comparable between arms 
(Table 2). Grade 3 or higher toxicities and infectious toxicities by treatment blocks are 
shown in Table 3. There have been 2 deaths on the non-bortezomib arm and 4 deaths on 
the bortezomib arm during Induction 1. 
 
Table 2a: Grade 3 or higher toxicities on AAML1031* 
Treatment block 
Bortezomib-
containing arm** 
Non-bortezomib 
containing arm** 
Induction 1 
93 of 112 (83%) 
84 of 110 (76%) 
Induction 2 
57 of 93   (61%) 
40 of 75   (53%) 
Intensification 1 
45 of 63   (71%) 
40 of 58   (69%) 
Intensification 2 
32 of 40   (80%) 
30 of 38   (79%) 
 
Table 2b: Grade 3 or higher infections or infestations on AAML1031* 

  
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Treatment block 
Bortezomib-
containing arm** 
Non-bortezomib 
containing arm** 
Induction 1 
49 of 112 (44%) 
51 of 110 (46%) 
Induction 2 
39 of 93   (42%) 
29 of 75   (39%) 
Intensification 1 
45 of 63   (71%) 
25 of 58   (43%) 
Intensification 2 
30 of 40   (75%) 
26 of 38   (68%) 
*Based on data as of September 30, 2012 
**n = total number of Grade 3 or higher infections and total number treated. If a subject 
has more than 1 infection it is considered more than one event. 
 
2.5.6 
Bortezomib and Bone Health 
Unlike many agents used to treat cancer, bortezomib promotes bone formation and may be 
protective against ON.131,132 At least eight different clinical trials (reviewed in PMID: 
22226939) have found bortezomib to have positive effects on bone health, including lower 
rates of pathologic fractures, increased bone volume and bone density, and prevention of 
development of steroid-induced bone disease. For example, on the Phase 3 VISTA trial, 
previously untreated multiple myeloma patients were randomized to receive up to 
54 weeks’ therapy with bortezomib, melphalan, and prednisone or melphalan and 
prednisone alone.133 Patients who developed osteopenia or evidence of lytic destruction of 
bone or osteopenia were to initiate bisphosphonates, following standardized ASCO 
guidelines.134 On the bortezomib arm there were lower rates of progression because of 
worsening bone disease and rates of skeletal AEs, (3% vs. 11% and 4% vs. 5%, 
respectively), as well as need for bisphosphonates (73% vs. 82%). There have been over 
30 clinical trials that have assessed biomarkers of bone formation in patients treated with 
bortezomib (also reviewed in PMID: 22226939). On many of these trials, patients were 
treated with corticosteroids (prednisone or DEX) with or without bortezomib. Consistently 
across all of these trials bortezomib was found to have a positive effect on biomarkers of 
bone health and to be protective against steroid-induced negative effects. No study has 
found a negative biomarker profile consistent with deleterious bone health in bortezomib 
treated patients. 
 
2.6 
Developmental Plans  
AALL1231 is the successor study to AALL0434, which is the current COG Phase 3 trial for patients 
with newly diagnosed T-ALL and T-LLy, and will open to enrollment when AALL0434 meets 
accrual goals in late 2014. 
 
AALL0434 is a COG group-wide Phase 3 clinical trial that uses a 2 x 2 factorial design to 
randomize patients with T-ALL and T-LLy to receive or not receive six 5-day courses of nelarabine 
and to randomize T-ALL patients to receive Capizzi MTX with PEG-ASP or HD MTX during a 
single IM phase. Nelarabine is given during Consolidation, the second half of DI, and the first 3 
Cycles of Maintenance. AALL1231 has been designed such that the treatment backbone can be 
modified easily to incorporate potential changes to the treatment backbone that might be indicated 
based on results of the AALL0434 randomized questions. As nelarabine and bortezomib have 
potentially overlapping toxicities, and the combination of these two agents has not been studied to 
date, bortezomib will not be given during the blocks of therapy that include nelarabine in 
AALL0434. Accordingly, if the nelarabine arm on AALL0434 is found to be superior after 
AALL1231 opens, this trial will be amended to incorporate nelarabine during the same therapeutic 
blocks. The proposed changes to the backbone of this study will also not affect the ability to 
incorporate nelarabine, as these changes do not occur during consolidation, the second half of DI, 
or during maintenance while receiving nelarabine. Nevertheless, if the trial is amended to include 
nelarabine, additional toxicity monitoring will be added to the amended trial. Patients with IR and 
VHR T-ALL and T-LLy on this study will receive 2 IM phases as described above. SR T-ALL 

  
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patients and T-LLy patients will receive a single IM, using Capizzi MTX with PEG-ASP. If 
AALL0434 determines HD MTX is superior to Capizzi MTX with PEG-ASP in T-ALL, this study 
will be amended to change the SR T-ALL IM to HD-MTX. Because HD MTX is given in 
AALL1231 to IR (during IM#1) and VHR (during HR BFM Blocks), no modification will be 
needed for these patients if HD MTX is found to be superior to Capizzi MTX with PEG-ASP on 
AALL0434. If Capizzi MTX is found to be superior, no changes will need to be made to any risk 
group. SR, IR, and VHR T-ALL and T-LL patients are all receiving Capizzi MTX. 
 
 
2.7 
Correlative Biology Studies 
 
2.7.1 
Minimal Residual Disease Determination at Serial Time Points During Therapy  
MRD is the single most powerful prognostic factor in childhood ALL.36-38 A number of 
large studies have investigated the sensitivity and specificity of MRD at different time 
points on a variety of treatment protocols, using either flow- or PCR-based technologies.39 
While the majority of data suggest that end Induction MRD assessment is the best predictor 
of outcome in B-ALL, recent data from AIEOP-BFM ALL 2000 strongly suggest that EOC 
MRD is a better predictor of adverse outcome in T-ALL, though response at early time 
points is essential to identify the patients with the best prognosis.38 Currently, therapeutic 
response in T-LLy is limited to bone marrow morphology and radiographic imaging. While 
MRD may be useful in determining prognosis, MRD has not been formally or extensively 
studied in patients with T-LLy. 
 
AALL1231 will test the following hypotheses: (1) the persistence of positive MRD at both 
end Induction and end Consolidation in the bone marrow will correlate with inferior EFS 
in patients with T-ALL, and persistence of positive MRD at end of induction in bone 
marrow will correlate with inferior EFS in patients with T-LLy; (2) rates of MRD positivity 
will be decreased in the bortezomib-containing arm as compared with the control (non-
bortezomib) containing arm; (3) the 3 HR BFM blocks will reduce MRD+ rates in VHR 
T-ALL and that the reduction in MRD+ rates will correlate with improved EFS and OS; 
and, (4) a higher percentage of ETP-ALL patients will be MRD >0.1% at the end of 
consolidation as compared with non-ETP ALL patients. Additional details regarding MRD 
testing are included in Appendix XI. 
 
2.7.2 
Evaluating Mechanisms of Bortezomib Response and Mechanisms of Bortezomib 
Resistance in T-cell ALL 
AALL1231 is designed to test the hypothesis that the proteasome inhibitor bortezomib can 
be safely and effectively incorporated into a modified BFM backbone in patients with T-
ALL and T-LLy. The goal of these correlative studies is to determine if changes in 
proteasome function or cell stress protein expression patterns can predict bortezomib 
response and drug resistance in T-ALL. The primary Aims of these correlative studies are: 
(1) to delineate the mechanisms of bortezomib action and resistance in T-ALL to determine 
if proteasome alterations correlate with clinical response, as measured by MRD and EFS; 
and (2) to determine if reverse phase protein lysate arrays (RPPA) predict chemotherapy 
response or resistance. Both arms are eligible for these optional studies.  
 
The central hypothesis is that UPR activation, or induction of other protein cell stress 
pathways in ALL-lymphoblasts, can predict chemotherapy response, and ultimately 
clinical outcome. These studies are optional and performed on a research basis. No results 
will be given back to patients. Additional details describing the rationale, feasibility, 
preliminary data, experimental methods, and statistical analysis are included in Appendix 
XII. 
 

  
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2.7.3 
Identifying Biomarkers and Mechanisms of Chemotherapy Resistance and Response in 
T-ALL, Focusing on ETP ALL. 
T-ALL is a heterogeneous disease with variable responses to therapy. To date, the ability 
to predict outcome based upon biologic features in T-ALL has been limited as the majority 
of identified genetic alterations are largely not prognostic in therapy stratified by disease 
response. ETP ALL is a newly identified phenotype of T-ALL with a poor prognosis in 
some reports. ETP ALL blasts have a heterogeneous mix of genetic mutations; however, 
these aberrations manifest biochemically as changes in a limited set of signal transduction 
pathways that preliminary data suggest may be important in the majority of ETP ALL. 
Accordingly, T-ALL patients may be better risk allocated based on biochemical pathway 
alterations. These correlative studies will identify biomarkers and mechanisms of 
chemotherapy resistance and response in T-ALL, focusing on ETP ALL.  
 
The central hypothesis is that the signaling network differences in ETP ALL with be 
distinct from signaling networks in non-ETP ALL and these differences will predict 
whether the leukemia will respond to chemotherapy. These studies are optional and 
performed on a research basis. No results will be given back to patients. Additional details 
describing the rationale, feasibility, preliminary data, experimental methods and statistical 
analysis are included in Appendix XII. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES 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 COG Registry 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 patient with a 
known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility, Screening, Biology and Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. 
Each patient will be assigned only one BPC number per COG Patient ID. For additional 
information about the labeling of specimens please refer to the Pathology and/or Biology 
Guidelines in this protocol. 
 
Please see Appendix XIII for detailed CTEP Registration Procedures for Investigators and 
Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures including: how 
to download site registration documents; requirement s for site registration, submission of 
regulatory documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. 
Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) 
Regulatory Office and 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 

  
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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 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. 
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the lead protocol 
organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org or 
from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com 
 
3.1.4 
Timing 
 
a. T-ALL 
PATIENTS 
MUST 
BE 
ENROLLED 
ON 
AALL08B1 
OR 
PROJECT:EVERYCHILD (APEC14B1, IF OPEN FOR CLASSIFICATION OF 
NEWLY DIAGNOSED ALL PATIENTS) BEFORE ENROLLING ON AALL1231. 
 
T-LLY: PATIENTS WITH T-LLY ARE INELIGIBLE FOR AALL08B1. 
 
EVERY EFFORT SHOULD BE MADE TO ACQUIRE AS MUCH TISSUE AS 
POSSIBLE. SPECIFIC INSTRUCTIONS REGARDING TISSUE SUBMISSION 
ARE OUTLINED IN SECTION 13.6. OF NOTE, T-LLY SPECIMENS, 
INCLUDING DIAGNOSTIC MRD, ARE SUBMITTED AS PER THE 
INSTRUCTIONS IN AALL1231 AS OUTLINED IN SECTIONS 13 AND 14. 
 

  
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b. 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. 
 
c. Study enrollment: Patients are randomized to receive or not receive bortezomib before 
protocol therapy begins. Accordingly, Patients must be enrolled on AALL1231 
before protocol therapy begins. The only exceptions are the first dose of intrathecal 
chemotherapy may be given before enrollment when administered as part of the initial 
diagnostic lumber puncture, and in select circumstances, corticosteroids or emergent 
radiation may be given before enrollment as defined in Section 3.2.2 and Section 3.3.  
 
The date protocol therapy is projected to start must be no later than five (5) calendar 
days after the date of study enrollment. 
 
d. Eligibility studies: Patients must meet all eligibility criteria prior to enrollment. Unless 
otherwise indicated in the eligibility section below, all clinical and laboratory studies to 
determine eligibility must be performed within 7 days prior to enrollment. 
 
e. Initiation of systemic protocol therapy: Systemic Induction therapy, with the exception 
of steroid pretreatment as outlined below (Section 3.2.2), must begin within 72 hours of 
the first dose of intrathecal chemotherapy. 
 
3.1.5 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study. 
 
3.1.6 
Randomization 
Randomization will take place at the time a patient is enrolled via OPEN. Randomization will 
occur prior to Induction therapy for all patients (T-ALL and T-LLy). 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the time of 
audit. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Imaging studies, if applicable, must be 
obtained within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
INCLUSION CRITERIA 
 
a. Classification Study:  
• 
T-ALL: 
T-ALL 
patients 
must 
be 
enrolled 
on 
AALL08B1 
or 
Project:EveryChild (APEC14B1, if open for the classification of ALL 
patients) prior to treatment and enrollment on AALL1231. 
 
b. Age at Diagnosis: All patients must be > 1 and < 31 years of age. 
 
c. Diagnosis: Patients must have newly diagnosed T-Lymphoblastic Leukemia (T-ALL) 
or T-Lymphoblastic Lymphoma (T-LLy) Stages II-IV (see Appendix VIII). 

  
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Note: A diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase 
or evidence of B-lineage derivation (CD19/CD22/CD20), and express either surface or 
cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, 
and are present either in peripheral blood or >25% in the bone marrow. If surface CD3 
is expressed on all leukemic cells, additional markers of immaturity, including TdT, 
CD34 or CD99 will be assessed for expression. Cases with uncertain expression will 
receive additional review within the appropriate COG reference laboratory. 
 
For T-LLy patients with tissue available for flow cytometry, the criterion for diagnosis 
should be analogous to T-ALL. For tissue processed by other means (i.e. paraffin 
blocks), the methodology and criteria for immunophenotypic analysis to establish the 
diagnosis of T-LLy defined by the submitting institution will be accepted. See 
pathologic diagnosis recommendation in Section 13.4 and required studies in Table 7.2, 
including diagnostic bone marrow MRD. 
 
d. Informed consent: All patients and/or their parents or legal guardians must sign a written 
informed consent. Assent, when appropriate, will be obtained according to institutional 
guidelines. 
 
3.2.2 
EXCLUSION CRITERIA 
 
a.  Prior Therapy: Patients must not have received any cytotoxic chemotherapy for either 
the current diagnosis of T-ALL, T-LLy or for any cancer diagnosis prior to the initiation 
of protocol therapy on AALL1231, with the exception of: 
• 
Steroid pretreatment: Prednisone or methylprednisolone for ≤ 120 hours (5 days) 
in the 7 days prior to initiating Induction chemotherapy or for ≤ 336 hours (14 
days) in the 28 days prior to initiating Induction chemotherapy. Prior exposure to 
ANY steroids that occurred > 28 days before the initiation of protocol therapy 
does not affect eligibility. The dose of prednisone or methylprednisolone does not 
affect eligibility. 
• 
Intrathecal cytarabine (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) Systemic 
chemotherapy must begin within 72 hours of this IT therapy; or  
• 
Pretreatment with hydroxyurea; or 
• 
600 cGy of chest irradiation, if medically necessary.  
Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy 
is not allowed with the exception of a single dose of dexamethasone used during 
sedation to prevent or treat airway edema. Inhalation steroids and topical steroids are 
not considered pretreatment. 
 
b. Peripheral neurotoxicity: Pre-existing ≥ grade 2 sensory or motor peripheral 
neurotoxicity. 
 
c. Seizures disorder: Uncontrolled seizure disorder 
 
d. Diagnosis of Down syndrome (Trisomy 21)  
 
e. Patients who are pregnant since fetal toxicities and teratogenic effects have been noted 
for several of the study drugs. A pregnancy test is required for female patients of 
childbearing potential. 
 

  
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f. 
Lactating females who plan to breastfeed. 
 
g. Sexually active patients of reproductive potential who have not agreed to use an 
effective contraceptive method for the duration of their study participation. 
 
h 
Patient has hypersensitivity to bortezomib, boron, or mannitol. 
 
i 
Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
 
j 
Participation in clinical trials with other investigational agents not included in this trial, 
within 14 days of the start of this trial and within 30 days of any dose of bortezomib. 
 
3.2.3 
Regulatory Requirement 
a. All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
3.3 
DEFINITIONS 
 
3.3.1 
INITIAL WBC  
The first WBC at the treating COG institution. If prior therapy (i.e. steroids) or IV hydration 
has been administered then the initial WBC prior to therapy and/or hydration should be 
used. 
 
3.3.2 
CNS STAGING AT DIAGNOSIS (for both T-ALL and T-LLy patients) 
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 of < 5/ μL WBCs and cytospin positive for blasts or ≥ 5/μL 
WBCs with negative Steinherz Bleyer algorithm (see below). 
 
CNS 2a:  < 10/ μL RBCs; < 5/ μL WBCs and cytospin positive for blasts; 
CNS 2b:  ≥ 10/ μL RBCs; < 5/ μL WBCs and cytospin positive for blasts; and 
CNS 2c:  ≥ 10/ μL RBCs; ≥ 5/ μL WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithm (see below). 
 
CNS3:  In CSF, presence of ≥ 5/ μL WBCs and cytospin positive for blasts and/or clinical 
signs of CNS Leukemia. 
 
CNS 3a:  < 10/ μL 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); and 
CNS 3c:  Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome). 
 
3.3.3 
TESTICULAR INVOLVEMENT AT DIAGNOSIS  
Unilateral or bilateral testicular disease based on clinical exam or imaging. Biopsy is 
required if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic 
mass. 
 
3.3.4 
BONE MARROW STATUS for T-ALL 
M1:  < 5% lymphoblasts 
M2:  5 - 25% lymphoblasts 
M3:  > 25% lymphoblasts. 
 

  
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3.3.5 
BONE MARROW STATUS FOR T-LLy PATIENTS 
The MRD status of T-LLy patients is required at diagnosis in the MRD central reference 
laboratory and patients will be risk-stratified as described below. Marrow must have <25% 
morphologic blasts to be classified as T-LLy. 
 
3.3.6 
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 = 
1500/L; blood WBC = 46000/L; blood RBC = 3.0 X 106/L: 
 
60  = 0.04  >  2X   46000   = 0.015 
1500                       3.0 X 106 
 
3.4 
RISK STRATIFICATION 
Criteria for risk stratification as Standard Risk (SR), Intermediate Risk (IR) or Very High Risk (VHR) 
for patients with T-ALL or T-LLy enrolled on this trial are outlined in the table below. 
 
Note: Chemotherapy should not be delayed awaiting formal risk stratification by the study team in 
iMEDIDATA Rave. Please contact the study chair if there are questions regarding risk stratification 
 
 
 
T-ALL 
 
T-LLy% 
 
SR# 
IR 
IR 
VHR 
SR 
IR 
IR 
VHR 
Bone Marrow 
Results 
 
 
 
 
 
 
 
 
MRD at 
diagnosis* 
 
 
 
 
<1% 
<1% 
≥1% 
Any 
Day 29 Status 
M1 
M1 
M1 or M2 
M3^ 
 
 
 
 
MRD at Day 29 
<0.01% 
<0.01% 
≥0.01% 
Any 
 
 
 
 
MRD at EOC+ 
 
 
<0.1% 
≥0.1%^ 
 
 
 
 
CNS Status** 
CNS1 
Any 
Any 
Any 
CNS1 
Any 
Any 
Any 
LP prior to 
steroids  
Yes 
Yes or No 
Yes or No 
Yes or No 
Yes  
Yes or 
No 
Yes or 
No 
Yes or 
No 
Other Considerations 
 
 
 
 
 
 
 
 
Testicular 
Involvement$ 
None 
Any 
Any 
Any 
None 
Any 
Any 
Any 
Steroid Pretreatment@ 
None 
Any 
Any 
Any 
None 
Any 
Any 
Any 
End Induction 
Response 
 
 
 
 
PR or 
CR 
PR or 
CR 
PR or 
CR 
SD or 
NR 
*MRD result from central reference lab 
 
^M3 at day 29 or MRD≥0.1% at EOC = VHR 
#SR=standard risk; IR=intermediate risk; VHR=very high risk 
**CNS status: Any patient who is CNS2 or CNS3 cannot be Standard Risk and will be assigned to IR or VHR based on 
MRD response (T-ALL) or end Induction radiographic response (T-LLy) 
$Testicular disease: Any patient who has testicular involvement at diagnosis cannot be Standard Risk and will be 
assigned to IR or VHR based on MRD response (T-ALL) or end Induction radiographic response (T-LLy) 
@Any patient receiving corticosteroids within 4 weeks prior to the diagnostic lumbar puncture cannot be standard risk 
and will be assigned to IR or VHR based on MRD response. 

  
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% T-LLy: See Section 10.4 for additional information regarding the type of imaging and subsequent evaluations used to 
determine response. See also, evaluation tables in Sections 7.2, 7.3, and 7.4. 
+ Patients with Day 29 MRD <0.01% do not need EOC MRD, regardless of features used in risk stratification, including 
steroid pretreatment, CNS or testicular disease status 
 
 
3.4.1 
CORTICOSTEROID PRETREATMENT AND RISK STRATIFICATION 
It is recognized that T-ALL and T-LLy patients often present with hyperleukocytosis 
and/or mediastinal mass that requires emergent therapy. In addition, many patients present, 
having already recently received corticosteroids prior to the diagnosis of T-ALL or T-LLy. 
Corticosteroid exposures that may affect eligibility for the trial are listed in Section 3.2.2. 
Note: Inhalation steroids and topical steroids are not considered pre-treatment. 
 
Patients with T-ALL receiving steroids within one month (Day -28 to Day -1) prior to the 
diagnostic lumbar puncture can not be SR and will be assigned to IR or VHR category 
depending on MRD response 
 
Patients with T-LLy receiving steroids within one month (Day -28 to Day -1) prior to the 
diagnostic lumbar puncture or bone marrow can not be SR and will be assigned to the IR 
or VHR category depending on end Induction response 
 
Patients with T-ALL or T-LLy who received steroids > 28 days preceding diagnosis but 
did not receive corticosteroids within the 28 days (Day -28 to Day -1) preceding diagnosis 
will not have risk allocation changed and can be SR. 
 
Pre-treatment with prednisone or equivalent does not change the classification of CNS 
status, e.g. if a patient is pre-treated with corticosteroids and diagnostic LP demonstrates 
CNS 1 or CNS2, then that patient is NOT treated as CNS3 because of the prior steroid 
exposure. 
 
Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is 
not allowed with the exception of a single dose of dexamethasone used during sedation to 
prevent or treat airway edema. Patients who receive a single dose of dexamethasone to 
prevent or treat airway edema in the 28 days preceding diagnosis as described in section 
3.2.2 are eligible for study; however, if this dose was given prior to the diagnostic lumbar 
puncture they can not be SR and will be assigned IR or VHR category based on MRD 
response. Pre-treatment with a single dose of dexamethasone does not change the 
classification of CNS status. 
 
3.5 
PHILADELPHIA CHROMOSOME POSITIVE (Ph+) 
BCR-ABL1 (formerly known as BCR-ABL) fusion determined by FISH or RT-PCR 
 
T-ALL patients entered onto AALL1231 who are later found to meet eligibility criteria for the 
AALL1122 Ph+ ALL study (or successor) are not eligible for post-Induction therapy on 
AALL1231 and should be taken off protocol therapy prior to Day 15 of Induction therapy. 
 
T-LLy patients entered onto AALL1231 who are later found to meet the criteria for Ph+ T-LLy are 
not eligible for post-Induction therapy on AALL1231 and should be removed from protocol therapy 
prior to or at the end of Induction. 
 
 

  
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4.0 
TREATMENT PLAN 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
See Experimental Design Schema T-ALL and Experimental Design Schema:T-LLy 
 
4.1.1 
Randomization 
All T-ALL and T-LLy patients will be randomized upon enrollment to receive Induction 
treatment ± bortezomib. Arm A is treatment without bortezomib and Arm B is 
treatment with bortezomib. After Induction, all patients will receive the same 8 weeks of 
Consolidation therapy. Subsequent therapy will be dependent on risk assignment, as 
detailed below. 
 
4.1.2 
Treatment based on Risk Assignment  
(see also Experimental Design Schema T-ALL and Experimental Design Schema: T-LLy) 
 
a. Standard Risk T-ALL and T-LLy patients will be assigned to backbone therapy with 
one Interim Maintenance (IM) phase with Capizzi Methotrexate (CMTX) ± 
bortezomib. (See Section 3.3 for definition of SR-T-ALL and SR-T-LLy) 
 
Standard Risk T-ALL and T-LLy patients will NOT receive CRT. Pretreatment 
with steroids may preclude Standard Risk status (see Section 3.3). 
 
b. Intermediate Risk T-ALL and T-LLy will be assigned to backbone therapy with 2 IM 
phases: the first IM phase with High Dose Methotrexate (HDMTX) and the second 
occurring after Delayed Intensification (DI) with Capizzi Methotrexate (CMTX) ± 
bortezomib. (See Section 3.3 for definition of IR-T-ALL and IR T-LLy) 
 
Only Intermediate Risk T-ALL and T-LLy patients who are CNS3 will receive 
CRT (1800 cGy) during 1st cycle (first 4 weeks) of Maintenance.  
 
c. Very High Risk T-ALL patients will be assigned to backbone therapy that includes 3 
HR Intensification Blocks. These patients will be risk assessed again after the 3 HR 
Blocks: T-ALL patients who are MRD positive (detectable by flow cytometry at any 
level) will be taken off protocol therapy and T-ALL patients who are MRD negative 
(undetectable at any level by flow cytometry) will remain on protocol therapy and will 
receive one DI (with or without bortezomib as randomized) and one CMTX IM phase. 
(See Section 3.3 for definition of VHR-T-ALL) 
 
All VHR T-ALL patients receive CRT during the first cycle of Maintenance. 
CNS1 or CNS2 will receive 1200 cGy prophylactic CRT. CNS3 will receive 1800 
cGy therapeutic CRT. 
 
d. Very High Risk T-LLy patients will initially receive backbone therapy for Induction 
and Consolidation and then receive 3 HR Intensification Blocks. Disease evaluation 
will again be performed after the 3 HR Blocks. 
1. T-LLy patients with no response or progressive disease as defined in Section 
10.4 will be removed from protocol therapy. 

  
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2. Patients with a radiographic partial response as defined in Section 10.4 should 
be re-biopsied. T-LLy patients with biopsy proven persistent disease and/or 
morphologically positive bone marrow will be taken off protocol therapy. If 
re-biopsy is not feasible because of surgical morbidity concerns, the study 
chair should be contacted and the subject may be eligible to continue on 
therapy. 
3. T-LLy patients who are radiographic partial responders with negative biopsies 
or complete responders will remain on protocol therapy and be treated with 
backbone therapy with 1 DI and 1 CMTX IM phase in treatment Arm A 
(without bortezomib)-VHR or Arm B (with bortezomib)-VHR. (See Section 
3.3 for definition of VHR-T-LLy) 
 
VHR T-LLy patients who are CNS3 will receive 1800 cGy therapeutic 
CRT. 
 
4.1.3 
Treatment Arms (T-ALL and T-LLy) 
 
Risk Category- Arm A (Without Bortezomib) 
(See Appendix I for Therapy Delivery Maps) 
Standard Risk (A-SR) 
Intermediate Risk (A-
IR) 
Very High Risk (A-
VHR) 
Induction (no 
bortezomib) 
Induction (no 
bortezomib) 
Induction (no 
bortezomib) 
Consolidation 
Consolidation 
Consolidation 
IM (CMTX) 
IM#1 (HDMTX) 
3 HR Intensification 
blocks 
DI (no bortezomib) 
DI (no bortezomib) 
DI (no bortezomib) 
Maintenance 
IM#2 (CMTX) 
IM (CMTX) 
 
Maintenance 
Maintenance 
Risk Category- Arm B (With Bortezomib) 
(See Appendix II for Therapy Delivery Maps) 
Standard Risk (B-SR) 
Intermediate Risk (B-
IR) 
Very High Risk (B-
VHR) 
Induction (with 
bortezomib) 
Induction (with 
bortezomib) 
Induction (with 
bortezomib) 
Consolidation 
Consolidation 
Consolidation 
IM (CMTX) 
IM#1 (HDMTX) 
3 HR Intensification 
blocks 
DI (with bortezomib) 
DI (with bortezomib) 
DI (with bortezomib) 
Maintenance 
IM#2 (CMTX) 
IM (CMTX) 
 
Maintenance 
Maintenance 
 
4.2 
Concomitant Therapy Restrictions 
 
4.2.1 
Drug Interactions with Conventional Chemotherapy 
Since concurrent use of enzyme inducing anticonvulsants (e.g., phenytoin, phenobarbital, 
and carbamazepine) with anti-leukemic therapy has recently been associated with inferior 
EFS, every effort should be made to avoid these agents, as well as rifampin, which also 
induces many drug metabolizing enzymes.62 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 

  
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table below) may have potent inhibitory effects on drug-metabolizing enzymes, and the 
doses of some anti-leukemic drugs (e.g., vincristine, anthracyclines, etoposide) may need to 
be reduced in some patients on chronic azole antifungals or antibiotics (see table below). 
 
DRUG or  
DRUG CLASS^ 
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, 
etoposide, steroids 
Macrolide Antibiotics 
erythromycin 
clarithromycin 
azithromycin 
roxithromycin 
telithromycin 
Inhibition of drug 
metabolizing enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
May need dose reductions of 
vincristine, anthracyclines, 
etoposide, steroids 
* Itraconazole should NOT be used in patients who are receiving vincristine due to a serious drug-
drug interaction leading to severe neurotoxicity.63,64  
^ For a more complete list of CYP 3A 4/5 Inhibitors and Inducers, go to: 
http://medicine.iupui.edu/flockhart/ 
 
4.2.2 
Drug Interactions Specific to Bortezomib 
In vitro and in vivo studies showed that green tea compounds, ascorbic acid (vitamin C) and 
other antioxidants, have the potential to significantly inhibit the activity of bortezomib.135,136 
One study concluded that there is not an interaction when plasma concentrations are 
commensurate with dietary oral intake.137 To avoid the risk of possible interaction it is 
recommended that green tea containing products, and supplemental products containing 
vitamin C, flavonoids or other antioxidants (e.g., vitamins, herbal supplements), be 
discontinued for at least 24 hours prior to the initiation of bortezomib through 72 hours after 
the last bortezomib dose. In addition, it is recommended that the total dietary intake of 
vitamin C not exceed the recommended daily allowance (RDA) for age (i.e., normally 
balanced diets are acceptable). 
 
4.2.3 
Drug Interactions Specific to High-Dose Methotrexate 
 
Possible Drug Interactions with Methotrexate: 
Avoid non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole 
(TMP/SMX), penicillins, probenecid, IV contrast media, proton pump inhibitors, 
phenytoin and fosphenytoin. Urinary acidifiers can cause methotrexate to precipitate in the 
urinary tract. 
 
Hold such agents on the days of a high dose methotrexate infusion and for at least 72 hours 
after the start of the infusion, until the methotrexate level is < 0.4 µM. If there is delayed 
methotrexate clearance, continue to hold such medications until the methotrexate level is < 

  
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0.1 µM. 
 
4.3 
General Guidelines  
See Section 6.0, DRUG INFORMATION, for detailed information about drug administration. 
 
4.3.2 
Parenteral Chemotherapy Administration Guidelines 
See Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuideli
nes.pdf for special precautions and suggestions for patient monitoring during the infusion. 
As applicable, also see the CAG for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
4.3.3 
Supportive Care 
4.3.3.1   
Supportive Care Guidelines Regarding Management of Invasive 
 
Fungal  Infections. 
All treating physicians should have a low index of suspicion for invasive 
fungal infection (IFI), especially during Induction and during periods of 
prolonged neutropenia, including consolidation, delayed intensification, 
and the 3 intensification blocks. In patients with a new or unusual 
mucocutaneous lesion(s), prompt biopsy of suspicious lesions in an effort 
to confirm the diagnosis and guide further therapy is recommended as well 
as targeted imaging and sampling/culture of other clinically suspected 
areas of infection. 
 
Children with prolonged fever in the setting of neutropenia that does not 
resolve with the use of antibiotics should receive empiric anti-mold 
antifungal therapy according to the COG endorsed fever and neutropenia 
guidelines: 
(https://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline
_Document.pdf ). Please follow the guidelines for patients at high risk for 
Invasive Fungal Infections. 
 
For patients with documented or suspected invasive fungal infection and 
neutropenia, consider growth factor support with GM-CSF (sargramostim) 
and/or G-CSF (filgrastim or pegfilgrastim). 
 
While receiving corticosteroids, elevated blood glucose levels may be an 
additional risk factor. Thus, in patients with sustained hyperglycemia 
consider endocrinology evaluation. Treating oncologists are encouraged 
to work in close collaboration with their dermatology, infectious disease, 
otolaryngology, and surgical colleagues to aggressively and timely treat 
patients affected by IFIs with medical and surgical interventions, as 
indicated. 
 
If an IFI is identified, please notify the study chair immediately. 
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
 
 
 

  
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4.4 
INDUCTION ARM A (without bortezomib) 
This Induction is for all T-ALL and T-LLy patients randomized to treatment on Arm A (without 
bortezomib). See Section 4.1 for details. The therapy delivery map (TDM) for INDUCTION-Arm 
A (without bortezomib) is in APPENDIX I-A. 
 
CRITERIA TO BEGIN INDUCTION 
Patients must complete and sign the appropriate informed consent and undergo bortezomib 
randomization before starting Induction therapy. Treatment on Arm A is for patients who are 
randomized to treatment WITHOUT BORTEZOMIB. 
 
Intrathecal Cytarabine: IT 
Given at time of diagnostic lumbar puncture (if within 72 hours from the start of protocol therapy) 
OR Day 1. 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
30 mg 
2 – 2.99 
50 mg 
≥ 3 
 
70 mg 
 
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: Administer IV push over 1 minute or infusion via minibag per institutional policy 
Days: 1, 8, 15 and 22 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
Of note, corticosteroid pretreatment using prednisone or methylprednisolone DOES NOT 
CHANGE the number of doses of dexamethasone. 
 

  
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DAUNOrubicin: IV push/infusion (over 1-15 minutes) 
Days 1, 8, 15 and 22 
Dose: 25 mg/m2/dose 
 
The reconstituted solution or the commercially available solution (5mg/ml) can be administered 
diluted or undiluted 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 
DAUNOrubicin be administered through the tubing of rapidly infusing solution of D5W or 0.9% 
NaCl and that it is infused into a large vein. Protect from sunlight. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DAUNOrubicin is available in a liposomal formulation 
(DAUNOrubicin citrate). The conventional and liposomal formulations are NOT 
interchangeable. The liposomal formulation is not allowed. 
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl 
Days 4 and 18 
Dose: 2500 International units/m2/dose 
 
Intrathecal Methotrexate: IT 
Days 8 and 29 (CNS3 patients ONLY also receive IT MTX on Days 15 & 22). 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.  
 
CRITERIA TO BEGIN CONSOLIDATION 
Following completion of Induction Arm A, the next course (Consolidation, Section 4.6) starts on 
Day 36 (7 days following day 29 LP) or when peripheral counts recover, whichever occurs later. If 
the Day 29 marrow is M2 or M3 or has MRD >5%, the patient should begin Consolidation therapy as 
soon as possible and should not wait until Day 36 or for count recovery to occur. See below for 
additional details regarding peripheral count parameters. All patients receive common 
Consolidation therapy. 
 
TESTICULAR BIOPSY 
A testicular biopsy should be performed in patients with persistent testicular disease at the end of 
Induction if the clinical findings are equivocal.  
 
DAY 29 ± 1 BONE MARROW MRD SAMPLES 
THESE SAMPLES MUST BE OBTAINED AND SHIPPED TO THE COG ALL FLOW 
CYTOMETRY REFERENCE LABORATORY SO THAT RESULTS ARE AVAILABLE 
FOR RISK STRATIFICATION AT THE END OF CONSOLIDATION. ANY DEVIATION 
THAT EXCEEDS 1 DAY FROM DAY 29 MUST BE DISCUSSED WITH THE STUDY 
CHAIR. IF MRD IS NOT SENT THEN THE PATIENT WILL NOT BE ELIGIBLE TO 
CONTINUE ON A COG ALL TRIAL FOLLOWING COMPLETION OF INDUCTION 
THERAPY. 
 

  
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4.5 
INDUCTION ARM B (with bortezomib) 
 
CRITERIA TO BEGIN INDUCTION 
Patients must complete and sign the appropriate informed consent and undergo bortezomib 
randomization before starting Induction therapy. Treatment on Arm B is for patients who are 
randomized to treatment WITH BORTEZOMIB. The therapy delivery map (TDM) for 
INDUCTION ARM B (with bortezomib) is in APPENDIX II-A. 
 
Bortezomib: IV push over 3-5 seconds 
Days 1, 4, 8, and 11 
Dose: 1.3 mg/m2/dose 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing bortezomib must be clearly labeled “For intravenous use 
only -Fatal if given by other routes.” 
 
Note: Consecutive doses of bortezomib must be separated by at least 72 hours. Grapefruit and its 
juice should be avoided for the duration of treatment with bortezomib during each course. To avoid 
the risk of any possible interaction it is recommended that green tea containing products and any 
supplemental products containing vitamin C, flavonoids or other antioxidants (e.g., vitamins, herbal 
supplements) be discontinued from at least 24 hours prior to the initiation of bortezomib through 
72 hours after the last bortezomib dose. In addition, it is recommended that the total dietary intake 
of vitamin C not exceed the RDA for age (i.e., normally balanced diets are acceptable). 
 
Bortezomib is supplied by Millennium Pharmaceuticals and distributed by the NCI DTCD. Do not 
use commercially available drug. 
 
If bortezomib is not available on Day 1 of Induction, then administer the first bortezomib dose as 
soon as possible and do not delay the start of other Induction chemotherapy. Subsequent bortezomib 
doses should be given after 72 and 144 hours. All doses must be at least 72 hours apart. 
 
Intrathecal Cytarabine: IT 
Given at time of diagnostic lumbar puncture (if within 72 hours from the start of protocol therapy) 
OR Day 1. 
 
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: Administer IV push over 1 minute or infusion via minibag per institutional policy 
Days 1, 8, 15 and 22 
Dose: 1.5 mg/m2/dose (max dose 2 mg) 
 

  
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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.” 
 
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 (maybe 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) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
DAUNOrubicin: IV push/infusion over 1-15 minutes  
Days 1, 8, 15 and 22 
Dose: 25 mg/m2/dose 
 
The reconstituted solution or the commercially available solution (5mg/ml) can be administered 
diluted or undiluted 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 
DAUNOrubicin 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. Protect from sunlight. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DAUNOrubicin is available in a liposomal formulation 
(DAUNOrubicin citrate). The conventional and liposomal formulations are NOT 
interchangeable. The liposomal formulation is not allowed. 
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl. 
Day 4 and 18 
Dose: 2500 International units/m2/dose 
 
Intrathecal Methotrexate: IT 
Administer on Days 8 and 29 (CNS3 patients also receive IT MTX on Days 15 & 22).  
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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).  
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 

  
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CRITERIA TO BEGIN CONSOLIDATION 
Following completion of INDUCTION ARM B (with bortezomib), the next course (Consolidation, 
Section 4.6) starts on Day 36 (7 days following day 29 LP) or when peripheral counts recover 
(whichever occurs later). If the Day 29 marrow is M2 or M3 or has MRD >5%, the patient should 
begin Consolidation therapy as soon as possible and should not wait until Day 36 or for count recovery 
to occur. See below for additional details regarding peripheral count parameters. All patients receive 
common Consolidation therapy.  
 
TESTICULAR BIOPSY 
A testicular biopsy should be performed in patients with persistent testicular disease at the end of 
Induction if the clinical findings are equivocal.  
 
DAY 29 ± 1 BONE MARROW MRD SAMPLES 
THESE SAMPLES MUST BE OBTAINED AND SHIPPED TO THE COG ALL FLOW 
CYTOMETRY REFERENCE LABORATORY SO THAT RESULTS ARE AVAILABLE 
FOR RISK STRATIFICATION AT THE END OF CONSOLIDATION. ANY DEVIATION 
THAT EXCEEDS 1 DAY FROM DAY 29 MUST BE DISCUSSED WITH THE STUDY 
CHAIR. IF MRD IS NOT SENT THEN THE PATIENT WILL NOT BE ELIGIBLE TO 
CONTINUE ON A COG ALL TRIAL FOLLOWING COMPLETION OF INDUCTION 
THERAPY. 
 
 
 
 

  
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4.6 
CONSOLIDATION-All Patients 
This Consolidation course is for all Arm A and Arm B T-ALL and T-LLy patients. See Section 4.1 
for details. The therapy delivery map (TDM) for CONSOLIDATION is in APPENDIX I-B (for 
subjects on Arm A) and APPENDIX II-B (for subjects on Arm B). 
 
CRITERIA TO BEGIN CONSOLIDATION 
Start Consolidation on Day 36 from Induction (7 days following Day 29 LP) or when peripheral 
counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later.) T-ALL 
patients who are M2 or M3 on Day 29 or have MRD >5% should proceed directly to Consolidation 
without waiting for count recovery, but there should be a minimum of 3 days between Day 29 
Induction IT therapy and Day 1 Consolidation IT therapy).  
 
Once Consolidation therapy has begun, interruptions for myelosuppression (ANC ≤ 750/µL 
and platelets ≤ 75,000/µL) should occur only at Day 29. Once the Day 1 or Day 29 
cyclophosphamide has been given, the remainder of the therapy should not be held solely for 
myelosuppression, which is expected to occur. Therapy must be interrupted for patients with 
serious proven or presumed 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. Hold Day 29 
chemotherapy until ANC ≥ 750/µL and platelets ≥ 75,000/µL. 
 
Intrathecal Methotrexate: IT 
Days 1, 8, 15# and 22# 
# if CNS3 T-ALL or CNS3 T-LLy: omit Days 15 & 22 and administer on days 1 and 8 only 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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).  
 
Cyclophosphamide: IV over 30-60 minutes 
Days 1 and 29 
Dose: 1000 mg/m2/dose  
 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid 
hypotonic solution) or further diluted. Mesna is not required for this dose of cyclophosphamide, 
but may be administered at institutional discretion. 
 
Cytarabine: IV (administer over 1-30 minutes) or SubQ 
Days 1-4, 8-11, 29-32 and 36-39 
Dose: 75 mg/m2/dose 
 
Subcutaneous Administration: 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. 
 
Mercaptopurine: PO 
Days 1-14 and 29-42 
Dose: 60 mg/m2/dose once daily* 
 

  
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Page 49 
*See Section 5.11 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 daily dose using the dosing 
nomogram in Appendix VI to attain a weekly cumulative dose as close to 420 mg/m2/week as 
possible. Do not escalate or reduce dose based on blood counts during this cycle. 
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl 
Days 15 and 43 
Dose: 2500 International units/m2/dose 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag per institutional policy 
Days 15, 22, 43 and 50 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://members.childrensoncologygroup.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. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
TESTICULAR RADIATION THERAPY 
T-ALL and T-LLy patients with persistent testicular disease at end-Induction should receive 
radiation to the testes during Consolidation. A testicular biopsy should be performed if the clinical 
findings are equivocal. During the first two weeks of Consolidation, testicular radiation therapy 
will be given at 2400 cGy in 12 once-daily fractions of 200 cGy (see Section 16.2). Testicular 
radiation must be started during Consolidation and should be completed before the end of this phase 
of therapy. Patients with testicular leukemia at diagnosis that clinically resolves completely by 
end-Induction, and those that have a negative testicular biopsy at end-Induction will NOT 
receive testicular irradiation. 
 
BONE MARROW AT END CONSOLIDATION 
a. T-ALL SR only: 
SR T-ALL patients DO NOT require a bone marrow at the end of Consolidation (see Section 
4.1 for definitions of risk assignment). These patients should start the next course of therapy 
(Interim Maintenance with CMTX) following the completion of Consolidation as soon as counts 
have recovered with an ANC ≥750/L and platelets ≥75,000/l. 
 

  
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BONE MARROW AT END CONSOLIDATION (CONT’D) 
b. T-ALL patients who are not SR and with end Induction BM MRD ≥ 0.01% : 
• 
Following completion of Consolidation, end of consolidation marrow MRD will determine 
risk assignment (see Section 4.1 for details) and the next course of therapy.  
 
• 
The end of Consolidation marrow should occur as close to Day 57 as possible, but should 
be delayed until counts have recovered with an ANC ≥ 500/µL and platelets ≥ 50,000/µL. 
The end of Consolidation marrow should not be performed prior to Day 57 even if counts 
have recovered. 
 
• 
If on Day 57, the counts have recovered with an ANC ≥ 500/µL and platelets ≥ 50,000/µL, 
the bone marrow for end of Consolidation MRD should be performed on that day. A one 
day deviation is allowed, but any deviation that is greater than 1 day after count recovery 
must be discussed with the study chair. 
 
• 
If on Day 57, the counts have not recovered (e.g., ANC< 500/µL or platelets < 50,000/µL), 
the bone marrow for end of Consolidation MRD should be delayed until ANC ≥ 500/µL and 
platelets ≥ 50,000/µL. The bone marrow for end of consolidation MRD should be performed 
within 2 days of count recovery (ANC ≥ 500/µL and platelets ≥ 50,000/µL). Any deviation 
that is greater than 3 days after count recovery must be discussed with the study chair. If 
counts have not recovered on Day 57, patients should have a CBC checked every 2-3 days 
(three times a week) at minimum until count recovery to minimize delay in obtaining the 
bone marrow. 
 
• 
Patients who have not had count recovery (e.g. ANC ≥ 500/µL and platelets ≥ 50,000/µL) 
by Day 72 should undergo bone marrow to ensure they are M1 and not M2 or M3. 
 
CRITERIA TO BEGIN NEXT COURSE OF THERAPY FOR T-ALL  
a. If the End of Consolidation marrow is M2 or M3, the patient should immediately proceed to 
Intensification Block 1 and not wait for MRD results to proceed. 
 
b. Patients should begin the next course of therapy (HD MTX if IR, HR BFM Block 1 if VHR) 
as soon as the results of EOC MRD are available and they have an ANC ≥750/L and platelets 
≥75,000/l. 
 
c. As there will likely be a few day delay waiting for MRD results between the end of 
Consolidation marrow and the start of the next course of therapy, the next block of therapy 
lumbar puncture with intrathecal chemotherapy should not be given early (e.g. at the same time 
as the end of consolidation bone marrow) and should be given with the next block of therapy. 
 
DAY 57 END OF CONSOLIDATION BONE MARROW FOR MRD 
THE END OF CONSOLIDATION BM MRD SAMPLES MUST BE OBTAINED AND 
SHIPPED TO COG ALL FLOW CYTOMETRY REFERENCE LABORATORY TO HAVE 
RESULTS 
AVAILABLE 
FOR 
END 
OF 
CONSOLIDATION 
(EOC) 
RISK 
STRATIFICATION. THE BONE MARROW FOR MRD MUST BE OBTAINED AS 
CLOSE TO DAY 57 AS POSSIBLE. DELAYS FOR COUNT RECOVERY AS DESCRIBED 
ABOVE ARE ALLOWED BUT OTHER DEVIATIONS MUST BE DISCUSSED WITH 
THE STUDY CHAIR. If MRD IS NOT SENT THEN THE PATIENT WILL NOT BE 
ELIGIBLE TO CONTINUE ON A COG ALL TRIAL FOLLOWING COMPLETION OF 
CONSOLIDATION THERAPY. 
 
c. T-LLy only: 
Following completion of Consolidation, the next course (based on risk assignment, see Section 
4.1 for details) will start as soon as counts have recovered as described in the relevant block of 

  
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Page 51 
therapy. Bone marrow is only required for patients who had morphologic evidence of disease at 
the end of induction. 
 
 
4.7 
INTERIM MAINTENANCE with CMTX- – All Patients 
This IM phase is administered to all patients. SR T-ALL and T-LLy patients receive it after 
Consolidation. IR T-ALL and T-LLy patients receive it after DI as IM#2. VHR T-ALL and T-LLy 
patients receive it after DI. See Section 4.1 for details. 
 
The therapy delivery map (TDM) for INTERIM MAINTENANCE with CMTX is in APPENDIX 
I-C (Arm A-SR) APPENDIX I-G (Arm A-IR), APPENDIX I-L (Arm A-VHR), APPENDIX II-C 
(Arm B-SR), APPENDIX II-G (Arm B-IR), APPENDIX II-L (Arm B-VHR). 
 
CRITERIA TO BEGIN INTERIM MAINTENANCE WITH CMTX: IR AND VHR PATIENTS 
Start when ANC ≥750/L and platelets ≥75,000/l and need to meet renal and hepatic function 
requirements to initiate methotrexate as described in Section 5.9. 
 
CRITERIA TO BEGIN INTERIM MAINTENANCE WITH CMTX: SR PATIENTS 
SR T-ALL and T-LLy patients receive this block immediately after consolidation and must meet 
all of following criteria.  
1. Post-Consolidation risk assignment has been completed as described in Section 4.1 
2. ANC ≥750/L and platelets ≥75,000/l. 
3. Need to meet renal and hepatic function requirements to initiate methotrexate as described 
in Section 5.9.1, Section 5.9.2, and Section 5.9.3 
 
VinCRIStine: Administer 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 (max 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.” 
 
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. 
Dose: Start dose at 100 mg/m2/dose and escalate by 50 mg/m2/dose on Days 1, 11, 21, 31 and 41 
based on blood count requirements as described in Section 5.10.5. Discontinue escalation and 
resume at 80% of last dose if delay is necessary as described in Section 5.10.5. 
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl. 
Days 2 and 22 
Dose: 2500 International units/m2/dose 
 

  
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Intrathecal Methotrexate: IT 
Days 1 and 31 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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). 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
The therapy delivery map (TDM) for INTERIM MAINTENANCE with CMTX is in APPENDIX 
I-C (Arm A-SR) APPENDIX I-G (Arm A-IR), APPENDIX I-L (Arm A-VHR), APPENDIX II-C 
(Arm B-SR), APPENDIX II-G (Arm B-IR), APPENDIX II-L (Arm B-VHR). 
 
Following completion of INTERIM MAINTENANCE with CMTX the next course (based on risk 
assignment, see Section 4.1 for details) starts on Day 57 or when blood count parameters are met 
(whichever occurs later). 
 
 
 
 

  
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4.8 
DELAYED INTENSIFICATION- Arm A (without bortezomib) 
This Delayed Intensification (DI) course is for all T-ALL and T-LLy patients randomized to 
treatment on Arm A (without bortezomib). See Section 4.1 for details. 
 
The therapy delivery maps (TDMs) for DELAYED INTENSIFICATION- ARM A are in 
APPENDIX I-D (Arm A-SR), APPENDIX I-F (Arm A-IR), and APPENDIX I-K (Arm A-VHR) 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION SR AND IR T-ALL AND T-LLY: 
1. ANC ≥ 750/µL  
2. Platelets ≥ 75,000/µL prior to starting therapy. 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION VHR T-ALL:  
VHR T-ALL patients receive this block immediately after HR Intensification 3 and must meet all 
of the following criteria 
1. Post-HR Intensification Block 3 MRD is undetectable as described in Section 4.13 
2. ANC ≥750/L 
3. Platelets ≥75,000/l 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION VHR T-LLY:  
VHR T-LLy patients receive this block immediately after HR Intensification 3 and must meet all 
of the following criteria 
1. Post-HR Intensification Block 3 disease evaluation demonstrates a radiographic CR OR a 
radiographic PR with a biopsy showing no residual disease as described in Section 10.4 
2. ANC ≥750/L 
3. Platelets ≥75,000/l 
 
ADDITIONAL GUIDELINES DURING DI FOR ALL RISK GROUPS. 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once 
Delayed Intensification has begun, it may be interrupted for myelosuppression (ANC ≤ 750/µL and 
platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide 
has been given, the remainder of the therapy should not be held solely for myelosuppression, which 
is expected to occur. Therapy must be interrupted for patients with serious proven or presumed 
infection and resumed when the signs of infection have abated. 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1, 8, 15, 43 and 50 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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 (maybe given IV) 
Days 1-7 and 15-21 
Dose: All patients, regardless of age, receive discontinuous dexamethasone at 5 mg/m2/dose BID 

  
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Page 54 
(i.e. total daily dose: 10 mg/m2/day, divided BID) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
DOXOrubicin: IV push (over 15 minutes) 
Days 1, 8 and 15 
Dose: 25 mg/m2/dose 
 
Administer at a concentration not to exceed 2mg/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. 
 
Special precautions: Medication errors have occurred due to confusion between 
DOXOrubicin and DAUNOrubicin. DOXOrubicin is available in a liposomal formulation. 
The conventional and liposomal formulations are NOT interchangeable.  
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl 
Days 4, 18 and 43 
Dose: 2500 International units/m2/dose 
 
Intrathecal Methotrexate: IT 
Administer on Days 1, 29 and 36.  
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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).  
 
Cyclophosphamide: IV over 30-60 minutes 
Day 29 
Dose: 1000 mg/m2/dose  
 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid 
hypotonic solution) or further diluted. Mesna is not required for this dose of cyclophosphamide, 
but may be administered at institutional discretion. 
 
Cytarabine: IV (Administer over 1-30 minutes) or SubQ 
Days 29-32 and 36-39 
Dose: 75 mg/m2/dose 
 
Subcutaneous Administration: 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. 
 
Thioguanine: PO 
Days 29-42 
Dose: 60 mg/m2/dose 
 

  
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Page 55 
Administer in the evening preferably on an empty stomach (at least 1 hour before or 2 hours after 
food or drink except water). 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 VII for details. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
Following completion of DELAYED INTENSIFICATION - Arm A, the next course (based on risk 
assignment, see Section 4.1 for details) starts on Day 64 or when blood count parameters are met 
(whichever occurs later). 
 
 
 
 

  
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Page 56 
4.9 
DELAYED INTENSIFICATION Arm B (with bortezomib) 
This Delayed Intensification (DI) course is for all T-ALL and T-LLy patients randomized to 
treatment on Arm B (with bortezomib). See Section 4.1 for details. 
 
The therapy delivery maps (TDMs) for DELAYED INTENSIFICATION- Arm B are in 
APPENDIX II-D (Arm B-SR), APPENDIX II-F (Arm B-IR) and APPENDIX II-K (Arm B-VHR). 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION SR AND IR T-ALL AND T-LLY: 
1. ANC ≥ 750/µL 
2. Platelets ≥ 75,000/µL 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION VHR T-ALL:  
VHR T-ALL patients receive this block immediately after HR Intensification 3 and must meet 
all of the following criteria 
1. Post-HR Intensification Block 3 MRD was completed and demonstrated undetectable MRD 
as described in Section 4.13 
2. ANC ≥750/L 
3. Platelets ≥75,000/l 
 
CRITERIA TO BEGIN DELAYED INTENSIFICATION VHR T-LLY:  
VHR T-LLy patients receive this block immediately after HR Intensification 3 and must meet all 
of the following criteria 
1. Post-HR Intensification Block 3 disease evaluation was completed and demonstrated a 
radiographic CR OR a radiographic PR and a biopsy showing no residual disease as described 
in Section 10.4 
2. ANC ≥750/L 
3. Platelets ≥75,000/l 
 
ADDITIONAL GUIDELINES DURING DI FOR ALL RISK GROUPS. 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once 
Delayed Intensification has begun, it may be interrupted for myelosuppression (ANC ≤ 750/µL and 
platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide 
has been given, the remainder of the therapy should not be held solely for myelosuppression, which 
is expected to occur. Therapy must be interrupted for patients with serious proven or presumed 
infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until 
ANC ≥ 750/µL and platelets ≥ 75,000/µL. 
 
Bortezomib: IV push over 3-5 seconds 
Days 1, 4, 15, and 18 
Dose: 1.3 mg/m2/dose 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing Bortezomib must be clearly labeled “For intravenous use 
only - Fatal if given by other routes.” 
 
Note: Consecutive doses must be separated by at least 72 hours. Grapefruit and its juice should be 
avoided for the duration of treatment with bortezomib during each course. To avoid the risk of any 
possible interaction it is recommended that green tea containing products and any supplemental 
products containing vitamin C, flavonoids or other antioxidants (e.g., vitamins, herbal supplements) 
be discontinued from at least 24 hours prior to the initiation of bortezomib through 72 hours after 
the last bortezomib dose. In addition, it is recommended that the total dietary intake of vitamin C 
not exceed the RDA for age (i.e., normally balanced diets are acceptable). 
 

  
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Page 57 
Bortezomib is supplied by Millennium Pharmaceuticals and distributed by the NCI DTCD. Do not 
use commercially available drug. 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1, 8, 15, 43 and 50 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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 (maybe given IV) 
Days 1-7 and 15-21 
Dose: All patients, regardless of age, receive discontinuous dexamethasone: 5 mg/m2/dose BID 
(i.e. total daily dose 10 mg/m2/day, divided BID) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
DOXOrubicin: IV push (over 15 minutes) 
25 mg/m2/dose on Days 1, 8 and 15 
 
Administer at a concentration not to exceed 2mg/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. 
 
Special precautions: Medication errors have occurred due to confusion between 
DOXOrubicin and DAUNOrubicin. DOXOrubicin is available in a liposomal formulation. 
The conventional and liposomal formulations are NOT interchangeable.  
 
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl 
Day 4, 18 and 43 
Dose: 2500 International units/m2/dose 
 
Intrathecal Methotrexate: IT 
Administer on Days 1, 29 and 36.  
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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). 

  
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Page 58 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 29 
Dose: 1000 mg/m2/dose 
 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid 
hypotonic solution) or further diluted. Mesna is not required for this dose of cyclophosphamide, 
but may be administered at institutional discretion. 
 
Cytarabine: IV (Administer over 1-30 minutes) or SubQ 
Days 29-32 and 36-39 
Dose: 75 mg/m2/dose 
 
Subcutaneous Administration: 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. 
 
Thioguanine: PO 
Days 29-42 
Dose: 60 mg/m2/dose 
 
Administer in the evening preferably on an empty stomach (at least 1 hour before or 2 hours after 
food or drink except water). 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 X for details. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
Following completion of DELAYED INTENSIFICATION- Arm B (with bortezomib), the next 
course (based on risk assignment, see Section 4.1 for details) starts on Day 64 or when blood count 
parameters are met (whichever occurs later). 
 
 
 
 

  
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Page 59 
4.10 
INTERIM MAINTENANCE #1 with HD MTX- ALL INTERMEDIATE RISK SUBJECTS 
This is IM#1 for all IR T-ALL and T-LLy patients randomized to either treatment Arm. SR and 
VHR T-ALL and T-LLy patients do not receive this block. See Section 4.1 for details. 
 
The therapy delivery maps (TDMs) for Interim Maintenance #1 with HD MTX are in APPENDIX 
I-E (Arm A-IR) and APPENDIX II-E (Arm B-IR). 
 
CRITERIA TO BEGIN INTERIM MAINTENANCE WITH HD MTX: IR PATIENTS ONLY 
IR T-ALL and T-LLy patients receive this block immediately after consolidation and must meet 
all of the following criteria 
1. Post-consolidation risk assignment completed as described in Section 4.1  
2. ANC ≥750/L and platelets ≥75,000/l. 
3. Need to meet renal and hepatic function to receive HD MTX as defined in Section 5.9.1, 
Section 5.9.2, and Section 5.9.3 
 
High Dose Methotrexate: IV over 24 hours 
Days 1, 15, 29, and 43 
Dose: 5000 mg/m2/dose (no maximum dose)  
 
For HD MTX Infusion Guidelines and liver and kidney requirements to administer drug see Section 
5.9 and Appendix IV. 
 
Leucovorin: PO/IV 
Days 3-4, 17-18, 31-32, and 45-46 
Dose: 15mg/m2/dose x minimum of 3 doses given at 42, 48, and 54 hours after the start of the HD 
MTX infusion. See Section 5.9 and Appendix IV for HD MTX Infusion and Leucovorin rescue 
guidelines. 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1, 15, 29, 43  
Dose: 1.5 mg/m2/dose (max 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.” 
 
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 1-56 
Dose: 25 mg/m2/dose once daily* 
 
*Other Considerations: 
*See Section 5.11 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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Page 60 
The liquid or tablet formulation may be used. If using tablets, adjust daily dose using the dosing 
nomogram in Appendix VI to attain a weekly cumulative dose as close to 175 mg/m2/week as 
possible. Do not escalate or reduce dose based on blood counts during this cycle. Mercaptopurine 
should be held for ANC < 750/μL or platelets < 75 000/μL. Do not make up missed doses (see 
Section 5.11.1). 
 

  
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Page 61 
Intrathecal Methotrexate: IT 
Days 1 and 29 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 
hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX 
bolus). 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
Following completion of Interim Maintenance #1 the next course (based on randomization 
assignment, see Section 4.1 for details) starts on Day 57 or when blood count parameters are met 
(whichever occurs later). 
 
 
 
 

  
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Page 62 
4.11 
INTENSIFICATION BLOCK 1 (HR1)- ALL VERY HIGH RISK SUBJECTS 
This phase of treatment is for all VHR T-ALL and T-LLy patients who are randomized to either 
treatment Arm. SR and IR T-ALL and T-LLy patients do not receive this block. 
 
The therapy delivery maps (TDMs) for INTENSIFICATION BLOCK 1 are in APPENDIX I-H 
(Arm A-VHR) and APPENDIX II-H (Arm B-VHR). 
 
CRITERIA TO BEGIN INTENSIFICATION BLOCK 1 
 
T-ALL patients who are M2 or M3 at the end of Consolidation should proceed directly to 
Intensification Block 1 without waiting for count recovery or MRD results to proceed. 
 
VHR T-ALL and T-LLy patients receive this block immediately after consolidation and must meet 
all of the following criteria 
1. Post-consolidation risk assignment must have been completed as described in Section 4.1 
2. ANC≥750/L  
3. Platelets ≥75,000/l 
4. Need to meet renal and hepatic function requirements to receive HD MTX as defined in Section 
5.9.2, Section 5.9.3, and Section 5.9.4. 
5. Need to meet renal function requirements to receive HD ARAC as defined in Section 5.4.4 
 
The 3 High Risk Intensification blocks are profoundly myelosuppressive and since they also 
include 5 days of high dose dexamethasone, clinical signs of infection may be blunted. Therefore, 
the following precautions are required for all subjects during each high risk block: 
 
• 
CBC with differential every 2 days after completion of chemotherapy until there is evidence of 
marrow recovery. Recovery is defined as ANC >0.2 x 109/L (200/L) and platelet transfusion 
independence. 
 
• 
G-CSF 5 µg/kg/day SC or IV starting anytime from 7 days to 11 days from the start of the 
block (e.g., at least 24 hours after completion of chemotherapy in each HR block) until the 
WBC count is >3.0 x 109/L (>3000/mm3). [Pegfilgrastim 100 µg/kg (max 6 mg/dose) s.c. given 
once during the 7-11th day from the start of the block may be considered as an alternative.]  
 
Additionally the following precautions are STRONGLY recommended for all subjects during each 
high risk block: 
 
• 
Hospitalization of patients for close observation after each intensive block of chemotherapy, 
particularly during the period of profound myelosuppression, until there is evidence of blood 
count recovery because this is the intervention most likely to reduce the death rate. 
 
• 
A very low threshold should be used for institution of empiric antimicrobial therapy since 
dexamethasone may blunt the signs of a life threatening infection. 
 
Dexamethasone: PO (maybe given IV) 
Days 1-5 
Dose: 10 mg/m2/dose (i.e. total daily dose: 20 mg/m2/day, divided BID) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 

  
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Page 63 
High Dose Methotrexate: IV over 24 hours 
Day 1 
Dose: 5000 mg/m2/dose (no maximum dose) 
 
For HD MTX Infusion Guidelines and renal and hepatic function requirements see Section 5.9 and 
Appendix IV): 
 
Leucovorin: PO/IV 
Days 3-4 
Dose: 15 mg/m2/dose x minimum of 3 doses given at 42, 48, and 54 hours after the start of the HD 
MTX infusion. See Section 5.9 and Appendix IV for HD MTX Infusion and Leucovorin rescue 
guidelines. 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1 and 6 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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. 
 
Cyclophosphamide: IV over 1-6 hours 
Day 2-4 
Dose: 200 mg/m2/dose Q12 hours x5doses 
 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid 
hypotonic solution) or further diluted. 
 
High Dose Cytarabine: IV (infuse over 3 hours)  
Day 5 
Dose: 2000 mg/m2/dose Q12 hours x 2 doses  
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% dexamethasone 
or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, beginning immediately 
before the first dose and continuing for 24 hours after the last dose. If patient does not tolerate 
steroid eye drops, may administer artificial tears on an every 2-4 hour schedule. 
 
Pegaspargase: IV over 1-2 hours 
Day 6* 
Dose: 2500 International units/m2/dose 
 
Administer over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% NaCl. 
*Administer 3 hours after completion of the second High Dose Cytarabine infusion. 
 

  
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Page 64 
Triple Intrathecal Therapy: IT 
Day 1* 
 
Age-based dosing:  
1 to < 2 yrs: MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 to < 3 yrs: MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 to < 9 yrs: MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 yrs:       MTX 15 mg, HC: 15 mg, ARAC: 30 mg 
 
*Should be given 2 hours after start of High Dose MTX infusion (window of -6 to +6 hours in 
relation to start of HD-MTX is acceptable) 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 7 and until WBC > 3000/L. 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W 
by IV infusion over 15-30 minutes or by continuous infusion. 
 
*Pegfilgrastim 100 mcg/kg (max 6 mg/dose) s.c. once during the 7-11th day from the start of the 
block may be considered as an alternative 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
Following 
completion 
of 
INTENSIFICATION 
BLOCK 
1 
Arm, 
the 
next 
course 
(INTENSIFICATION BLOCK 2 Section 4.12) starts on Day 22 or when blood count parameters 
are met (whichever occurs later). 
 
 
 
 

  
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Page 65 
4.12 
INTENSIFICATION BLOCK 2- ALL VERY HIGH RISK SUBJECTS 
This phase of treatment is for all VHR T-ALL and T-LLy patients who are randomized to either 
treatment Arm. SR and IR T-ALL and T-LLy patients do not receive this block. 
 
The therapy delivery maps (TDMs) for INTENSIFICATION BLOCK 2 are in APPENDIX I-I 
(Arm A-VHR) and APPENDIX II-I (Arm B-VHR). 
 
Start Day 1 when ANC ≥750/L and platelets ≥75,000/L. Need to meet renal and hepatic function 
requirements described in Section 5.9.2, Section 5.9.3, and Section 5.9.4. in order to receive HD 
MTX. HR2 lasts 21 days. 
 
The 3 High Risk Intensification blocks are profoundly myelosuppressive and since they also 
include 5 days of high dose dexamethasone, clinical signs of infection may be blunted. Therefore, 
the following precautions are required for all subjects during each high risk block: 
 
• 
CBC with differential every 2 days after completion of chemotherapy until there is evidence of 
marrow recovery. Recovery is defined as ANC >0.2 x 109/L (200/L) and platelet transfusion 
independence. 
 
• 
G-CSF 5 µg/kg/day SC or IV starting anytime from 7 days to 11 days from the start of the 
block (e.g., at least 24 hours after completion of chemotherapy in each HR block) until the 
WBC count is >3.0 x 109/L (>3000/mm3). [Pegfilgrastim 100 µg/kg (max 6 mg/dose) SC. 
given once during the 7-11th day from the start of the block may be considered as an 
alternative.] 
  
Additionally, the following precautions are STRONGLY recommended for all subjects during each 
high risk block: 
 
• 
Hospitalization of patients for close observation after each intensive block of chemotherapy, 
particularly during the period of profound myelosuppression, until there is evidence of blood 
count recovery because this is the intervention most likely to reduce the death rate. 
 
• 
A very low threshold should be used for institution of empiric antimicrobial therapy since 
dexamethasone may blunt the signs of a life threatening infection. 
 
Dexamethasone: PO (maybe given IV) 
Days 1-5 
Dose: 10 mg/m2/dose BID (i.e. total daily dose: 20 mg/m2/day) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
High Dose Methotrexate: IV over 24 hours 
Day 1 
Dose: 5000 mg/m2/dose (no maximum dose) 
 
For HD MTX Infusion Guidelines and renal and hepatic requirements to administer see Section 5.9 
and Appendix IV 
 
Leucovorin: PO/IV 
Days 3-4 
Dose: 15mg/m2/dose x minimum of 3 doses given at 42, 48, and 54 hours after the start of the HD 
MTX infusion. See Section 5.9 and Appendix IV for HD MTX Infusion and Leucovorin rescue 
guidelines. 
 

  
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Page 66 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1 and 6 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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. 
 
Ifosfamide: IV over 1 hour 
Days 2-4* 
Dose: 800 mg/m2/dose Q12hours x5 doses 
 
*Start immediately after completion of HD-MTX infusion 
 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing 
D5W/0.45% NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. 
Monitor for adequate urine output as per institution guidelines. May use diuretics (e.g., furosemide) 
to increase urine output. Consider adding potassium and magnesium to prevent electrolyte 
deficiencies. 
 
Mesna: IV  
Days: 2-4 
Dose: 300 mg/m2/dose Hour 0, 4, and 8 from start of each ifosfamide infusion 
 
Hydration following ifosfamide administration: If patient stops methotrexate hydration for 
whatever reason, need to continue until 12 hours post ifosfamide infusion. 
 
DAUNOrubicin: IV push/infusion over 1-15 minutes 
Day 5 
Dose: 30 mg/m2/dose  
 
The reconstituted solution or the commercially available solution (5mg/ml) can be administered 
diluted or undiluted 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 
DAUNOrubicin 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. Protect from sunlight. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DAUNOrubicin is available in a liposomal formulation 
(DAUNOrubicin citrate). The conventional and liposomal formulations are NOT 
interchangeable. The liposomal formulation is not allowed. 
  
Pegaspargase: IV over 1-2 hours through the tubing of a freely infusing solution of D5W or 0.9% 
NaCl 
Day 6 
Dose: 2500 International units/m2/dose IV 
 

  
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Triple Intrathecal Therapy: Day 1* 
Age-based dosing:  
1 to < 2 yrs:  MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 to < 3 yrs:  MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 to < 9 yrs:  MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 yrs:         MTX 15 mg, HC: 15 mg, ARAC: 30 mg 
 
*Should be given 2 hours after start of High Dose MTX infusion (window of -6 to +6 hours in 
relation to start of HD-MTX is acceptable) 
 
Filgrastim*: SubQ/IV 
Day 7 
Dose 5 mcg/kg/dose daily until WBC > 3000/l  
 
*Pegfilgrastim 100 mcg/kg (max 6 mg/dose) s.c. once during the 7-11th day from the start of the 
block may be considered as an alternative. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
CRITERIA FOR INITIATION OF INTENSIFICATION BLOCK 3 
Following 
completion 
of 
INTENSIFICATION 
BLOCK 
2 
Arm, 
the 
next 
course 
(INTENSIFICATION BLOCK 3, Section 4.13) starts on Day 22 or when blood count parameters 
are met (whichever occurs later). 
 
 
 
 

  
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4.13 
INTENSIFICATION BLOCK 3 (HR3) ALL VERY HIGH RISK SUBJECTS 
This phase of treatment is for all VHR T-ALL and T-LLy patients who are randomized to either 
treatment Arm. SR and IR T-ALL and T-LLy patients do not receive this block. 
 
The therapy delivery maps (TDMs) for INTENSIFICATION BLOCK 3 are in APPENDIX I-J 
(Arm A-VHR) and APPENDIX II-J (Arm B-VHR). 
 
CRITERIA FOR INITIATION OF INTENSIFICATION BLOCK 3 
Start Day 1 when ANC ≥ 750/L and platelets ≥ 75,000/L. HR3 lasts 21 days. Patients must meet 
renal function requirements described in Section 5.4.4. 
 
The 3 High Risk Intensification blocks are profoundly myelosuppressive and since they also 
include 5 days of high dose dexamethasone, clinical signs of infection may be blunted. Therefore, 
the following precautions are required for all subjects during each high risk block: 
 
• 
CBC with differential every 2 days after completion of chemotherapy until there is evidence of 
marrow recovery. Recovery is defined as ANC >0.2 x 109/L (200/L) and platelet transfusion 
independence. 
 
• 
G-CSF 5 µg/kg/day SC or IV starting anytime from 7 days to 11 days from the start of the 
block (e.g., at least 24 hours after completion of chemotherapy in each HR block) until the 
WBC count is >3.0 x 109/L (>3000/mm3). [Pegfilgrastim 100 µg/kg (max 6 mg/dose) s.c. given 
once during the 7-11th day from the start of the block may be considered as an alternative.]  
 
Additionally the following precautions are STRONGLY recommended for all subjects during each 
high risk block: 
 
• 
Hospitalization of patients for close observation after each intensive block of chemotherapy, 
particularly during the period of profound myelosuppression, until there is evidence of blood 
count recovery because this is the intervention most likely to reduce the death rate. 
 
• 
A very low threshold should be used for institution of empiric antimicrobial therapy since 
dexamethasone may blunt the signs of a life threatening infection. 
 
Dexamethasone: PO (maybe given IV) 
Days 1-5 
Dose: 10 mg/m2/dose BID (i.e. total daily dose: 20 mg/m2/day, divided BID) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
High Dose Cytarabine: IV (over 3 hours) 
Days 1-2 
Dose: 2 gm/m2/dose Q12 hours x 4 doses  
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% dexamethasone 
or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, beginning immediately 
before the first dose and continuing for 24 hours after the last dose. If patient does not tolerate 
steroid eye drops, may administer artificial tears on an every 2-4 hour schedule.  
 
Etoposide: IV over 1-2 hours 
100 mg/m2/dose Q12 hours x 5 doses on Days 3-5 
The first dose of etoposide should be given approximately 12 hours after the start of the 4th dose of 
high dose cytarabine on Day 2. Etoposide will be administered every 12 hours thereafter for a total 
of 5 doses. 

  
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Infuse diluted solution (concentration ≤ 0.4 mg/mL) over at least 60-120 minutes; slow rate of 
administration if hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) 
(hypotension risk). The use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes 
of D5W due to potential development of hyponatremia. 
 
Pegaspargase: IV, administer over 1-2 hours through the tubing of a freely infusing solution of 
D5W or 0.9% NaCl 
Day 6 
Dose: 2500 International units/m2/dose 
 
Triple Intrathecal Therapy: IT Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Day 5 
 
Age-based dosing:  
1 to < 2 yrs.:  
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2 to < 3 yrs.:  MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3 to < 9 yrs.:  
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
≥ 9 yrs.:         MTX 15 mg, HC: 15 mg, ARAC: 30 mg 
 
Filgrastim: SubQ/IV* 
5 mcg/kg/dose daily beginning on Day 7 and until WBC > 3000/l. 
 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W 
by IV infusion over 15-30 minutes or by continuous infusion. 
 
*Pegfilgrastim 100 mcg/kg (max 6 mg/dose) SC. once during the 7-11th day from the start of the 
block may be considered as an alternative. 
 
T-ALL: After completing the 3 HR Intensification Blocks, T-ALL patients continue on 
protocol therapy resuming at DI with or without bortezomib as randomized if MRD is 
undetectable. If MRD is detectable, patients are no longer eligible to continue on protocol 
therapy. 
 
T-LLy: After completing the 3 HR Intensification Blocks, T-LLy patients continue on 
protocol therapy resuming at DI with or without bortezomib as randomized if they have a 
complete response as defined in Section 10.4 and a morphologically negative marrow. 
Patients with persistent disease by imaging should be re-biopsied. If there is active disease by 
pathologic examination, patients are no longer eligible to continue on protocol therapy. 
 
TIMING OF BONE MARROW MRD FOR PATIENTS WITH VHR T-ALL. 
The marrow for MRD that is obtained after Intensification HR3 should occur as close to Day 21 as 
possible, but should be delayed until counts have recovered with an ANC ≥ 500/µL and platelets ≥ 
50,000/µL. OF NOTE, this is different from Day 29 MRD which must be sent on Day 29 regardless 
of counts. The end of HR3 marrow should not be performed before Day 21 even if the counts have 
recovered. 
 
If on Day 21, the counts have recovered with an ANC ≥ 500/µL and platelets ≥ 50,000/µL, the 
bone marrow for end of HR3 MRD should be performed that day. A 1 day deviation is allowed, 
but any deviation that is greater than 1 day after count recovery must be discussed with the study 
chair. 
 

  
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If on Day 21, the counts have not recovered (e.g., ANC< 500/µL or platelets < 50,000/µL), the 
bone marrow for end of HR3 MRD should be delayed until ANC ≥ 500/µL and platelets ≥ 
50,000/µL. The bone marrow for end of HR3 MRD should be performed within 2 days of count 
recovery (ANC ≥ 500/µL and platelets ≥ 50,000/µL). Any deviation that is greater than 2 days after 
count recovery must be discussed with the study chair.  If counts have not recovered on Day 21, 
patients should have a CBC checked every 2-3 days (three times a week) at minimum until count 
recovery to minimize delay in obtaining the bone marrow. 
 
As there will likely be a delay of a few days waiting for MRD results between the end of HR3 
marrow and the start of the next course of therapy (DI), the DI lumbar puncture with intrathecal 
chemotherapy should not be given early (e.g. at the same time as the end of HR3 bone marrow) 
and should be given with the next block of therapy.  
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
Following completion of INTENSIFICATION BLOCK 3 Arm A-VHR, subjects will either stop 
treatment due to lack of response or continue on to next course. The next course (based on 
randomization, see Section 4.1 for details) starts on Day 22 or when blood count parameters are 
met (whichever occurs later). 
 
 
 
 

  
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4.14 
MAINTENANCE - All Patients 
This Maintenance course is for all patients irrespective of study phase or treatment randomization 
assignment. 
 
CRITERIA FOR STARTING MAINTENANCE 
1. ANC ≥ 750/µL 
2. Platelets ≥ 75,000/µL. 
 
VinCRIStine: Administer IV push over 1 minute or infusion via minibag as per institutional 
policy. 
Days 1, 29 and 57 
Dose: 1.5 mg/m2/dose (max 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.” 
 
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 1-5, 29-33, 57-61 
Dose: 3 mg/m2/dose BID (i.e. total daily dose: 6 mg/m2/day, divided BID) 
 
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions are acceptable and 
intravenous preparations may be used on a temporary basis, if needed. 
 
Mercaptopurine: PO 
Days 1-84 
Dose: 75 mg/m2/dose* 
 
Other Considerations: 
*See Section 5.11 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. 
 
If using tablets, adjust daily dose using the dosing nomogram in Appendix VI to attain a weekly 
cumulative dose as close to 525 mg/m2/week as possible. See Section 5.11.2 for dose modifications 
during Maintenance.  
 
Methotrexate: PO 
Days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71 and 78 
Dose: 20 mg/m2/dose weekly 
* Omit Day 29 of first 4 cycles for SR T-ALL and T-LLy patients and for first 2 cycles of Maintenance for 
IR T-ALL and T-LLy patients. 
 
Administer on an empty stomach (at least 1 hour before or 2 hours after food or drink except water). 
 
Intrathecal Methotrexate: IT 
Administer on Day 1 (also on Day 29 of the first 4 cycles of Maintenance for Standard Risk T-
ALL and T-LLy patients ONLY and on Day 29 of the first 2 cycles of Maintenance for 
Intermediate Risk T-ALL and T-LLy patients ONLY). 
 

  
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Aged-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
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). 
 
Cranial Radiation Therapy  
All CRT will be given during the 1st cycle (first 4 weeks) of Maintenance. See the tables below to 
determine which subjects will receive CRT. See Section 16.1 for details.  
 
T-ALL- Cranial Radiation Therapy 
 
SR 
IR 
VHR 
CNS 1 
none 
none 
CRT (1200 cGy) 
CNS 2 
none 
none 
CRT (1200 cGy) 
CNS 3 
n/a 
CRT (1800 cGy) 
CRT (1800 cGy) 
 
T-LLy- Cranial Radiation Therapy 
 
SR 
IR 
VHR 
CNS 1 
none 
none 
none 
CNS 2 
none 
none 
none 
CNS 3 
n/a 
CRT (1800 cGy) 
CRT (1800 cGy) 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG 
MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
SEE SECTION 6.0, DRUG INFORMATION, FOR DETAILED INFORMATION ABOUT 
DRUG ADMINISTRATION. 
 
The therapy delivery maps (TDMs) for MAINTENANCE are in APPENDIX I-M (Arm A) and 
APPENDIX II-M (Arm B). 
 
CRITERIA TO BEGIN MAINTENANCE CYCLES 
Begin subsequent Maintenance cycles regardless of counts. Only mercaptopurine and PO 
methotrexate will be interrupted for myelosuppression as outlined in Section 5.10. 
 
DOSE MODIFICATIONS FOR MYELOSUPPRESSION DURING MAINTENANCE 
Only mercaptopurine and PO methotrexate will be interrupted for myelosuppression as outlined in 
Section 5.10. 
 
DURATION OF THERAPY 
 
1. GIRLS SR and IR T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the 
total duration of therapy is two years from the start of Interim Maintenance (~ Week 119). 
 
2. GIRLS VHR T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is two years from the start of Intensification Block #1 (~ Week 119). 
 
3. BOYS SR and IR T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the 
total duration of therapy is three years from the start of Interim Maintenance (~ Week 171). 
 

  
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4. 
BOYS VHR T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is three years from the start of Intensification Block #1 (~ Week 171). 
 
5. T-LLy patients (regardless of gender): Continue to repeat 12-week cycles of Maintenance 
therapy until the total duration of therapy is two years from the start of Interim Maintenance 
(~Week 119) 
 
6. May stop therapy on anniversary date if dexamethasone is completed for the 5-day 
dexamethasone pulse. Anniversary date is defined as the date marking two (2) years (for T-
ALL girls and all T-LLy patients, regardless of gender) and three (3) years (for T-ALL boys) 
from the start of Interim Maintenance #1 for SR and IR patients, and from the start of 
Intensification Block #1 for VHR patients. 
 

  
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5.0 
DOSE MODIFICATION 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] 
5.1.1 
Allergy 
Local Allergic Reactions (inflammation at injection site, swelling): Note these 
recommendations only apply when the asparaginase product is administered 
intramuscularly. Continue asparaginase administration in the presence of Grade 1 allergy 
as defined by CTCAE v4.0 (transient flushing or rash; drug fever < 38ºC).  
 
Systemic Allergic Reactions: In the event of Grade 1 reactions, characterized by transient 
flushing or rash and drug fever < 38ºC, without the need for treatment with antihistamines 
or steroids, the dose of asparaginase being administered intravenously may be continued 
with close observation. 
 
Discontinuation is recommended for Grade 2 or higher allergic reactions, as defined by 
CTCAE v4.0, that require medical intervention. 
 
Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms is 
strongly discouraged since anti-histamine use may mask the appearance of systemic 
allergy. Systemic allergy is frequently associated with the presence of asparaginase 
neutralizing antibodies, which render asparaginase therapy ineffective. In the event of 
Grade 2 or higher systemic or recurrent local allergic reaction, Erwinia asparaginase should 
be substituted.  
 
Arm A ONLY: Patients with allergy/anaphylaxis to pegaspargase may be eligible to 
receive IV pegcrisantaspase, a pegylated form of Erwinia asparaginase, on COG 
AALL1421 at doses prescribed on that protocol. Patients who have previously received 
Erwinia asparaginase or are receiving other investigational agents (including patients on 
Arm B of AALL1231) are not eligible for AALL1421. 
 
5.1.2 
Anaphylaxis  
Discontinue pegaspargase or E. coli 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 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.138,139 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.140 Current COG trials have 
adopted pegaspargase as the preparation of choice, based on the results of CCG 1962.141 
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. 

  
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PATIENTS ENROLLED IN AALL0932, AALL1131 OR AALL1231 MAY BE 
ELIGIBLE TO ENROLL IN AALL1421 IF THEY DEVELOP AN ALLERGIC 
REACTION 
TO 
PEGASPARGASE 
THAT 
PRECLUDES 
FURTHER 
ADMINISTRATION OF THAT DRUG. The new AALL1421 trial was developed to study 
the pharmacokinetics and tolerability of pegcrisantaspase in patients with hypersensitivity 
to PEG-asparaginase. On AALL1421 patients will receive pegcrisantaspase at the assigned 
dose via 1 hour IV infusion as a replacement for each scheduled dose of PEG-asparaginase 
remaining on the original treatment protocol. Please see the AALL1421 protocol web page 
for more information.  
 
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 
Drug(s) 
Replacement 
Schedule for Erwinia 
asparaginase# 
Important 
Notes 
Induction, 
Consolidation, 
Interim 
Maintenance 
(CMTX), Delayed 
Intensification, 
Intensification 
Blocks 1, 2, and 3 
One or more 
doses of 
pegaspargase 
(2,500 IU/m2) 
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 
 
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. 
 
5.1.3 
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.  
 

  
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5.1.4 
Hyperbilirubinemia 
Asparaginase may need to be withheld in patients with an elevated direct bilirubin, since 
asparaginase has been associated with hepatic toxicity. No specific guidelines are 
available. 
 
5.1.5 
Hyperglycemia 
Do not modify dose. Treat hyperglycemia as medically indicated. 
 
5.1.6 
Hyperlipidemia 
Do not modify dose  
 
5.1.7 
Ketoacidosis 
Hold asparaginase until blood glucose can be regulated with insulin. 
 
5.1.8 
Pancreatitis 
Discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the case of 
asymptomatic Grade 2 pancreatitis (enzyme elevation or radiologic findings only), 
asparaginase should be held until symptoms and signs subside, and amylase/lipase levels 
return to normal and then resumed. Grade 3 or 4 pancreatitis is a contraindication to 
additional asparaginase administration. 
 
5.1.9 
Thrombosis 
Withhold asparaginase until symptoms have 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, which is 
not catheter-related, consider evaluation for inherited predisposition to thrombosis.  
 
CNS Events (bleed, thrombosis or infarction): Hold asparaginase. Treat with FFP, factors or 
anticoagulation as appropriate. Consider resuming 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 pegasparaginase 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 
Bortezomib Related Toxicities 
Special criteria will be followed for peripheral neuropathy and pulmonary toxicities thought to be 
possibly, probably or definitely related to bortezomib  
 
5.2.1 
Bortezomib-related peripheral neuropathy 
Peripheral neuropathy will be closely monitored during each block of treatment that 
includes bortezomib and toxicities graded. 
 
Neuropathy grading should be based on the maximum toxicity occurring during the 
previous block. Neuropathy should be graded using the “BALIS” scale (see Section 5.13). 
All dose modifications should be based on the worst preceding toxicity. Bortezomib dose 
will be decreased for sensory peripheral neuropathy as follows:  
 
Table 2: Dose Modifications for Bortezomib-Related Neuropathic Pain and / or Peripheral 
Sensory Neuropathy 

  
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Severity of peripheral 
sensory neuropathy 
Bortezomib modification 
 
Grades 1-2 without pain 
None  
 
Grade 1 with pain 
Decrease bortezomib to 1 mg/m2/dose 
 
Grade 2 with pain or  
any Grade 3  
Hold bortezomib treatment until symptoms  Grade 1. 
Do not make up missed doses. When toxicity resolves, 
re-initiate bortezomib at 1 mg/m2/dose 
 
Grade 2 with or any 
Grade 3 > 2 weeks 
duration or recurrence 
after prior dose 
reduction 
Discontinue bortezomib 
 
Grade 4 
Discontinue bortezomib 
 
5.2.2 
Bortezomib-associated pulmonary toxicity 
There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown 
etiology such as pneumonitis, interstitial pneumonia, lung infiltration and acute respiratory 
distress syndrome (ARDS) in patients receiving bortezomib. For this reason, pulmonary 
toxicity will be monitored carefully during the study. See below for management of new-
onset dyspnea, hypoxia or chest infiltrates not explained by infection or other known cause. 
 
5.2.2.1  Identification and Management of Bortezomib-Related Pulmonary Toxicity  
Pulmonary toxicities are more commonly seen when bortezomib is given to elderly 
adults. Pulmonary toxicity due to bortezomib may be delayed and can occur up to 
3 weeks after the final dose of bortezomib is administered. Bortezomib-related 
pulmonary toxicities are rare in children and were not seen during AALL0P1. 
Nevertheless, as pulmonary toxicities secondary to bortezomib can be serious, a 
low threshold to evaluate for pulmonary toxicity is recommended. Patients with 
abnormal respiratory symptoms, including dyspnea, cough, or pleuritic chest pain 
or abnormal respiratory findings on exam, including tachypnea, increased work of 
breathing, or ausculatory abnormalities should have a chest radiograph and pulse 
oximetry performed. 
 
If the patient develops pulmonary toxicity, including a decrease in oxygen 
saturation to < 90%, and/or bilateral infiltrates on chest x-ray, and/or pulmonary 
opacities on CT scan, in the absence of evidence of pneumonia or congestive heart 
failure, the following steroid therapy is recommended. Therapy can be tailored 
based on the severity of the pulmonary toxicity: 
 
- Methylprednisolone 200-400 mg/m2 IV X 1, followed by 250 mg/m2 IV 
daily for 3 days (max dose 1000 mg/day), or  
- Dexamethasone 6 mg/m2 IV BID hrs. or  
- Prednisone 40 mg/m2 PO daily divided BID. 
 
Other similar steroid regimens suitable for treatment of non-infectious 
pneumonitis may be used. In addition, it is suggested that a formal consultation 
from a pulmonologist be obtained. Bronchoscopy is encouraged if clinically 
indicated. The steroid dosage should be tapered as clinically appropriate once the 
clinical condition improves. 
 
5.2.2.2 Dose De-escalation or Discontinuation of Bortezomib for Pulmonary Toxicity and 

  
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Other Bortezomib-Related Toxicities (Excluding Peripheral Neuropathy) 
Bortezomib will be dose de-escalated to 1 mg/m2 for any resolving Grade 3 
pulmonary toxicity (excluding voice changes/laryngitis), including hypoxia 
(oxygen saturation below the threshold listed in 5.2.2.1) that is possibly, probably 
or definitely related to bortezomib. Patients that experience a Grade 4 pulmonary 
toxicity possibly, probably or definitely related to bortezomib (excluding voice 
changes/laryngitis) will discontinue bortezomib.  
 
5.2.2.3  Patients re-experiencing the same bortezomib-related qualifying Grade 3 
pulmonary toxicity following a single bortezomib dose reduction will discontinue 
bortezomib.  
 
5.2.3 
Bortezomib-Related Electrolyte Abnormalities 
Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia 
in some studies. Serum sodium, potassium, and phosphorus should be checked at the 
beginning of Induction and DI. Consider correcting low levels as clinically appropriate, 
balancing the risk of correction of these abnormalities with the risks of developing 
hyperkalemia or hyperphosphatemia from tumor lysis during induction chemotherapy. 
Also, consider monitoring electrolyte levels periodically during induction and DI and 
correcting if clinically indicated. Bortezomib will not be dose de-escalated for bortezomib-
related electrolyte abnormalities 
 
5.2.4 
Non-Hematologic and non-Electrolyte Grade 3 or 4 Bortezomib-Related Toxicity 
The bortezomib dose should be de-escalated to 1 mg/m2 for non-hematologic and non-
electrolyte Grade 3 and 4 toxicities that are possibly, probably or definitely related to 
bortezomib (see below).  
 
Dose de-escalation within a block (Induction or DI): 
If a patient experiences a Grade 3 or 4 bortezomib-related toxicity that does not require 
cessation of bortezomib (see above), and once this Grade 3 or 4 toxicity resolves to ≤ Grade 
1, bortezomib can be restarted at a decreased dose of 1 mg/m2 for subsequent doses. 
Missed doses of bortezomib will not be made up. Patients who have a qualifying Grade 3 
pulmonary toxicity that worsens (i.e., > Grade 3) by the next scheduled dose of bortezomib 
should discontinue bortezomib.  
 
Dose de-escalation between Induction and DI: 
The bortezomib dose will be decreased to 1 mg/m2 for qualifying Grade 3 or 4 toxicities 
(see above) that resolve to ≤ Grade 1 prior to the beginning of DI. Doses reduced for an 
adverse event will not be re-escalated, even if there is minimal or no toxicity at the reduced 
dose.  
 
5.2.5  Bortezomib Dose Reductions for Hyperbilirubinemia:  
Patients with mild hepatic impairment do not require dose adjustment of bortezomib. 
Patients with moderate or severe hepatic impairment should receive bortezomib at 
modified doses as outlined below:  
 
 
Direct Bilirubin 
Level 
Bortezomib Dose Modification  
Moderate  
> 1.5x – 3x upper 
limit of normal 
Reduce bortezomib to 0.7 mg/m2 for all doses in 
the cycle in which hepatotoxicity is present. 

  
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Severe 
> 3x upper limit of 
normal 
Consider dose escalation to 1 mg/m2 in 
subsequent cycles if transaminitis and 
hyperbilirubinemia resolves and hepatic toxicity 
was not possibly, probably, or definitively 
related to bortezomib. 
* No adjustment necessary for elevated SGOT (ALT). 
 
5.3 
Cyclophosphamide 
5.3.1 
Hematuria  
5.3.1.1 
Omit in the presence of macroscopic hematuria.  
5.3.1.2 
If there is a history of previous significant hematuria: 
• 
Hydrate before cyclophosphamide until specific gravity is <1.010  
• 
Hydrate at 125 mL/m2/hr for 24 hours after dose 
• 
Monitor for adequate urine output as per institutional guidelines.  
• 
Give IV mesna at a total dose that is 60% of the cyclophosphamide 
dose divided to 3 doses (e.g., if the cyclophosphamide dose is 1000 
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. 
 
5.3.2 
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. 
 
5.4 
Cytarabine (ARAC) 
5.4.1 
Fever 
• Do not withhold ARAC for fever if it is likely to have been caused by the ARAC 
(ARAC Syndrome).  
• Obtain blood cultures if a central line is present.  
 
5.4.2 
Rash or Conjunctivitis 
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.  
 
5.4.3 
Myelosuppression 
Once Consolidation (C) or Delayed Intensification (DI) has started do not interrupt for 
uncomplicated myelosuppression; do hold for proven or presumed serious infection. Do 
make up missed doses. 
 
5.4.4 
Renal Function 
Adequate renal function (defined as creatinine within normal range) is required for the 
administration of high dose ARAC. Creatinine Clearance should be measured for patients 
with elevated creatinine or suspected renal insufficiency. For CrCl < 60 mL/min/1.73 m2, 
hold pending recovery and omit if recovery requires > 3 weeks. 
 

  
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5.5 
Daunorubicin and Doxorubicin  
5.5.1 
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. 
 
5.5.2 
Myelosuppression (beyond Induction) 
If patient has severe infection or severe mucositis (Grade 3-4) and an ANC < 500/µL delay 
anthracycline during phases other than Induction. During Induction, continue with 
anthracycline administration. Subsequent doses should be given at full dose.  
 
5.5.3 
Hyperbilirubinemia 142 
 
Direct Bili  
% 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. 
5.5.7 
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. 
 
5.6 
Etoposide 
5.6.1 
Allergic Reaction 
Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose -50 mg). If 
symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use premedication 
before etoposide in future. Also consider substituting an equimolar amount of etoposide 
phosphate, in the face of significant allergy and/or hypotension.  
 
5.6.2 Hypotension 
If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce infusion 
rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to recover or falls 
further. Stop infusion if BP does not recover, continue NS. If the patient has had any 
episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours prior to any 
subsequent infusion. 
 
5.6.3 
Renal Insufficiency 
If renal function decreases, adjust etoposide as follows: CrCl 10-50 mL/min/1.73 m2, 
decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 50%. 
 
5.6.4 
Hyperbilirubinemia 
If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct bilirubin is > 5 mg/dL, hold 
etoposide. 
 

  
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5.7 
Ifosfamide 
5.7.1 
Hematuria 
Grade 2 – 3: Administer Mesna as under Section 4.12 with ifosfamide. Grade 4 notify 
Study Chair. 
 
5.8 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
5.8.1 
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.  
 
5.8.2 
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.143-145 
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.145-150 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 2000,151 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 radiation therapy 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.152 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.153-155 Additional studies, including MR angiography and/or 
venogram should be considered, if clinically indicated (e.g., focal deficits). 

  
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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.156 For patients who return to their “pre-event” status, without residual 
deficits of 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, substitute IT Ara-C 
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 
one case series.156 There have been questions about potential interference of leucovorin 
with the efficacy of the IT MTX, but there are 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.157-160 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.161-164 
At doses thought to be therapeutic, side effects have included nystagmus, nausea and 
vomiting, distorted vision, ataxia, and dizziness. In addition, Hollander et al165 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. 
 
5.8.3 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. 
 
5.8.4 
Viral, bacterial, or fungal meningitis  
Omit until resolved. 
 
5.9 
High-Dose Methotrexate (HDMTX) and Leucovorin Rescue  
[Please note that HDMTX refers to IV MTX 5g/m2 given over 24 hrs] 
Note: Review of methotrexate dosing on BFM-based protocols indicated that excessive 
methotrexate toxicity has not been encountered in patients larger than 2 m2 who receive more than 

  
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10 grams of methotrexate. The investigator should base the methotrexate on the patient's meter-
squared dosing and not cap at 10 grams of methotrexate.  
 
5.9.1 
HD MTX Infusion Guidelines 
See Appendix IV for a flowchart of the HDMTX / LCV guidelines. 
 
When IT therapy and HDMTX are scheduled for the same day, deliver the IT therapy 
within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the 
start of the MTX bolus). 
 
Hold TMP-SMX on the days of HDMTX infusion and for at least 72 hours after the start of 
the HDMTX 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. 
 
Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors 
or aspirin-containing medications on the day of HDMTX infusion and for at least 72 hours 
after the start of the HD 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. 
 
Recommended Prehydration with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour 
until urine specific gravity is ≤ 1.010 and pH is ≥ 7.0 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. An acetate or bicarbonate bolus (0.5-1 mEq/kg over 15 min) may be given to 
raise the urine pH relatively quickly; a normal saline bolus may also be helpful in 
facilitating hydration. Continue hydration and alkalinization throughout HDMTX infusion, 
and for a minimum of 54 hours after the MTX bolus started for patients who meet expected 
clearance parameters. In patients with delayed MTX clearance, continue hydration and 
leucovorin as instructed (Appendix IV) until the plasma MTX concentration is below 
0.1uM. 
 
Hour 0: MTX 500 mg/m2 IV infused over 30 minutes. This is followed, immediately, by 
MTX 4500 mg/m2 given by continuous IV infusion over 23.5 hours. Be certain that the 
HDMTX infusion is completed in the 24 hour period. Unintentional prolongation to as long 
as 26 hours though not encouraged is acceptable. 
 
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine. NOTE: 36 hour level 
is only drawn if needed (see below). 
 
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 (serum CR >125% of baseline), 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 (carboxypeptidase G2) (see below). 
For patients with delayed clearance 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. 
 
If the 24 hour level is < 150 M draw the next level at hour 42 and refer to table below.  

  
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If the 24 hour level is ≥ 150 M and/or creatinine > 125% baseline, repeat level if MTX 
contamination is possible. If the value is “real” refer to the changes in hydration, etc., 
described above and repeat the level with a serum Cr at hour 36. Then refer to the table 
below.  
 
If the 42 and 48 hour levels are ≤ 1 and 0.4 M, respectively, give Leucovorin at 15 
mg/m2 IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No 
additional levels are needed, nor is additional leucovorin. 
 
** If the 36 hour level exceeds 3 M, 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 glucarpidase if 36 hour MTX level exceeds 10 M (see 
below). 
 
++ 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 ≤ 1 and/or ≤ 0.4 µM at hours 42 and 48, respectively, resume standard leucovorin 
and hydration as long as urine output remains satisfactory. 
 
5.9.2 
Nephrotoxicity 
Postpone course if pre-treatment (MTX) serum creatinine is > 1.5x baseline or GFR 
creatinine clearance < 65 mL/minute/1.73m2. If renal function does not recover, omit 
MTX. Do not give HDMTX to a patient with this degree or renal impairment, assuming 
that prolonged excretion can be managed with glucarpidase. 
36 hr MTX level 
42 hr MTX level 
48 hr MTX level 
Leucovorin 
Rescue++ 
Only required if 24 
hr level is ≥ 150 
µM.** 
1.01 to 9.9 µM 
0.41 to 5.9 µM 
Continue 15 mg/m2 
q 6h until MTX 
level < 0.1 M 
(draw q12-24 h). 
 
10 to 19.9 µM 
6 to 9.9 µM 
Increase to 15 
mg/m2 q 3h until 
MTX level < 0.1 
M (draw q 6-24 
h). 
Consider 
glucarpidase. 
 
20 to 200 µM 
10 to 100 µM 
Increase to 100 
mg/m2 q 6h until 
MTX level < 0.1 
M (draw q 6-24 
h). 
Consider 
glucarpidase. 
 
> 200 µM 
> 100 µM 
Increase to 1000 
mg/m2 q 6h until 
MTX level < 0.1 
M (draw q 6-24 
h). 
Consider 
glucarpidase. 

  
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NOTE: For patients who have markedly delayed MTX clearance secondary to renal 
dysfunction, consider using glucarpidase (carboxypeptidase G2, Voraxaze).166,167 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 regarding product 
availability through ASD Healthcare, Cardinal, and McKesson. Canadian sites should 
contact McKesson at (877) 384-7425 for further information. Sites in Australia and New 
Zealand 
should 
contact 
Hospira 
at 
1300-046-774 
(local) 
or 
medicalinformationAUS@hospira.com. Patients requiring glucarpidase rescue will remain 
on study. 
 
5.9.3 
Elevated Transaminases 
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. 
 
* *Please see COG Supportive care Guidelines at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp for TMP/SMX 
substitutions. 
 
5.9.4 
Hyperbilirubinemia 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
5.9.5 
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. 
 
5.9.6 
Myelosuppression 
All chemotherapy should be held for ANC < 750/µL and platelets < 75 000/µL. 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 consecutive 
cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then 
resume at full dose at point of interruption. 
Do not skip doses. 
> 20 X ULN 
Hold therapy until ALT < 10 X ULN, then 
resume at full dose at point of interruption.  
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, bili, alkaline phosphatase, 
PT, albumin, total protein, and hepatitis A, B, 
C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy 
given.  
Notify Study Chair. 

  
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5.10 
Capizzi Methotrexate Regimens  
 
5.10.1 Liver Dysfunction 
Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to a 
course of intravenous MTX. Blood samples for ALT should not be drawn following the start 
of MTX infusions as MTX causes significant short term elevation in ALT levels. 
 
 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 
cycle 
10 – 20 X ULN for 2 consecutive cycles Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then 
resume at full doses at point of interruption. 
Do not skip doses. 
> 20 X ULN 
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 serologies. 
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. 
 
5.10.2 Nephrotoxicity 
Postpone course if serum creatinine is >1.5 x baseline or GFR creatinine clearance 
< 65 mL/1.73m²/minute. 
 
5.10.3 Hyperbilirubinia 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
5.10.4 Mucositis 
For Grade 3-4 mucositis, withhold IV MTX until resolved. Discontinue MTX dose escalation 
and resume at 80% of last dose if therapy is delayed for myelosuppression or Grade 3 or 
greater mucositis. If mucositis persist or recurs, consider culturing lesions for herpes simplex. 
 
5.10.5 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) and pegaspargase (if due) (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 or platelets ≥ 50 000/µL, reduce dose 
of IV MTX by 20% (Do not make up missed dose of MTX). For 
subsequent doses, resume escalation as per A-C. 

  
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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 but < 750/µL and platelets ≥ 50 000 but < 75 000/µL, give same 
dose of MTX as previously (i.e., no escalation). 
 
C)  If ANC ≥ 750 and platelets ≥ 75 000 escalate MTX by 50 mg/m2. 
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. 
 
5.11 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
 
5.11.1 
Interim Maintenance #1 with HDMTX 
If ANC is < 750/µL and/or platelets < 75 000/µL, hold mercaptopurine. Restart 
mercaptopurine at full dose with next cycle of HD MTX when ANC is  750/L and 
platelets are  75 000/L. Do not make up missed doses. Consider a marrow evaluation in 
the face of persistent or prolonged cytopenias. If patient develops severe or unexpected 
myelosuppression, see section below on thiopurine pharmacology testing. 
 
If patient develops severe or unexpected myelosuppression, see section below on thiopurine  
pharmacology testing. 
 
5.11.2 Maintenance:  
a) Dose reduction for myelosuppression:  
If neutrophil count falls below 500/L or if platelet count falls below 50,000/L during 
Maintenance, MP and MTX will be held until recovery above these levels. For the first 
drop in ANC or platelets, resume chemotherapy (both MP and MTX) at the same dose 
the patient was taking prior to the episode of myelosuppression. If neutrophil count falls 
below 500/L or if platelet count falls below 50 000/L for a second (or greater) time, 
discontinue doses of MP and MTX until ANC is ≥ 750/µL and platelets are ≥ 75 000/µL. 
Restart both MP and MTX at 50% of the dose prescribed at the time the medication was 
stopped. Then continue to increase to 75% and then 100% of the dose prescribed prior to 
stopping the medication at 2-4 week intervals provided ANC remains ≥ 750/µL and 
platelets remain ≥ 75 000/µL. May increase both MP and MTX simultaneously. Consider 
discontinuing 
TMP/SMX 
as 
per 
COG 
Supportive 
care 
Guidelines 
at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. If neutrophil 
count falls below 500/L or if platelet count falls below 50 000/L on > 2 occasions 
during Maintenance, perform thiopurine pharmacology testing as described below. 
Should therapy be withheld for myelosuppression or elevated transaminase, do not “make 
up” that week. Resume therapy at the correct point, chronologically. 
 
b) Dose escalation:  
For ANC ≥ 1500/L on 3 CBC(s) done over 6 weeks or 2 successive monthly CBC(s) 
alternately increase doses of MTX or MP by 25%. As a general rule, do not increase doses 
more often than every 4 weeks. 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 RBC thioguanine nucleotides (TGNs). Consider observing the 
administration of an oral dose of MTX and checking plasma MTX concentration 2-4 

  
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hours later. This will document whether or not poor absorption contributes to lack of 
response and may facilitate discussions about noncompliance.  
 
c) 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. 
 
d) 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 every 2 weeks during Consolidation and 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 MTX and monitor labs as above, weekly. Restart at full dose 
therapy when the transaminase is less than 5x ULN, if bilirubin is normal. If liver 
dysfunction persists, consider a trial period with MTX but without MP, especially if red 
cell MP methylated derivatives are elevated. Also consider liver biopsy. 
 
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT 
or SGOT/AST above 5x ULN. 
 
 
5.11.3 Thiopurine Pharmacology Testing and Dosage Adjustments in All Blocks that Contain 
Thiopurines  
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 is moderately deficient in TPMT activity 
because they have inherited one variant (non-functional) TPMT allele (i.e., 
heterozygotes).168-171  Patients with low TPMT form higher concentrations of the 6-
thioguanine nucleotides (6-TGN) and are more susceptible to acute thiopurine toxicity 
(primarily myelosuppression, involving neutropenia, thrombocytopenia, and anemia). 
Patients with the complete deficiency of TPMT tolerate less than 10% of protocol doses of 
MP (10 to 30 mg/m2/day 3 days per week). About 35% of heterozygotes require a lower 
dose of MP to avoid dose-limiting myelosuppression.172  
 
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. 173 
 
There are now CLIA certified tests for TPMT genotype and phenotype, for thiopurine 
metabolites (6-methyl mercaptopurine [6-MMP] and 6-TGN) measurements, and for 
NUDT15 polymorphisms. Only 3 SNPs constitute well over 90% of the inactivating 
mutations in the gene, based on studies in numerous racial and ethnic groups 
worldwide.168,174-177 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 

  
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would potentially confound assessments of RBC TPMT activity. When the genotyping 
result is coupled with a phenotyping test for TPMT or with thiopurine metabolite 
concentrations in erythrocytes, the reliability of the tests will be even greater. Moreover, 
metabolite levels can provide an index of patient compliance with thiopurine therapy. 
 
Recommendations for Thiopurine Monitoring and Dosage Adjustments:  
When myelosuppression has led to significant delays in therapy (> 2 weeks) or is 
disproportionate to the therapy, thiopurine testing should be performed: 
 
-  
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. 
 
5.11.4 Suggested Dose Adjustments in Patients With Unacceptable Myelosuppression 
 
- 
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 heterozygous 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. 
 
5.12 
Steroids (Dexamethasone and Prednisone) 
5.12.1 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 
prohemorrhagic effect.  
 
5.12.2 Hyperglycemia  
Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be employed 
to control the blood glucose level. 
 

  
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5.12.3 
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.  
 
5.12.4 Osteonecrosis (ON)  
Do not modify corticosteroid therapy for osteonecrosis (also referred to as avascular 
necrosis) during Induction or Delayed Intensification. Consider omitting Maintenance 
steroid for osteonecrosis Grade 1 (clinically asymptomatic, radiographic finding only). 
Omit Maintenance steroid for osteonecrosis Grade 2 or greater, and notify study chair. 
Consider resuming Maintenance steroid after 6 months if joint symptoms have resolved 
and if MRI findings have significantly improved or normalized. 
 
5.12.5 Varicella  
Steroids should be held during active infection except during Induction. Do not hold during 
incubation period following exposure. 
 
5.12.6 Inability to use oral doses 
For dexamethasone, substitute the IV preparation mg for mg. For prednisone, substitute IV 
methylprednisolone at 80% of the oral prednisone dose. Note that if substituting oral 
prednisolone for prednisone, the doses are the same; prednisone is converted in the liver to 
prednisolone. 
 
5.12.7 Severe infection  
Do not hold or discontinue steroids during Induction without serious consideration, as this 
is a critical period in the treatment of ALL. Later in therapy, one may consider holding 
steroid until patient achieves cardiovascular stability, except for “stress doses.” 
 
5.12.8 Severe psychosis  
Dexamethasone dose may be reduced by 50% for severe psychosis. If symptoms persist, 
consider switching to an equivalent dose of prednisone. 
 
5.13 
PO 6-Thioguanine (TG) 
Delayed Intensification 
Oral TG will be held for suspected or proven serious infection. 
 
For severe and/or unexpected myelosuppression, evaluate for TPMT activity as described in 
Section 5.10. 
 
5.14 
Vincristine 
PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See text box below) 
 
5.14.1 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. 

  
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5.14.2 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.  
 
5.14.3 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. 
 
5.14.3 
Jaw pain  
Treat with analgesics; do not modify vincristine dose. 
 
5.14.4 Hyperbilirubinemia178,179  
 
Direct Bili 
 
Dose reduction 
 
< 3.1 mg/dL 
 
Full dose (maximum dose: 2 mg), 
3.1- 5.0 mg/dL  
50% of calculated dose (maximum dose: 1 mg), 
5.1-6.0 mg/dL  
75% of calculated dose (maximum dose: 0.5 mg), 
> 6.0 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has 
resolved. 
 
 
 
Do not make up missed doses. 
 
5.14.5 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. 
 
5.14.6 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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Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
 
Peripheral Motor Neuropathy: 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal 
deep tendon reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using eating 
utensils) or unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity 
function. 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without 
causing loss of function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using 
eating utensils) or gait, without abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function (gait, 
fine motor skills as outlined above), or quality of life (loss of sleep, ability to perform normal activities 
severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 

  
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6.0 
DRUG INFORMATION  
 
6.1 
BORTEZOMIB 
(VelcadeTM, N-Pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid, PS-341, MLN341, 
LDP-341) NSC# 681239, IND# 58443  
 
 
 
 
(05/21/19) 
 
Source and Pharmacology: 
Bortezomib (PS-341) is a reversible inhibitor of the chymotrypsin-like activity of the 26S 
proteasome (a multicatalytic protease present in all eukaryotic cells). The 26S proteasome is a large 
protein complex that degrades proteins that have been conjugated to ubiquitin. The ubiquitin-
proteasome pathway plays an essential role in regulating the intracellular concentration of specific 
proteins, and constitutes the major mechanism for intracellular protein degradation (80%). Those 
intracellular proteins that maintain homeostasis within cells include numerous regulatory proteins 
involved in cellular integrity, such as cell-cycle control, cellular apoptosis, transcription factor 
activation, and tumor growth via ATP-dependent processes. Inhibition of the 26S proteasome 
prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This 
disruption of normal homeostatic mechanisms can lead to cell death.  
 
The binding of bortezomib to human plasma proteins averages 83% over a concentration range of 
100 to 1000 ng/mL. The mean elimination half-life of bortezomib after multiple dosing ranged 
from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. In vitro 
studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes 
indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 
2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major 
metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo 
hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S 
proteasome inhibitors.  
 
In vitro and in vivo studies showed that green tea compounds, ascorbic acid (vitamin C) and other 
antioxidants, have the potential to significantly inhibit the activity of bortezomib. Green tea 
constituents, in particular epigallocatechin gallate (EGCG) and other polyphenols with 1,2-
benzenediol moieties, effectively prevented tumor cell death induced by bortezomib both in vitro 
and in vivo. In multiple myeloma cell lines or mouse xenografts, EGCG directly reacted with 
bortezomib and blocked its proteasome inhibitory function. As a result, bortezomib could not 
trigger endoplasmic reticulum stress or caspase-7 activation and could not induce tumor cell death. 
A more recent study investigated whether clinically relevant levels of EGCG or ascorbic acid could 
inhibit the antitumor activity of bortezomib in murine xenograft tumors. The addition of EGCG to 
bortezomib demonstrated no effect on tumor growth inhibition at lower concentrations of EGCG 
that the investigators compare to human dietary intake. Similar results were found for ascorbic acid 
at normal daily doses. When bortezomib was given concurrently with much higher concentrations 
of EGCG, the investigators found that all antitumor activity was eliminated. The authors concluded 
that there is no interaction between EGCG and ascorbic acid when plasma concentrations are 
commensurate with dietary oral intake. 
 
Vitamin C, at concentrations achieved during vitamin supplementation, has also been shown to 
inhibit the activity of bortezomib both in vitro and in vivo. Direct binding between the hydroxyl 
group of vitamin C and the boronic acid of bortezomib reduced the affinity of the proteasome 
inhibitor for the chymotrypsin-like subunit of the proteasome. In addition, it was noted that besides 
vitamin C, other natural agents carrying a hydroxyl group, such as flavonoid compounds (quercetin 
among others), bind and inhibit the activity of bortezomib in vitro.  
 
To avoid the risk of any possible interaction it is recommended that green tea containing products 
and any supplemental products containing vitamin C, flavonoids or other antioxidants (e.g., 

  
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vitamins, herbal supplements) be discontinued from at least 24 hours prior to the initiation of 
bortezomib through 72 hours after the last bortezomib dose. Injectable multivitamins used as a 
component of parenteral nutrition should also be avoided during this time period to minimize the 
risk of direct vitamin C inactivation of bortezomib. In addition, it is recommended that the total 
dietary intake of vitamin C not exceed the RDA for age. Normally balanced diets are acceptable; 
supplementation with high doses of vitamin C or injectable vitamin C should be avoided. See 
Section 4.2.2 for additional information. 
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bortezomib (Velcade, NSC 681239) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. 
In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below). 
 
Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further 
clarification. Frequency is provided based on 2084 patients. Below is the CAEPR for bortezomib (Velcade). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
Version 2.7, March 25, 20191 
 
 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 5.0 Term) 
[n= 2084] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
 
Gastrointestinal perforation3 
  
 
Ileus 
 
 Ileus (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 3) 

  
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 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 5.0 Term) 
[n= 2084] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure4 
  
 
 
Hepatobiliary disorders - 
Other (hepatitis)4 
  
INFECTIONS AND INFESTATIONS 
  
Infection5 
 
 
 Infection5(Gr 4) 
INVESTIGATIONS 
  
 
 
Alanine aminotransferase 
increased4 
  
 
 
Alkaline phosphatase 
increased4 
  
 
 
Aspartate aminotransferase 
increased4 
  
 
 
Blood bilirubin increased4 
  
 
 
GGT increased4 
  
 
 
INR increased4 
  
 
 
Investigations - Other 
(albumin)4 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
 Back pain (Gr 3) 
 
Bone pain 
 
 Bone pain (Gr 2) 
 
Muscle cramp 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Pain in extremity 
 
 Pain in extremity (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 3) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Leukoencephalopathy 
  
 
Neuralgia 
 
 Neuralgia (Gr 3) 
 
Paresthesia 
 
  
Peripheral motor neuropathy 
 
 
 Peripheral motor neuropathy (Gr 
3) 
Peripheral sensory neuropathy  
 
 Peripheral sensory neuropathy 
(Gr 3) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  

  
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 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 5.0 Term) 
[n= 2084] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Adult respiratory distress 
syndrome 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
 
Pulmonary hypertension 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 4) 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and 
Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation 
under the GASTROINTESTINAL DISORDERS SOC. 
 
4Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and 
with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in 
liver enzymes, and hyperbilirubinemia. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on bortezomib (Velcade) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that bortezomib (Velcade) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hematocrit low, hematocrit); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and 
lymphatic system disorders - Other (pancytopenia); Disseminated intravascular coagulation; Febrile 
neutropenia; Hemolytic uremic syndrome; Leukocytosis 
CARDIAC DISORDERS - Asystole; Atrial fibrillation; Atrial flutter; Atrioventricular block complete; 
Cardiac arrest; Cardiac disorders - Other (cardiac amyloidosis); Cardiac disorders - Other (cardiomegaly); 
Chest pain - cardiac; Left ventricular systolic dysfunction; Mobitz type I; Myocardial infarction; Palpitations; 

  
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Pericardial effusion; Pericardial tamponade; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; 
Sinus tachycardia; Supraventricular tachycardia; Ventricular arrhythmia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Blurred vision; Dry eye; Extraocular muscle paresis; Eye disorders - Other (chalazion); 
Eye disorders - Other (choroidal effusion); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - 
Other (retinal hemorrhage with bilateral vision impairment); Keratitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Belching; Bloating; Colitis; Dry 
mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux 
disease; Gastrointestinal disorders - Other (colonic wall thickening); Gastrointestinal disorders - Other (early 
satiety); Gastrointestinal disorders - Other (ileitis); Gastrointestinal disorders - Other (ischemic bowel); 
Gastrointestinal disorders - Other (mouth/tongue ulceration); Gastrointestinal disorders - Other (retching); 
Gastrointestinal pain; Gingival pain; Hemorrhoids; Mucositis oral; Oral pain; Pancreatitis; Small intestinal 
obstruction; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other (catheter related 
complication); General disorders and administration site conditions - Other (hepato-renal syndrome); 
Hypothermia; Injection site reaction; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death 
NOS 
HEPATOBILIARY DISORDERS - Portal vein thrombosis; Sinusoidal obstruction syndrome 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Fracture; Vascular 
access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; CD4 lymphocytes decreased; CPK 
increased; Carbon monoxide diffusing capacity decreased; Cardiac troponin I increased; Cardiac troponin T 
increased; Cholesterol high; Creatinine increased; Ejection fraction decreased; Investigations - Other (BUN); 
Investigations - Other (low chloride); Lipase increased; Lymphocyte count decreased; Serum amylase 
increased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypoglycemia; 
Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to 
thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; 
Buttock pain; Chest wall pain; Generalized muscle weakness; Joint range of motion decreased; Muscle 
weakness lower limb; Osteonecrosis of jaw 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Akathisia; Ataxia; Cognitive 
disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Edema cerebral; 
Encephalopathy; Facial muscle weakness; Facial nerve disorder; Hypersomnia; Intracranial hemorrhage; 
Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous system disorders - Other (autonomic 
neuropathy, autonomic dysfunction); Nervous system disorders - Other (cranial palsy); Nervous system 
disorders - Other (dysautonomia); Nervous system disorders - Other (L sided facial droop); Nervous system 
disorders - Other (paralysis); Nervous system disorders - Other (polyneuropathy); Nervous system disorders - 
Other (tongue paralysis); Presyncope; Seizure; Somnolence; Spinal cord compression; Stroke; Syncope; 
Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Delirium; Depression; Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Proteinuria; Renal and urinary disorders - Other (bilateral hydronephrosis); Renal and urinary 
disorders - Other (glomerular nephritis proliferative); Renal calculi; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract pain 

  
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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Aspiration; 
Atelectasis; Bronchopulmonary hemorrhage; Bronchospasm; Epistaxis; Hiccups; Hypoxia; Laryngeal edema; 
Mediastinal hemorrhage; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; Postnasal 
drip; Pulmonary edema; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(obstructive airways disease); Respiratory, thoracic and mediastinal disorders - Other (respiratory distress); 
Respiratory, thoracic and mediastinal disorders - Other (tachypnea); Tracheal mucositis; Tracheal stenosis; 
Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; Erythema 
multiforme; Erythroderma; Hyperhidrosis; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; 
Pruritus; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (angioedema); Skin and 
subcutaneous tissue disorders - Other (leukoclastic vasculitis); Skin and subcutaneous tissue disorders - Other 
(skin lesion NOS); Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hematoma; Hypertension; 
Thromboembolic event; Vascular disorders - Other (trach site); Vasculitis 
 
Note: Bortezomib (Velcade) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Effect in Pregnancy and Lactation: 
At ½ the clinical dose bortezomib was not teratogenic in non-clinical developmental toxicity studies in 
rats and rabbits. However, pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg 
(0.6 mg/m2) experienced significant post-implantation loss and decreased number of live fetuses. Live 
fetuses from these litters also showed significant decreases in fetal weight. It is not known whether 
bortezomib is excreted in human milk. 
 
Formulation and Stability:  
Bortezomib is supplied as a lyophilized powder in sterile vials containing 3.5 mg and 35 mg mannitol, USP. 
Unopened vials may be stored at controlled room temperature 25ºC (77ºF); excursions permitted from 15ºC 
to 30ºC (59ºF to 86ºF). Retain in original package to protect from light.  
 
Reconstitute bortezomib with 3.5 mL normal saline, USP. Each milliliter of solution will contain 1 mg of 
bortezomib at a pH of approximately 5 to 6. The drug solution is clear and colorless. Bortezomib contains 
no antimicrobial preservative. When reconstituted as directed, bortezomib may be stored at 25°C (77°F). 
Reconstituted bortezomib should be administered within 8 hours of preparation. The reconstituted material 
may be stored in the original vial and/or the syringe prior to administration. The product may be stored for 
up to 8 hours in a syringe; however total storage time for the reconstituted material must not exceed 8 hours 
when exposed to normal indoor lighting.  
  
Guidelines for Administration: 
See Treatment and Dose Modification sections of the Protocol. 
Bortezomib is to be given without further dilution as an IV push over 3 to 5 seconds. Consecutive doses 
must be separated by at least 72 hours. Grapefruit and its juice should be avoided for the duration of 
treatment with bortezomib. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The syringe containing bortezomib should be clearly labeled “For intravenous use only. Fatal if given by 
other routes.” Additional wording may be considered at the institution’s discretion. Three fatalities have 
been reported following accidental intrathecal administration of bortezomib. Special precautions should be 
employed to ensure that intravenous bortezomib and intrathecal medications are not inadvertently 
interchanged. 
 

  
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Supplier: Supplied by Millennium Pharmaceuticals and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Obtaining the Agent 
Agent Ordering:  
NCI supplied agent may be requested by the Principal Investigator (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained). The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission of FDA form 
1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead investigator at 
that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees must submit agent requests through the PMB Online Agent Order Processing (OAOP) application 
< https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP requires the establishment of 
a CTEP Identity and Access Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the 
maintenance of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability: 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI 
Drug 
Accountability 
Record 
Form 
(DARF). 
(See 
the 
CTEP 
home 
page 
at 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs for the Procedures for Drug 
Accountability and Storage and http://ctep.cancer.gov/forms/default.htm to obtain a copy of the DARF and 
Clinical Drug Request form.) 
 
Agent Returns: 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical 
repository as soon as possible when: the agent is no longer required because the study is completed or 
discontinued and the agent cannot be transferred to another DCTD sponsored protocol; the agent is outdated 
or the agent is damaged or unfit for use. Regulations require that all agents received from the DCTD, NCI 
be returned to the DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do NOT 
return opened or partially used vials/bottles unless specifically requested otherwise in the protocol. See the 
CTEP web site for Policy and Guidelines for Investigational agent Returns at:  
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms may be 
obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf. 
 
 
6.2 
CYCLOPHOSPHAMIDE - INJECTION 
 
 
 
 
(03/13/13) 
(Cytoxan) NSC #26271 
 
Source and Pharmacology:   
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is inactive 
until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active 
compounds. The initial product is 4-hydroxycyclophosphamide (4-HC), which is in equilibrium with 
aldophosphamide, which spontaneously releases acrolein to produce phosphoramide mustard. 

  
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Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent 
in vitro than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those 
produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the 
urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. Cyclophosphamide is well 
absorbed orally with a bioavailability greater than 75%. The plasma half-life ranges from 4.1 to 16 
hours after IV administration and 1.3 to 6.8 hours after oral administration. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, nausea & 
vomiting (acute and 
delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid 
administration, arrhythmias (rapid 
infusion), skin rash, anaphylaxis, 
SIADH 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose 
(acute – CHF hemorrhagic 
myocarditis, myocardial necrosis) 
(L), hyperpigmentation, nail 
changes, impaired wound healing, 
infection secondary to immune 
suppression 
Delayed: 
Any time later 
during therapy, 
excluding the above 
conditions 
Gonadal dysfunction: 
azoospermia or 
oligospermia 
(prolonged or 
permanent)1 (L) 
amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder carcinoma 
(long term use > 2 years), bladder 
fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination 
with other antineoplastic agents) have been noted in humans. Toxicities include: 
chromosomal abnormalities, multiple anomalies, pancytopenia, and low birth weight. 
Cyclophosphamide is excreted into breast milk. Cyclophosphamide is contraindicated 
during breast feeding because of reported cases of neutropenia in breast fed infants 
and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment 
2 Risk increased with pulmonary chest irradiation and higher doses 
(L) Toxicity may also occur later 
 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The 
product will withstand brief exposures to temperatures up to 30ºC (86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Cyclophosphamide for Injection:  
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then reconstitute 
to 20 mg/mL with NS ONLY to avoid a hypotonic solution.  If the drug will be further diluted prior 
to administration, then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection 

  
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(paraben preserved only) to a concentration of 20 mg/mL.  Following reconstitution further dilute 
in dextrose or saline containing solutions for IV use. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.3 
CYTARABINE - ALL ROUTES 
 
 
 
 
 
(07/13/15) 
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878 
 
Source and Pharmacology: 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but significant, 
incorporation of cytarabine into both DNA and RNA has also been reported. It exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain 
conditions blocking the progression of cells from the G1 phase to the S-phase. Cytarabine is 
metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate 
(Ara-CTP), an effective inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). It appears that 
the balance of kinase and deaminase levels may be an important factor in determining sensitivity 
or resistance of the cell to cytarabine. It has an initial distributive phase t½ of about 10 minutes, 
with a secondary elimination phase t½ of about 1 to 3 hours. Peak levels after intramuscular or 
subcutaneous administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized and eliminated 
more slowly with a t½ of about 2 hours. 
 
Toxicity: (Intravenous, SubQ, IM) 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of receiving 
drug 
Nausea, vomiting, 
anorexia  
 
With High Dose: 
conjunctivitis  
Flu-like symptoms 
with fever, rash  
 
Ara-C syndrome (fever, myalgia, bone pain, 
occasionally chest pain, maculopapular rash, 
malaise, conjunctivitis), anaphylaxis, 
swelling, pain and redness at the site of the 
medication injection (SubQ or IM injection) 
 
With High Dose: cardiomyopathies 
(vasculitis, and pericarditis), cerebral and 
cerebellar dysfunction including: 
encephalopathy, aseptic meningitis, ataxia, 
dysphasia, nystagmus, a decreased level of 
consciousness, personality changes, 
somnolence, seizures  
Prompt: 
Within 2-3 weeks, prior to the 
next course 
Myelosuppression 
(anemia, 
thrombocytopenia, 
leukopenia, 
megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia 
Diarrhea, 
hypokalemia, 
hypocalcemia, 
hyperuricemia 
 
With High Dose: 
capillary pulmonary 
leak syndrome (RDS, 
pulmonary edema) 
Hepatotoxicity, sinusoidal obstruction 
syndrome (SOS, formerly VOD), urinary 
retention, renal dysfunction, pain and 
erythema of the palms and soles 
 
Delayed: 
Any time later during therapy, 
excluding the above conditions 
 
 
Asymptomatic nonoliguric rhabdomyolysis 
Unknown Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It is 
unknown whether the drug is excreted in breast milk. 
 
 

  
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Toxicity: (Intrathecal) 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
fever, headache 
 
Arachnoiditis 
Rash, somnolence, meningismus, 
convulsions, paresis 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia 
Delayed: 
Any time later during 
therapy, excluding the above 
condition 
 
 
Necrotizing leukoencephalopathy, 
paraplegia, blindness (in combination 
with XRT & systemic therapy) 
 
Formulation:  
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a sterile 
powder for reconstitution. It is also available at a 20 mg/mL concentration with benzyl alcohol (25 
mL per vial) or as a preservative free solution (5 mL, 50 mL per vial), and at a 100 mg/mL 
concentration with benzyl alcohol (20 mL vial) or as preservative free solution (20 mL vial). 
Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); 
excursions permitted to 15°-30°C (59°-86°F). Cytarabine solutions should be protected from light.  
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
IV Infusion: 
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection. Solution 
containing bacteriostatic agent should not be used for the preparation of doses > 200 mg/m2. May be 
further diluted with dextrose or sodium chloride containing solutions. May give by IV push 
injection, by IV infusion, or by continuous infusion. 
 
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a concentration of 20-
100 mg/mL. 
 
High Dose (≥ 1000 mg/m²/dose): Administer steroid eye drops (dexamethasone or prednisolone), 
2 drops each eye q6h beginning immediately before the first dose and continuing 24 hours after the 
last dose. If patient does not tolerate steroid eye drops, administer artificial tears on a q2-4 hour 
schedule. 
 
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 hours 
at room temperature. Solutions reconstituted without a preservative should be used immediately. 
Discard if solution appears hazy. Diluted solutions in D5W or NS are stable for 8 days at room 
temperature; however, the diluted cytarabine should be used within 24 hours for sterility concerns. 
 
Subcutaneous or IM: 
Dilute with Bacteriostatic Water for Injection or NS to a concentration not to exceed 100 mg/mL. 
Rotate injection sites for subcutaneous/IM administration. 
 
 
 
 

  
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6.4 
DAUNORUBICIN 
 
 
 
 
 
 
 
(05/09/11) 
(Daunomycin, rubidomycin, Cerubidine®) NSC #82151  
 
 
 
 
 
Source and Pharmacology:  
Daunorubicin is an anthracycline antibiotic isolated from cultures of Streptomyces coeruleorubidus. 
Daunorubicin is closely related structurally to doxorubicin only differing in that the side chain of 
daunorubicin terminates in a methyl group rather than an alcohol. The cytotoxic effect of 
daunorubicin on malignant cells and its toxic effects on various organs are similar to those of 
doxorubicin and are thought to be related to nucleotide base intercalation and cell membrane lipid 
binding activities. Intercalation inhibits nucleotide replication and action of DNA and RNA 
polymerases. The interaction of daunorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of cytocidal activity. Daunorubicin cellular 
membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of 
daunorubicin by a variety of oxidases, reductases, and dehydrogenases generate highly reactive 
species including the hydroxyl free radical (OH•), which may lead to DNA damage or lipid 
peroxidation. Daunorubicin is metabolized more rapidly by aldoketoreductases to the active 
metabolite, daunorubicinol, than is doxorubicin. Daunorubicin hydrochloride is rapidly and widely 
distributed in tissues, with the highest levels in the spleen, kidneys, liver, lungs, and heart. 
Daunorubicin serum decay pattern is multiphasic. The initial t½ is approximately 45 minutes 
followed by a terminal t½ of 18.5 hours. By 1 hour after drug administration, the predominant 
plasma species is daunorubicinol, which disappears with a half-life of 26.7 hours. Twenty five 
percent of an administered dose of daunorubicin is eliminated in an active form by urinary excretion 
and an estimated 40% by biliary excretion. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, pink 
or red color to urine, 
sweat, tears, and saliva 
Hyperuricemia, sclerosis 
of the vein 
Diarrhea, anorexia, abdominal 
pain, extravasation (rare) but if 
occurs = local ulceration, 
anaphylaxis, fever, chills, rash, 
urticaria, acute arrhythmias  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
myocarditis-pericarditis 
syndrome, conjunctivitis and 
lacrimation 
Delayed: 
Any time later 
during therapy 
 
  
 
Cardiomyopathy1 
 (uncommon at cumulative 
doses ≤ 550 mg/m², 400 mg/m² 
with mediastinal radiation, 
300 mg/m² in children, or 
10 mg/kg in children < 2 yrs or 
0.5 m²) (L), hyper-pigmentation 
of nail beds 
Late: 
Any time after 
completion of 
treatment 
 
Subclinical cardiac 
dysfunction 
 
CHF (on long term follow up in 
pediatric patients), 
secondary malignancy (in 
combination regimens) 
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of daunorubicin have been noted in animals. It is 
unknown whether the drug is excreted in breast milk. 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age.  
(L) Toxicity may also occur later 
 

  
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Formulation and Stability:  
Daunorubicin is available as red-orange lyophilized powder1 for injection in 20 mg single dose vials 
and a preservative free 5 mg/mL solution2 in 20 mg (4 mL) and 50 mg (10 mL) vials. 
¹ Each vial contains 21.4 mg of daunorubicin hydrochloride (equivalent to 20 mg of daunorubicin) 
and 100 mg mannitol.  
² Each mL contains 5.3 mg daunorubicin hydrochloride (equivalent to 5 mg of daunorubicin), 
9 mg of sodium chloride, sodium hydroxide or hydrochloric acid to adjust pH, and Sterile Water 
for Injection. 
 
Powder for Injection: 
Store intact, unreconstituted vials at room temperature, 15°-30°C (59°-86°F). Protect from light. 
Retain in carton until contents are used. Reconstitute a 20 mg vial with 4 mL SWFI to a final 
concentration of 5 mg/mL. After adding the diluent, the vial should be shaken gently and the 
contents allowed to dissolve. The reconstituted solution is stable for 24 hours at room temperature 
and 48 hours refrigerated. Protect from exposure to sunlight.   
 
Aqueous Solution: 
Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in carton until contents are used. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Administer by IV side arm into a rapidly flowing infusion solution. Alternately, daunorubicin may 
be further diluted in saline or dextrose containing solutions and administered by infusion. Protect final 
preparation from light. To avoid extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.5 
DEXAMETHASONE  
 
 
 
 
 
 
(05/09/11) 
(Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521  
Source and Pharmacology:  
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects. 
Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to approximately 5 mg 
of prednisone. Glucocorticoids produce widespread and diverse physiologic effects on carbohydrate, 
protein, and lipid metabolism, electrolyte and water balance, functions of the cardiovascular system, 
kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce the concentration of 
thymus-dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 
selectively bind to the cortisol receptors on human lymphoid cells that are found in larger numbers 
on leukemic lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors 
and inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose transport 
or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. Elimination half-lives 
for the following age groups have been reported to be: infants and children under 2 years of age: 2.3 
to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults (age not specified): 3 to 6 hours. The 
biologic half-life is 36-72 hours. It is primarily metabolized in the liver and excreted by the kidneys. 
 
 
 

  
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-adrenal 
axis suppression, acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial, fungal, parasitic, 
viral), edema 
Pancreatitis (L), increased 
intraocular pressure (L), 
hypertension, psychosis, 
vertigo, headache 
Delayed: 
Any time later 
during therapy 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising, muscle 
weakness, osteopenia  
Spontaneous fractures (L), 
growth suppression, peptic ulcer 
and GI bleeding, pseudotumor 
cerebri (increased intracranial 
pressure with papilledema, 
headache), aseptic necrosis of 
the femoral and humeral 
heads (L), urolithiasis1 (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (which may be 
reversible on 
discontinuation of 
dexamethasone in 
children) 
 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54% 
metabolized by enzymes in the placenta. In animal studies, large doses of cortisol 
administered early in pregnancy produced cleft palate, stillborn fetuses, and decreased fetal 
size. Chronic maternal ingestion during the first trimester has shown a 1% incidence of cleft 
palate in humans. There are no reports of dexamethasone excretion into breast milk in 
humans; however, it is expected due to its low molecular weight that it would partition into 
breast milk. 
1 Mainly reported in pediatric patients with ALL. Howard SC et al. Urolithiasis in pediatric patients with acute 
lymphoblastic leukemia. Leukemia 2003; 17: 541-6. 
 
(L) Toxicity may also occur later. 
 
 
Formulation and Stability:  
Oral: 
 
Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid formulations are 
available in 0.5 mg/5 mL and 1 mg/1 mL concentrations. Inactive ingredients vary depending on 
manufacturer but tablet formulations may include: calcium or magnesium stearate, corn starch, 
lactose, and various dyes. Liquid formulations may include: 5%-30% alcohol, benzoic acid, sorbitol, 
sodium saccharin, glycerin, purified water, and various dyes.  
 
Injection: 
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL, 5 mL, and 
30 mL vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Vials are available in multi-dose vials as 
well as unit of use vials and syringes. Inactive ingredients vary depending on manufacturer but 
include creatinine, sodium citrate, sodium hydroxide to adjust pH, Water for Injection, sodium 
sulfite, bisulfite and metabisulfite, methyl and propyl paraben, benzyl alcohol, and EDTA. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 

  
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Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV use, it 
may be further diluted in dextrose or saline containing solutions. Avoid using benzyl alcohol-
containing dexamethasone solutions in neonates. Diluted solutions that contain no preservatives 
should be used within 24 hours, but maintain stability for at least 14 days in PVC bags at room 
temperature protected from light. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further information. 
 
 
6.6 
DOXORUBICIN  
 
 
 
 
 
 
 
(05/09/11) 
(Adriamycin®) NSC #123127  
 
Source and Pharmacology:  
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic effect 
of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related 
to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. 
Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The 
interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be 
an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding 
may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety 
of oxidases, reductases, and dehydrogenases generate highly reactive species including the 
hydroxyl free radical (OH•). Free radical formation has been implicated in doxorubicin 
cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level. Cells treated with 
doxorubicin have been shown to manifest the characteristic morphologic changes associated with 
apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component 
of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 
minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects a 
slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are 
indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 
20 mL/min/kg and is predominately by metabolism and biliary excretion. The P450 cytochromes 
which appear to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. 
Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and 
its metabolites appear in the urine during the same time period. Binding of doxorubicin and its 
major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent of 
plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink 
or red color to urine, 
sweat, tears, and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, erythematous 
streaking of the vein (flare 
reaction), extravasation (rare) but 
if occurs = local ulceration, 
anaphylaxis, fever, chills, 
urticaria, acute arrhythmias 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
Cardiomyopathy1 (CHF occurs in 
< 5% at cumulative doses 

  
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Any time later during 
therapy 
cumulative doses 
≥ 450 mg/m²) (L) 
 
≤ 400 mg/m²) (L), ulceration and 
necrosis of colon, 
hyper-pigmentation of nail bed 
and dermal crease, onycholysis 
Late: 
Any time after completion 
of treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy (in 
combination regimens) 
Unknown Frequency and 
Timing:  
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin 
have been noted in animal models. Doxorubicin is excreted into breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later. 
 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 
50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² vials. 
¹: Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid dissolution 
formula) also contains methylparaben, 1 mg per each 10 mg of doxorubicin, to enhance dissolution. 
²  Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in carton until 
contents are used. 
 
Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). Retain 
in carton until contents are used. Reconstitute with preservative-free NS to a final concentration of 
2 mg/mL. After adding the diluent, the vial should be shaken and the contents allowed to dissolve. 
The reconstituted solution is stable for 7 days at room temperature and 15 days under refrigeration, 
2°-8°C (36°-46°F) when protected from light. Doxorubicin further diluted in 50 – 1000 mL of NS 
or D5W is stable for up to 48 hours at room temperature (25°C) when protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol.  
 
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl preferably into 
a large vein. Protect the diluted solution from sunlight. To avoid extravasation, the use of a central 
line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.7 
ETOPOSIDE -– INJECTION  
 
 
 
 
 
(11/15/16) 
(Toposar ®, Etopophos®,VP-16) NSC #141540 
 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and 
DNA which results in single and double strand DNA breaks. Its main effect appears to be in the S 
and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 
11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is 
excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 
10 mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². 
Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary 
excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion 
appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is 
recovered in the bile as etoposide. Metabolism accounts for most of the non renal clearance of 
etoposide. 
 

  
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The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a 
high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily 
serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related 
to toxicity. Preliminary data suggests that systemic exposure for unbound etoposide correlates 
better than total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide that is rapidly and completely converted 
to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide 
phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension during 
infusion; anaphylaxis (chills, 
fever, tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks, prior 
to next course 
Myelosuppression 
(anemia, 
leukopenia), 
alopecia 
Thrombocytopenia, 
diarrhea, abdominal 
pain, asthenia, malaise, 
rashes and urticaria 
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, congestive heart 
failure, Stevens-Johnson 
Syndrome, exfoliative dermatitis 
Delayed: 
Any time later during 
therapy 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory cycles, 
hypomenorrhea, onycholysis of 
nails 
Late: 
Any time after 
completion of treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals 
at 1/20th of the human dose. It is unknown whether the drug is excreted in breast 
milk. 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 
mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL 
contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 
80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace 
contains nitrogen.  Unopened vials of etoposide are stable until expiration date on package at 
controlled room temperature (20˚--25˚C or 68˚-77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 
32.7 mg sodium citrate USP, and 300 mg dextran 40.  Etoposide phosphate must be stored under 
refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide phosphate are stable until the 
expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are stable 
at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours 

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

  
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6.8 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ   
 
(11/15/16) 
 (Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen® Granix®, Zarxio 
®) NSC #614629 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant 
DNA technology. Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons 
manufactured by recombinant DNA technology utilizing E coli bacteria into which has been 
inserted the human granulocyte colony stimulating factor gene. It differs from the natural protein in 
that the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a lineage specific 
colony-stimulating factor that regulates the production of neutrophils within the bone marrow and 
affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional 
activation (including enhanced phagocytic ability, priming of the cellular metabolism associated 
with respiratory burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens.) Filgrastim exhibits nonlinear pharmacokinetics with 
clearance dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared by the 
kidney. The elimination half-life is similar for subcutaneous and intravenous administration, 
approximately 3.5 hours. The time to peak concentration when administered subcutaneously is 
2-8 hours 
 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more common 
with IV administration than 
subq):skin (rash, urticaria, facial 
edema), respiratory (wheezing, 
dyspnea) and cardiovascular 
(hypotension, tachycardia), low 
grade fever  
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic rupture, 
rash or exacerbation of pre-existing 
skin rashes, sickle cell crises in 
patients with SCD, excessive 
leukocytosis, Sweet’s syndrome 
(acute febrile neutrophilic 
dermatosis) 
Delayed: 
Anytime later during 
therapy 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined to patients 
with severe chronic neutropenia 
and long term administration) 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. 
Conflicting data exist in animal studies and filgrastim is known to pass the placental 
barrier. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability:  
Neupogen® supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. Neupogen® vials 
are preservative free single use vials. Discard unused portions of open vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes containing 
300 mcg/0.5 mL or 480 mcg/0.8 mL of filgastrim for subcutaneous administration. 

  
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Store refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not shake. Prior to injection, 
filgrastim and filgrastim-sndz may be allowed to reach room temperature for a maximum of 
24 hours (infusion must be completed within 24 hours of preparation). TBO-filgrastim may be 
removed from 2°C - 8°C (36°F - 46°F) storage for a single period of up to 5 days between 23°C to 
27°C (73°F to 81°F). Avoid freezing and temperatures > 30ºC. 
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to concentrations 
between 5 mcg/mL and 15 mcg/mL. At concentrations below 5 and 15 mcg/mL, human serum 
albumin should be added to make a final albumin concentration of 0.2% (2 mg/mL) in order to 
minimize the adsorption of filgrastim to plastic infusion containers and equipment for all 3 products 
(communication on file from Teva Pharmaceuticals USA). Filgrastim or filgrastim-sndz dilutions 
of 5 mcg/mL or less are not recommended. Tbo-filgrastim dilutions below 2 mcg/mL are not 
recommended. Diluted filgrastim biosimilar products should be stored at 2º-8ºC (36º-46ºF) and 
used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
Guidelines for Administration: 
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
 
Filgrastim biosimilar products should not be administered within 24 hours of (before AND after) 
chemotherapy. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.9 
HYDROCORTISONE – INTRATHECAL 
 
 
 
 
(07/30/14) 
(Hydrocortisone sodium succinate, Solu-cortef®) NSC #010483 
 
Source and Pharmacology:  
Hydrocortisone is a synthetic compound closely related to cortisol. Glucocorticoids produce 
widespread and diverse physiologic effects on carbohydrate, protein, and lipid metabolism, 
electrolyte and water balance, functions of the cardiovascular system, kidney, skeletal muscle, and 
the nervous systems. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes 
(T-lymphocytes), monocytes, and eosinophils. Glucocorticoids selectively bind to the cortisol receptors 
on human lymphoid cells, which are found in larger numbers on leukemic lymphoblasts. They also 
decrease binding of immunoglobulin to cell surface receptors and inhibit the synthesis and/or 
release of interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing expansion of 
the primary immune response. The specific cellular mechanisms that act to halt DNA synthesis are 
thought to be related to inhibition of glucose transport or phosphorylation, retardation of mitosis, and 
inhibition of protein synthesis. Hydrocortisone is approximately 90% protein bound with a plasma t½ 
of 1-2 hours. The elimination of hydrocortisone from the CNS is prolonged. 
 
Toxicity: 
(Toxicities for Hydrocortisone Intrathecal and Methotrexate and/or Cytarabine)1 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoiditis: 
(headache, fever, 
vomiting, meningismus 
and pleocytosis)  
Rash, anaphylaxis (L), 
paresis, bleeding into 
subarachnoid or subdural 
space (risk > with platelet 
counts < 20,000), confusion, 

  
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fatigue, disorientation, 
seizures 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, 
somnolence, ataxia, cranial 
nerve palsy, transient 
paraplegia, (L) speech 
disorders 
Delayed: 
Any time later during 
therapy, excluding 
the above condition 
 
Cognitive disturbances 
(L), learning disabilities 
(L) 
Demyelinating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after the 
completion of 
treatment 
 
 
Progressive CNS 
deterioration2 
1 Toxicity for hydrocortisone alone has not been described 
2 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial 
irradiation. 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
For intrathecal administration, use hydrocortisone sodium succinate 100 mg vial sterile powder for 
injection WITHOUT preservative. Do not reconstitute vial with bacteriostatic water for injection. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol  
 
For recommended mixing directions for Intrathecal triples [Hydrocortisone, Methotrexate and 
Cytarabine] refer to the monograph for Intrathecal Triples. 
 
Intrathecal Methotrexate and Hydrocortisone: 
Optimal Volume (20 mL): Final concentration of Intrathecal Methotrexate and Hydrocortisone: 
Methotrexate 1 mg/mL and Hydrocortisone 1 mg/mL  
The following is a suggested method for preparing the IT using the 25 mg/mL concentration of 
preservative free methotrexate. Institutional practices may be used as clinically appropriate. 
• Withdraw 0.8 mL (20 mg) of methotrexate 25 mg/mL concentration 
• Reconstitute hydrocortisone 100 mg vial with 10 mL of preservative free NS to a 
concentration of 10 mg/mL. Withdraw 2 mL (20 mg) of hydrocortisone 
• Combine 0.8 mL (20 mg) methotrexate and 2 mL (20 mg) hydrocortisone  
QS with 17.2 mL of NS for a total volume of 20 mL 
 
Alternative Volume (12 mL): Final concentration of Intrathecal Methotrexate and Hydrocortisone: 
Methotrexate 1.5 mg/mL and Hydrocortisone 1.5 mg/mL 
 
The following is a suggested method for preparing the IT using the 25 mg/mL concentration of 
preservative free methotrexate. Institutional practices may be used as clinically appropriate. 
Withdraw 0.72 mL (18 mg) of methotrexate 25 mg/mL concentration 
• Reconstitute hydrocortisone 100 mg vial with 10 mL of preservative free NS to a 
concentration of 10 mg/mL. Withdraw 1.8 mL (18 mg) of hydrocortisone 
• Combine 0.72 mL (18 mg) methotrexate and 1.8 mL (18 mg) hydrocortisone  
•  QS with 9.48 mL of NS for a total volume of 12 mL 
 
Intrathecal Cytarabine and Hydrocortisone: 
Optimal Volume (20 mL): Final concentration of Intrathecal Cytarabine and Hydrocortisone: 
Hydrocortisone 1 mg/mL and Cytarabine 2 mg/mL 

  
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The following is a suggested method for preparing the IT. Institutional practices may be used as 
clinically appropriate. 
• Reconstitute Hydrocortisone 100 mg vial with 10 mL of preservative free NS to a 
concentration of 10 mg/mL. Withdraw 2 mL (20 mg) of hydrocortisone 
• Reconstitute Cytarabine 100 mg vial with 5 mL of preservative free NS to a concentration 
of 20 mg/mL. Withdraw 2 mL (40 mg) of cytarabine. 
• Combine 2 mL (20 mg) hydrocortisone and 2 mL (40 mg) of cytarabine.  
• QS with 16 mL of NS for a total volume of 20 mL. 
 
Alternative Volume (12 mL): Final concentration of Intrathecal cytarabine and hydrocortisone: 
Hydrocortisone 1.5 mg/mL and Cytarabine 3.0 mg/mL. 
The following is a suggested method for preparing the IT. Institutional practices may be used as 
clinically appropriate. 
Reconstitute Hydrocortisone 100 mg vial with 10 mL of preservative free NS to a concentration of 
10 mg/mL. Withdraw 1.8 mL (18 mg) of hydrocortisone 
Reconstitute Cytarabine 100 mg vial with 5 mL of preservative free NS to a concentration of 
20 mg/mL. Withdraw 1.8 mL (36 mg) of cytarabine 
Combine 1.8 mL (18 mg) hydrocortisone and 1.8 mL (36 mg) of cytarabine  
QS with 8.4 mL of NS for a total volume of 12 mL 
 
Intrathecal Methotrexate and/or cytarabine and hydrocortisone are stable in preservative free NS for 
24 hours at 25ºC but contain no preservative and should be administered as soon as possible after 
preparation. 
 
Supplier: Hydrocortisone is commercially available. See package insert for further information 
 
 
6.10 
INTRATHECAL TRIPLES (Methotrexate/Hydrocortisone/Cytarabine, IT-3)  (05/08/12) 
 
Source and Pharmacology:  
The intrathecal route of administration of a drug produces more consistent CSF drug concentrations 
at relatively smaller doses because of the volume difference between the CSF and blood 
compartments (140 mL vs. 3500 mL in an adult). (The CSF volume of children after the first 3 years 
is equivalent to that of an adult). Drug half-lives are longer as well because clearance is related to 
flow rather than metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination 
curve from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT injection of cytarabine 
the elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 hours respectively, which 
is 8-fold longer than the clearance from plasma. The elimination of hydrocortisone is similarly 
prolonged. 
 
Intrathecal Triple Therapy (Methotrexate/ Hydrocortisone/Cytarabine) Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days 
of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoiditis: 
(headache, fever, 
vomiting, meningismus 
and pleocytosis)  
Rash, anaphylaxis (L), 
paresis, bleeding into 
subarachnoid or subdural 
space (risk > with platelet 
counts < 20,000), confusion, 
fatigue, disorientation, 
seizures 
Prompt: 
 
 
Myelosuppression, 
somnolence, ataxia, cranial 
nerve palsy, transient and 

  
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Within 2-3 weeks, 
prior to the next 
course 
rarely permanent paraplegia 
(L), speech disorders 
Delayed: 
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive 
disturbances (L), learning 
disabilities (L) 
Demyelinating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after the 
completion of 
treatment 
 
 
Progressive CNS 
deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial 
irradiation. 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg preservative free sterile 
powder for injection vial. Cytarabine 100 mg preservative free sterile powder for injection. 
Hydrocortisone sodium succinate 100 mg vial sterile powder for injection. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
For intrathecal administration, dilute each agent with 5-10 mL preservative free NS, lactated ringers or 
Elliot’s B solution or as per institutional standard of practice. The volume of CSF removed should be 
equal to at least half the volume delivered. 
 
*Rieselbach, *R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med 1962 Dec 20; 
267:1273-8 
 
Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with 
the patient remaining prone after the procedure may facilitate drug distribution. These procedures have 
not been validated in clinical trials. They are allowed but not mandated for patients on COG studies. 
 
Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative and should be 
administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.11 
IFOSFAMIDE  
 
 
 
 
 
 
(05/09/11) 
(Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724 
 
Source and Pharmacology:  
Patient Age 
(years) 
Doses (MTX/Hydrocortisone/Ara-C) 
 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
0 – 0.99 
7.5 mg / 7.5 mg / 15 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
1 – 1.99 
8 mg / 8 mg / 16 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
2 – 2.99 
10 mg / 10 mg / 20 mg 
5-10 mL 
8 mL 
80 + 20 mL  
(younger children) 
3 – 8.99 
12 mg / 12 mg / 24 mg 
5-10 mL 
10 mL 
100 + 20 mL  
(older children) 
9 or greater 
15 mg / 15 mg / 30 mg 
5-10 mL 
13 mL 
130 + 30 mL  
(adults) 

  
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Ifosfamide is a structural analogue of cyclophosphamide. Ifosfamide requires hepatic microsomal 
activation (P450 3A isoenzymes) for the production of the reactive 4-hydroxyoxazaphorine 
intermediate, which serves as a carrier molecule for the ultimate intracellular liberation of acrolein 
and phosphoramide mustard, which is an active bifunctional alkylating species. Acrolein is thought 
to be the cause of the hemorrhagic cystitis as seen with cyclophosphamide. Ifosfamide demonstrates 
dose-dependent pharmacokinetics whereby the terminal half-life ranges from 7 to 16 hours at doses 
of 1.6-2.4 g/m² to 3.8-5 g/m², respectively. At 1.6-2.4 g/m²/d, 12 to 18% of the dose was excreted as 
unchanged drug in the urine, whereas at a 5 g/m² single-dose, 61% was excreted in the urine as the 
parent drug. Evidence also exists to suggest that ifosfamide metabolism is inducible, with more rapid 
clearance occurring in the second and later doses when a course of therapy is given as fractionated 
doses over 3 to 5 days. There is more chloroethyl side chain oxidation of ifosfamide (up to 50%) 
than of cyclophosphamide (< 10%), and the degree of such metabolism is more variable than with 
cyclophosphamide. Oxidation of the chloroethyl groups produces chloroacetaldehyde, which is 
thought to be responsible for the neurotoxicity and renal toxicity that have been seen with 
ifosfamide therapy. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea & vomiting 
(acute and delayed) 
CNS toxicity 
(somnolence, depressive 
psychosis and confusion) 
Anorexia, diarrhea, 
constipation, encephalopathy 
which may progress to coma 
(L), seizure, SIADH, 
phlebitis, hypokalemia 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, cardiac toxicities 
(arrhythmia, 
asymptomatic ECG 
changes), microscopic 
hematuria, metabolic 
acidosis 
↑ liver enzymes, ↑ bilirubin, 
hemorrhagic cystitis with 
macroscopic hematuria, 
dysuria, cystitis and urinary 
frequency (< 5% with mesna 
and vigorous hydration) (L), 
bladder fibrosis 
Delayed: 
Any time later during 
therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or permanent)1 
(L) 
 
Renal failure acute or chronic, 
renal tubular acidosis, 
Fanconi-like syndrome 
gonadal dysfunction, ovarian 
failure1 (L), CHF 
Late: 
Any time after 
completion of 
treatment 
Moderate nephrotoxicity (↓ 
in glomerular filtration rate, 
renal tubular threshold for 
phosphate, and serum 
bicarbonate) 
 
Secondary malignancy, 
hypophosphatemic rickets  
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of ifosfamide have been noted in animals. 
Ifosfamide is excreted into breast milk.  
1 Dependent on dose, age, gender and degree of pubertal development at time of treatment 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Ifosfamide is available in 1 g and 3 g single dose vials of lyophilized white powder without 
preservatives and as a 50 mg/mL solution in 20 mL and 60 mL vials.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Reconstitute ifosfamide lyophilized powder with sterile water for injection or bacteriostatic water for 
injection (use 20 mL for the 1 g vial and 60 mL for the 3 g vial) to produce a final concentration of 

  
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50 mg/mL. Use sterile water for injection without benzyl alcohol for neonates and infants < 2 years 
of age or patients with hypersensitivity to benzyl alcohol. Although the reconstituted product is stable 
for 7 days at room temperature and up to 6 weeks under refrigeration, the manufacturer recommends 
refrigeration and use within 24 hours to reduce the possibility of microbial contamination. Store 
unreconstituted vials at room temperature 20°-25°C (68°-77°F). Protect from temperatures above 
30°C (86° F). Ifosfamide may liquefy at temperatures > 35°C. 
 
Reconstituted solutions of ifosfamide or ifosfamide solution should be diluted further to 
concentrations of 0.6 to 20 mg/mL in dextrose or saline containing solutions. Such admixtures, 
when stored in large volume parenteral glass bottles, Viaflex bags or PAB bags, are physically and 
chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C (41°F). The manufacturer 
recommends refrigeration and use within 24 hours to reduce the possibility of microbial 
contamination. 
 
Mesna must always be administered in conjunction with ifosfamide. Adequate hydration is 
required. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. Refer to the 
Chemotherapy Administration Guidelines for additional information. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further information 
 
 
6.12 
LEUCOVORIN CALCIUM   
 
 
 
 
           (05/09/11) 
(LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590 
 
Source and Pharmacology:   
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid 
(THF). The biologically active compound of the mixture is the (-)- l-isomer, known as Citrovorum 
factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate 
reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. 
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid 
antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, 
leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer 
therapy, such as 5-fluorouracil. Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid (an 
active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition of this 
enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at approximately 
1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life of total reduced folates 
was approximately 6.2 hours. Following oral administration, leucovorin is rapidly absorbed and 
expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer (the 
biologically active form) but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin 
is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 
75% for 50 mg, and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the CSF folate 
levels. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Anaphylaxis, urticaria, 
seizure 

  
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Unknown Frequency 
and timing: 
Fetal toxicities and teratogenic effects of leucovorin in humans are unknown. It is 
unknown whether the drug is excreted in breast milk. 
 
 
Formulation and Stability:  
Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile powder for 
injection. The 10 mg/mL preservative free liquid is available in 50 mL vials containing sodium 
chloride 400 mg/vial. Store preservative free liquid in the refrigerator at 2°-8°C (36°-46°F) 
protected from light. The powder for injection is available in 50 mg, 100 mg, 200 mg, and 350 mg 
vials. Store at room temperature 15°-25°C (59°-77°F) protected from light. Reconstitute the sterile 
powder with sterile water for injection or bacteriostatic water for injection to a concentration of 
10 mg/mL leucovorin calcium. Do not use diluents containing benzyl alcohol for doses 
> 10 mg/m² or in infants < 2 years of age or patients with allergy to benzyl alcohol. When 
Bacteriostatic Water is used, the reconstituted solution is good for 7 days. If reconstituted with SWFI, 
use solution immediately as it contains no preservative. One milligram of leucovorin calcium 
contains 0.004 mEq of leucovorin and 0.004 mEq of calcium. 
 
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: corn starch, 
dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose, microcrystalline 
cellulose, and sodium starch glycolate. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.  
 
Injection: 
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin 
should be injected intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV 
leucovorin and sodium bicarbonate are incompatible. 
 
Oral: 
Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and may be 
taken without regard to meals. Doses > 25 mg should be given IV due to the saturation of 
absorption. 
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain 
methotrexate unless there are special circumstances. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.13 
MERCAPTOPURINE  
 
 
 
 
 
(12/05/16) 
(6-MP, Purinethol®, PurixanTM, 6-mercaptopurine) NSC #000755 
 
Source and Pharmacology:  
Mercaptopurine is an analogue of the purine bases adenine and hypoxanthine. The main intracellular 
pathway for MP activation is catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl 
transferase (HGPRT) that catalyzes the conversion of MP to several active nucleotide metabolites 
including thioinosinic acid, a ribonucleotide that can interfere with various metabolic reactions 
necessary for nucleic acid (RNA and DNA) biosynthesis. It can also cause pseudofeedback 
inhibition of the first step in de novo purine biosynthesis or convert to another ribonucleotide, 
which can cause feedback inhibition. Mercaptopurine can be incorporated into DNA in the form of 

  
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Page 118 
TG nucleotides as well and thus produce toxicity. The absorption of an oral dose of MP is 
incomplete and variable, with only about 16%-50% of an administered dose reaching the systemic 
circulation secondary to a first pass metabolism in the liver. Food intake and co-administration with 
cotrimoxazole (TMP/SMX) significantly reduces absorption of MP. After IV administration, MP 
has a plasma half-life of 21 minutes in children and 47 minutes in adults. Approximately 19% is 
bound to protein. Mercaptopurine is well distributed into most body compartments except the CSF. 
(With high dose IV MP the CSF to plasma ratio is 0.15.) MP is metabolized by xanthine oxidase in 
the liver to 6-Thiouric acid an inactive metabolite. In patients receiving both MP and allopurinol (a 
xanthine oxidase inhibitor) the dose of MP must be reduced by 50-75%. Since TPMT, 6-thiopurine 
methyltransferase, is also one of the enzymes involved in the metabolism of MP, those individuals 
who have an inherited deficiency of the enzyme may be unusually sensitive to the 
myelosuppressive effects of MP and prone to develop rapid bone marrow suppression following 
the initiation of treatment. Mercaptopurine is excreted in urine as metabolites and some unchanged 
drug; about half an oral dose has been recovered in 24 hours. A small proportion is excreted over 
several weeks. 
 
 
Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Neutrophil count decreased, white blood cell decreased, anorexia, fatigue. 
Occasional 
(4 - 20% of patients) 
Diarrhea, nausea, vomiting, oligospermia, infection, fever, platelet count 
decreased, anemia, mucositis, stomach pain, ulcerative bowel lesion, skin 
rash, alanine aminotransferase increased, aspartate aminotransferase increased 
Rare 
(≤3% of patients) 
Urticaria, skin hyperpigmentation, alopecia, hyperuricemia, hepatic failure, 
hepatic necrosis, blood bilirubin increased, pulmonary fibrosis, secondary 
malignant neoplasm, renal toxicity, uricosuria, pancreatitis 
Pregnancy and 
Lactation 
Pregnancy Category D 
Mercaptopurine can cause fetal harm, including an increased incidence of 
abortion and stillbirth. Advise women to avoid becoming pregnant while 
receiving mercaptopurine. Mercaptopurine was embryo-lethal and teratogenic 
in several animal species (rat, mouse, rabbit, and hamster). It is not known 
whether mercaptopurine is excreted in human milk; breastfeeding should be 
avoided. 
 
Formulation and Stability:  
Mercaptopurine is available as a 50 mg tablet containing mercaptopurine and the inactive ingredients 
corn and potato starch, lactose, magnesium stearate, and stearic acid. Store at 15°-25°C (59°-77°F) in 
a dry place. In the United States, mercaptopurine is also available as an oral suspension in a 
concentration of 20 mg/mL (2000 mg/100 mL per bottle). The oral suspension is a pink to brown 
viscous liquid supplied in amber glass multiple-dose bottles with a child resistant closure. It should be 
stored at 15°-25°C (59°-77°F) in a dry place. 
 
NOTE: the concentration of the commercially available suspension (20 mg/mL) and the compounded 
suspension (50 mg/mL) are NOT the same; doses should be prescribed in the milligrams required, not 
mL. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Mercaptopurine should be taken consistently at the same time every day. 
 
If allopurinol is also given, the oral dose of mercaptopurine should be reduced by 67-75%. Patients 
with severe myelosuppression should have their thiopurine S-methyltransferase (TPMT) status 
and/or their thiopurine metabolite concentrations evaluated, so that the dose of mercaptopurine can 

  
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be reduced in patients with a TPMT defect. Patients with the rare homozygous deficient TPMT 
phenotype may tolerate only 1/10th to 1/20th the average mercaptopurine dose. TPMT testing and 
thiopurine metabolite measurements are commercially available. 
 
Suspension: 
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be compounded. 
The suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a mortar and adding 8.5 
mL sterile water for irrigation. The mixture is triturated to form a smooth paste. Next, 16.5 mL simple 
syrup (pH=7) are added with continuous mixing and finally cherry syrup (pH=7.1) is added to a total 
volume of 50 mL. The suspension is stable in amber glass bottles at room temperature (19ºC -23ºC) 
for up to 5 weeks. The suspension should be shaken well before each use. Procedures for proper 
handling and disposal of cytotoxic drugs should be used when preparing the suspension. (Aliabadi 
HM, Romanick M, Desai S et al. Effect of buffer and antioxidant on stability of mercaptopurine 
suspension. Am J Heath-Syst Pharm. 65:441-7, 2008.) 
 
Supplier: The tablets are commercially available from various manufacturers. In the United States, 
the commercially available oral suspension is available through AnovoRx Distribution, LLC (1-
888-470-0904). See package insert for further information. PLEASE NOTE there is a difference 
in the concentration of the commercially available (20 mg/mL) and extemporaneously 
compounded (50 mg/mL) oral suspensions. 
 
 
 
6.14 
MESNA - INJECTION 
 
      
 
 
 
 
(11/15/16) 
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891 
 
Source and Pharmacology:   
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced 
by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). 
Mesna disulfide remains in the intravascular compartment and is rapidly eliminated by the 
kidneys. In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which 
reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) 
resulting in their detoxification. The first step in the detoxification process is the binding of mesna 
to 4-hydroxy-ifosfamide forming a nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to 
the double bonds of acrolein and to other urotoxic metabolites. In multiple human xenograft or 
rodent tumor model studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold 
as single or multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half-lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine 
in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was 
eliminated within 4 hours. 
 
 
Toxicity1: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Nausea, vomiting, 
stomach pain, fatigue, 
headache 
Facial flushing,  fever, pain in 
arms, legs, and joints, rash, 
transient hypotension, 
tachycardia, dizziness, anxiety, 
confusion, periorbital swelling, 
anaphylaxis, coughing 

  
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Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 
10 times the recommended human doses. There are however no adequate and well-
controlled studies in pregnant women. It is not known if mesna or dimesna is 
excreted into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has 
been associated with death in pre-term infants weighing less than 2500 g and receiving 99-
405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine 
in the liver, and excreted as hippuric acid. In pre-term infants, however, this metabolic pathway may 
not be well developed. Onset of toxic illness in these infants occurred between several days and a few 
weeks of age with a characteristic clinical picture that included metabolic acidosis progressing to 
respiratory distress and gasping respirations. Many infants also had central-nervous-system 
dysfunction, including convulsions and intracranial hemorrhage; hypotension leading to 
cardiovascular collapse was a late finding usually preceding death. [For comparison in the ICE 
regimen of 3000 mg/m²/day of ifosfamide and a daily mesna dose of 60% of the ifosfamide dose = to 
1800 mg/m²/day; a child would be expected to receive 18 mL/m²/day of mesna (concentration of 
100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol or 
6.24 mg/kg/day.]   
 
Formulation and Stability: 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 0.25 mg/mL 
edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection multidose vials also 
contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product at controlled room 
temperature 15º-25C (68º-77ºF). Mesna is not light-sensitive, but is oxidized to dimesna when 
exposed to oxygen. Mesna as benzyl alcohol-preserved vials may be stored and used for 8 days. 
 
Guidelines for Administration: See Treatment, Dose Modifications, and Supportive Care sections 
of the protocol. 
 
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing solutions. 
Mesna may be mixed with ifosfamide or cyclophosphamide. After dilution for administration, 
mesna is physically and chemically stable for 24 hours at 25ºC (77ºF). Mesna may cause false 
positive test for urinary ketones.  
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
CANADIAN SITES 
Preservative-free Mesna is commercially available in Canada from Baxter Corporation 
(Urometixan®); supplied as a 100mg/mL solution which contains edentate disodium and sodium 
hydroxide for pH adjustment, 4mL and 10mL single-use ampoules. It is also available from Baxter 
and Fresenius Kabi Canada in multi-dose vials containing antibacterial preservatives. 
 
 
6.15 
METHOTREXATE - All Routes 
 
 
 
 
(02/29/12) 
(MTX, amethopterin, Trexall®) NSC #000740 
 
Source and Pharmacology:  
A folate analogue that reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic acid 
to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one carbon 

  
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fragments necessary for the synthesis of purines and the conversion of deoxyuridylate to thymidylate 
in the synthesis of DNA and cell reproduction. The polyglutamated metabolites of MTX also 
contribute to the cytotoxic effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity is 
highly dependent on the absolute drug concentration and the duration of drug exposure. MTX is 
actively transported across cell membranes. At serum methotrexate concentrations exceeding 
0.1 µmol/mL, passive diffusion becomes a major means of intracellular transport of MTX. The drug 
is widely distributed throughout the body with the highest concentration in the kidney, liver, spleen, 
gallbladder and skin. Plasma concentrations following high dose IV MTX decline in a biphasic 
manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of 8-15 hours. About 50% is 
bound to protein. After oral administration, approximately 60% of a 30 mg/m2 dose is rapidly 
absorbed from the GI tract, with peak blood levels at 1 hour. At doses > 30 mg/m² absorption 
decreases significantly. Even at low doses absorption may be very erratic, varying between 23% and 
95%. The elimination of MTX from the CSF after an intrathecal dose is characterized by a biphasic 
curve with half-lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the lumbar 
concentration of MTX is ~100 times higher than in plasma. (Ventricular concentration is ~ 10% of 
lumbar concentration). MTX is excreted primarily by the kidneys via glomerular filtration and active 
secretion into the proximal tubules. Renal clearance usually equals or exceeds creatinine clearance. 
Small amounts are excreted in the feces. There is significant entero-hepatic circulation of MTX. The 
distribution of MTX into third-space fluid collections, such as pleural effusions and ascitic fluid, can 
substantially alter MTX pharmacokinetics. The slow release of accumulated MTX from these third 
spaces over time prolongs the terminal half-life of the drug, leading to potentially increased clinical 
toxicity. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Transaminase 
elevations 
Nausea, vomiting, 
anorexia 
Anaphylaxis, chills, fever, dizziness, 
malaise, drowsiness, blurred vision, acral 
erythema, urticaria, pruritus, toxic epidermal 
necrolysis, Stevens-Johnson Syndrome, 
tumor lysis syndrome, seizures1, 
photosensitivity 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
Myelosuppression, 
stomatitis, gingivitis, 
photosensitivity, 
fatigue 
Alopecia, folliculitis, acne, renal toxicity 
(ATN, increased creatinine/BUN, 
hematuria), enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 (headache, 
drowsiness, aphasia, paresis, blurred vision, 
transient blindness, dysarthria, hemiparesis, 
decreased reflexes) diarrhea, conjunctivitis 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
Learning disability1 
(L) 
Pneumonitis, pulmonary fibrosis (L), hepatic 
fibrosis (L), osteonecrosis (L), 
leukoencephalopathy1 (L), pericarditis, 
pericardial effusions, hyperpigmentation of 
the nails 
Late: 
Any time after 
the completion of 
therapy 
 
 
Progressive CNS deterioration1 
Unknown 
Frequency and 
Timing:  
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of methotrexate 
have been noted in humans. The toxicities include: congenital defects, chromosomal 
abnormalities, severe newborn myelosuppression, low birth weight, abortion, and fetal death. 
Methotrexate is excreted into breast milk in low concentrations. 
1 May be enhanced by HDMTX and/or cranial irradiation. 
 (L) Toxicity may also occur later. 

  
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Intrathecal Therapy (Methotrexate Single Agent) 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days 
of 
receiving drug 
Nausea, headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus, nuchal rigidity, 
and pleocytosis)  
Anaphylaxis, vomiting, 
seizures (L), malaise, 
confusion, back pain, rash, 
bleeding into subarachnoid 
or subdural space (risk 
> with platelet counts 
< 20,000), 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve 
palsy, subacute myelopathy 
(paraparesis/paraplegia), 
speech disorders, pain in the 
legs, bladder dysfunction 
Delayed: 
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive disturbances (L)1, 
learning disability (L)1 
 
 
Leukoencephalopathy1 (L) 
Late: 
Any time after 
the completion 
of treatment 
 
 
Progressive CNS 
deterioration1 
1 May be enhanced by HDMTX and/or cranial irradiation. 
(L) Toxicity may also occur later. 
 
Formulation & Stability:  
Methotrexate for oral use is available as 2.5 mg, 5 mg, 7.5 mg, 10 mg and 15 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: anhydrous 
lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline 
cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium carbonate 
monohydrate, talc and titanium dioxide and various dyes. Store at controlled room temperature 
15°-30°C (59°-86°F) and protect from light. 
 
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg vials. The 
powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. Methotrexate for 
Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL preservative free vials 
and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL solutions contain 
approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, respectively. The preserved 
vials contain 0.9% benzyl alcohol as a preservative. 
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions permitted to 
15º-30ºC (59º- 86 Fº). Protect from light 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
Leucovorin rescue may be necessary with certain doses of methotrexate. 
 
Oral administration: Food or milk delays absorption and reduces peak concentration. 
Methotrexate for oral use should preferentially be given on an empty stomach, 1 hour before or 
2 hours after food or milk and at the same time each day. Methotrexate injection diluted in water 

  
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can be used for oral administration (Marshall PS, Gertner E. Oral administration of an easily 
prepared solution of injectable methotrexate diluted in water: a comparison of serum concentrations 
vs methotrexate tablets and clinical utility. J Rheumatol 23:455-8, 1996). 
 
For IM/IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free SWFI, 
D5W or NS to a 50 mg/mL concentration. The powder for injection may be further diluted in NS 
or dextrose containing solutions to a concentration of ≤ 25mg/mL for IV use. 
 
The 25 mg/mL solution may be given directly for IM administration or further diluted in Saline or 
Dextrose containing solutions for IV use. Do not use the preserved solution for high dose 
methotrexate administration due to risk of benzyl alcohol toxicity. Methotrexate dilutions are 
chemically stable for at least 7 days at room temperature but contain no preservative and should be 
used within 24 hours. Diluted solutions especially those containing bicarbonate exposed to direct 
sunlight for periods exceeding 4 hours should be protected from light. 
 
High dose methotrexate requires alkalinization of the urine, adequate hydration and leucovorin 
rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors, and NSAIDS 
as renal excretion of MTX is inhibited by these agents. 
 
For Intrathecal use: Use preservative free 25 mg/mL solution. 
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s, or Elliot’s 
B solution as per institutional standard of practice. The volume of CSF removed should be equal to 
at least half the volume delivered. 
 
Note: When IT therapy and ID MTX are scheduled for the same day, deliver the IT therapy within 
6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX 
bolus). 
 
For IT administration, use the preservative free formulation. The volume to be given IT should be 
in the range of 5-10 mL. The volume of CSF removed should be equal to at least half the volume 
delivered (see drug monograph). 
 
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. 
 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 
20; 267:1273-8 
 
Patient Age 
(years) 
Methotrexate 
dose 
Recommended volume 
10% CSF volume 
CSF Volume * 
1–1.99 
8 mg 
5–10 mL 
5 mL 
50 + 10 mL 
(babies) 
2–2.99 
10 mg 
5-10 mL 
8 mL 
80 + 20 mL 
(younger children) 
3–8.99 
12 mg 
5-10 mL 
10 mL 
100 + 20 mL 
(older children) 
9 or greater 
15 mg 
5-10 mL 
13 mL 
130 + 30 mL 
(adults) 

  
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Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with 
the patient remaining prone after the procedure may facilitate drug distribution. These procedures have 
not been validated in clinical trials. They are allowed but not mandated for patients on COG studies. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains no 
preservative and should be administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.16 
PEGASPARGASE 
 
 
 
 
 
 
(11/15/16) 
(PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase, Oncaspar®)  
NSC #624239 
 
Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase is modified by 
covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 
5000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-
asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is 
derived from Escherichia coli, which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a 
reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is 
notably lacking in malignancies of lymphoid origin. Asparaginase depletes L-asparagine from 
leukemic cells (especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic 
acid and ammonia. In predominately L-asparaginase naive adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of 
pegaspargase were determined. Apparent volume of distribution was equal to estimated plasma 
volume. L-asparaginase was measurable for at least 15 days following the initial treatment with 
Pegaspargase. The approximate t½ in adult patients is 5.73 days. The enzyme could not be detected 
in the urine. The half-life is independent of the dose administered, disease status, renal or hepatic 
function, age, or gender. In a study of newly diagnosed pediatric patients with ALL who received 
either a single intramuscular injection of pegaspargase (2500 IU/m2), E. coli L-asparaginase 
(25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-lives for the three forms of 
L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The 
plasma half-life of pegaspargase is shortened in patients who are previously hypersensitive to native 
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is cleared by the 
reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal fluid levels 
are < 1% of plasma levels. 
 
Toxicity: 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Allergic reactions (total 
likelihood of local, and or 
systemic reaction 
especially if previous 
hypersensitivity reaction 
to native asparaginase), 
pain at injection site, 
weakness, fatigue, 
diarrhea  
Allergic reactions 
(total likelihood of 
local, and or systemic 
reaction if no previous 
hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, hyper/hypotension, 
tachycardia, periorbital edema, 
chills, fever, dizziness, dyspnea, 
bronchospasm, lip edema, 
arthralgia, myalgia, urticaria, mild 
nausea/vomiting, abdominal pain, 
flatulence, somnolence, lethargy, 
headache, seizures (L), 
hyperuricemia  

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

  
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CANADIAN SITES 
Pegaspargase is not commercially available in Canada. Sites may purchase and import the USA 
commercial supply directly from Baxalta under the authority of the protocol’s No Objection Letter 
(NOL). The Canadian Senior Medical Officer (SMO)’s office is responsible for coordinating the 
“Fax Back” approval with Health Canada’s Biologics and Genetic Therapies Directorate for all lots 
for use in Canada on behalf of all Canadian sites. A list of approved lot numbers is posted on the 
C17 website (www.c17.ca) under the protocol titled Oncaspar. If an unapproved lot is received 
from Baxalta, quarantine the lot and contact the COG Canada Regulatory Affairs Office at 1-780-
492-7064.  Note: Pegaspargase may have orders placed and Drug Accountability Logs maintained 
on a multiple protocol basis (Multiple Protocol—Imported Biologic) as long as each protocol has 
a NOL.  Drug Accountability Logs (DAL) must record Lot #’s and expiry dates of shipments 
received and doses dispensed. Sites may use their own DAL as long as it complies with all elements 
of ICH GCP and Division 5 of the Food and Drugs Act.  Sites may import and manage a single 
clinical trial supply for multiple protocols as long as each protocol has an NOL and the protocol 
the patient is registered on is recorded on the DAL. 
 
6.17 
THIOGUANINE 
 
 
 
 
 
 
(12/05/16) 
(6-thioguanine, tioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141, Tabloid®, 
Lanvis®) NSC #752   
 
Source and Pharmacology:  
Thioguanine is a purine analogue of the nucleic acid guanine with the substitution of a thiol group in 
place of the hydroxyl group on guanine. The main intracellular pathway for 6-TG activation is 
catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT), which 
catalyzes the conversion of 6-TG to the active nucleotide, 6-thioguanylic acid. The monophosphate 
nucleotide form of 6-TG inhibits de novo purine synthesis and purine interconversion reactions, 
whereas the nucleotide triphosphate metabolite is incorporated directly into nucleic acids. 
Incorporation of fraudulent nucleotides into DNA interferes with DNA replication and results in 
the formation of DNA strand breaks. The net consequence of its action is a sequential blockade of 
the synthesis and utilization of the purine nucleotides. The relative contribution of each of these 
actions to the mechanism of cytotoxicity of 6-TG is unclear. The absorption of an oral dose of 6-
TG is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% 
to 46%). 
 
6-TG undergoes deamination by the enzyme guanine deaminase resulting in 6-thioxanthene, which 
is then oxidized by xanthine oxidase to 6-thiouric acid. In contrast to mercaptopurine, 6-TG is not 
a direct substrate for xanthine oxidase. Because the inhibition of xanthine oxidase results in the 
accumulation of 6-thioxanthene, an inactive metabolite, adjustments in 6-TG dosage are not 
required for patients receiving allopurinol. Since TPMT, 6-thiopurine methyltransferase, is one of 
the enzymes involved in the deactivation of 6-TG, those individuals who have an inherited 
deficiency of the enzyme may be unusually sensitive to the myelosuppressive effects of 6-TG and 
prone to developing rapid bone marrow suppression following the initiation of treatment. 
 
Peak levels occur 2 to 4 hours after oral administration with a median half-life is about 90 minutes 
(range: 25-240 minutes). Very little unchanged drug is excreted renally. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Anorexia, nausea, 
vomiting, diarrhea, 
malaise 
Urticaria, rash, hyperuricemia 

  
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Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
 
Toxic hepatitis (L), increased 
SGOT (AST)/SGPT (ALT), 
ataxia, mucositis 
Delayed: 
Anytime later during 
therapy 
 
 
Hepatic fibrosis(L), sinusoidal 
obstruction syndrome (SOS, 
formerly VOD) (L), 
hyperbilirubinemia 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of thioguanine have been noted in animals. It is 
unknown whether the drug is excreted in breast milk. 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Each greenish-yellow, scored tablet contains 40 mg thioguanine. Store at 15°-25°C (59°-77°F) in 
a dry place. 
For patients unable to swallow tablets, a 20 mg/mL oral suspension may be compounded. Crush 
fifteen (n=15) 40 mg tablets in a mortar and reduce to a fine powder. Add 10 mL methylcellulose 
1% in incremental proportions and mix to a uniform paste. Transfer to a graduated cylinder, rinse 
mortar with simple syrup, and add quantity of simple syrup sufficient to make 30 mL. Dispense in 
an amber glass bottle and label "shake well" and "refrigerate". If methylcellulose is not available, 
substitute 15 mL of Ora-Plus in place of the methylcellulose and qs with Ora-Sweet (in place of 
simple syrup) to a final volume of 30 mL. Both preparations are stable for 63 days at 19°C – 
23°C. (Aliabadi HM, Romanick M, Somayah V, et al. Stability of compounded thioguanine oral 
suspensions. Am J Health Syst Pharm 2011;68:1278. Dressman JB, Poust RI. Stability of 
Allopurinol and Five Antineoplastics in Suspension. Am J Hosp Pharm 1983;40(4):616-8.) 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Thioguanine should be taken consistently at the same time every day. 
 
Substantial dosage reductions may be required in patients with an inherited deficiency of the 
enzyme thiopurine methyltransferase (TPMT) due to accumulation of active thioguanine 
metabolites resulting in a higher incidence of myelosuppression. 
 
Supplier: Commercially available. See package insert for more detailed information. 
 
6.18 
VINCRISTINE SULFATE 
 
 
 
 
 
(08/16/12) 
(Oncovin®, VCR, LCR) NSC #67574 
 
Source and Pharmacology:  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, disrupting 
microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. The initial, middle, 
and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of 
the terminal half-life in humans is from 19 to 155 hours. The liver is the major excretory organ in 
humans and animals; about 80% of an injected dose of vincristine sulfate appears in the feces and 
10% to 20% can be found in the urine. The p450 cytochrome involved with vincristine metabolism 
is CYP3A4. Within 15 to 30 minutes after injection, over 90% of the drug is distributed from the 
blood into tissue, where it remains tightly, but not irreversibly bound. It is excreted in the bile and 
feces. There is poor CSF penetration. 
 
 
 

  
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Toxicity: 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-
20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = 
local ulceration, shortness of breath, 
and bronchospasm 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Alopecia, constipation 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
Paralytic ileus, ptosis, diplopia, 
night blindness, hoarseness, vocal 
cord paralysis, SIADH, seizure, 
defective sweating 
Delayed: 
Any time later during 
therapy 
Loss of deep tendon 
reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
Difficulty walking or inability to 
walk; sinusoidal obstruction 
syndrome (SOS, formerly VOD) (in 
combination); blindness, optic 
atrophy; urinary tract disorders 
(including bladder atony, dysuria, 
polyuria, nocturia, and urinary 
retention); autonomic neuropathy 
with postural hypotension; 8th 
cranial nerve damage with 
dizziness, nystagmus, vertigo and 
hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination 
with other antineoplastic agents) have been noted in humans. The toxicities include: 
chromosome abnormalities, malformation, pancytopenia, and low birth weight. It is 
unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 mg 
(1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are added for pH control. The 
pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a sterile, preservative 
free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until 
time of use. 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the 
Safety and Quality Council (Australia) all support the use of minibag rather than syringe for the 
infusion of vincristine. The delivery of vincristine via either IV slow push or minibag is acceptable 
for COG protocols. Vincristine should NOT be delivered to the patient at the same time with any 
medications intended for central nervous system administration. Vincristine is fatal if given 
intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine 
sulfate must be administered via an intact, free-flowing intravenous needle or catheter. Care should 
be taken to ensure that the needle or catheter is securely within the vein to avoid extravasation 
during administration. The solution may be injected either directly into a vein or into the tubing of 
a running intravenous infusion. 
 

  
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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.” 
 
Supplier: Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
Note: Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate liposomal injection, 
VSLI, Marqibo®). The conventional and liposomal formulations are NOT interchangeable; use of 
the liposomal formulation is not permitted in this trial. 
 
 
 
 

  
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
7.1 
Required & Optional Clinical, Laboratory and Disease Evaluations: Diagnosis, Induction, 
Consolidation Arm A and Arm B: T-ALL ONLY 
1 Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients 
must use an acceptable method of birth control 
2 End of consolidation bone marrow is not performed on SR T-ALL patients. It is REQUIRED for T-ALL patients with 
end Induction BM MRD ≥ 0.01% ONLY  
3 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 
saturation) and Chest x-ray documented within 12 hours prior to each dose of bortezomib.  
4 See Section 15.1 for details. Peripheral blood can be substituted if >80% blasts. Please send AALL1231 specimen 
transmittal form and institutional immunophenotype report with the sample submission to the laboratory 
5 Patients who are not in a morphologic remission at end of induction or consolidation remain on protocol therapy. 
6 Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia in some studies. Serum 
phosphorus should be checked at the beginning of Induction. See Section 5.2.4 for optional recommendations on 
correction and monitoring. 
7 Done as part of AALL08B1 or APEC14B1. See AALL08B1 or APEC14B1 Manual of Procedures for details. Also note 
that specimens are requested at time of relapse as part of AALL08B1 or APEC14B1. 
 
 
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). 
STUDIES**  
Diagnosis 
Induction 
Consolidation 
Required Observations: Arms A and B T-ALL ONLY 
Hx/PE with VS/Wt (BSA)  
X 
Weekly 
Start of Course 
CBC/diff/plts 
X 
Weekly 
Weekly 
CSF cell count & cytospin 
X 
With each IT 
With each IT 
Bilirubin (total and direct), ALT, AST 
creatinine 
Baseline 
Days 1 and 29 
Start of Course 
Performance Status 
Baseline 
 
Prior to Day 1 therapy 
Pregnancy Test1 
Baseline 
 
 
Bone Marrow MRD and cytomorphology 
Assessment 
X$ 
End of Induction5 
End of Consolidation2,5 
Chest x-ray 
Baseline 
 
 
Required Observations: Patients receiving bortezomib (Arm B) T-ALL ONLY 
Pulse Oximetry (O2 saturation) and 
Chest x-ray 
 
X3 
 
Electrolytes including PO4 
 
Start of Course6 
 
Optional Observations:  Arms A and B T-ALL ONLY 
(All optional studies require patient consent) 
Bone Marrow (BM)/Peripheral Blood 
(PB) for bortezomib response  (ETP-
ALL)  study (open to Arm A and B)4 
BM: 
Pre-treatment 
 
PB:Day 1 Hour 0, 6, 24 
BM &PB:End of Induction  
 
Cell Banking7 
Baseline7 
End of Induction7 
 
Recommended Observations:  Arms A and B T-ALL ONLY 
TPMT and NUDT15 genotype (if 
available) 
 
During Induction 
 

  
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7.2 
Required & Optional Clinical, Laboratory and Disease Evaluations: Diagnosis, Induction, 
Consolidation: Arm A and Arm B: T-LLy ONLY 
1Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients must use an 
acceptable method of birth control 
2 Obtain chest CT for all T-LLy patients at Baseline and at end-Induction. The baseline chest CT may be delayed until the patient is 
stable. If patient has CR at end-Induction, no subsequent chest CT is required but a chest x-ray will be performed at end-Consolidation 
and end of therapy. If patient does not have CR at end-Induction, a chest CT will be performed at end-Consolidation. Patients who 
have PD at end of consolidation are off protocol therapy. 
3 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and 
Chest x-ray documented within 12 hours prior to each dose of bortezomib.  
4 Determined by morphology on bilateral bone marrow aspirates/biopsies (not MRD or flow). Bilateral bone marrow aspirates and 
biopsies are strongly preferred but not required for study eligibility.  A unilateral bone marrow aspirate for morphology and for central 
MRD bone marrow assessment are required to be eligible. 
5 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. A PET scan can be used as a 
substitute for bone scan; however, a bone scan is preferred in patients with bone symptoms. 
6 Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia in some studies. Phosphorus should be 
checked at the beginning of Induction. See Section 5.2.3 for optional recommendations on correction and monitoring. 
7 If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on APEC14B1, submit as part of this protocol (see Section 
14.2 for details). 
8 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at baseline are negative, no repeat scans 
are required. 
9 See Section 14.2 for details.  
 
 
 
 
# If positive at diagnosis or a residual mass present 
STUDIES**  
Diagnosis 
Induction 
Consolidation 
Required Observations: Arms A and B T-LLy ONLY 
 
 
 
 
Hx/PE with VS/Wt (BSA)  
Baseline 
Weekly 
Start of Course 
CBC/diff/plts 
Baseline 
Weekly 
Weekly 
CSF cell count & cytospin 
X 
With each IT 
With each IT 
Bilirubin (total and direct), ALT, AST, 
creatinine 
Baseline 
Days 1 and 29 
Start of Course 
Performance Status 
Baseline 
 
Prior to Day 1 therapy 
Pregnancy Test1 
Baseline 
 
 
Disease Evaluation 
 
 
 
Chest & neck CT/Chest x-ray2 
Baseline2 
End of Induction2 
End of Course2 
Abdomen/Pelvis CT or MRI 8 
Baseline 
End of Induction8 
End of Course8 
Bone scan5 
Baseline 
End of Induction5 
End of Course5 
Diagnostic Biopsy/Cytology4 
Baseline 
 
End of Course if PD or 
NR 
Bone Marrow MRD Assessment7 
X 
 
 
Bilateral bone marrow aspirate and biopsy 
cytomorphology 4 
X7 
End of Induction only if positive 
at diagnosis 
End of Course only if 
+ at end of Induction 
Required Observations: Patients receiving bortezomib (Arm B) T-LLy ONLY 
Pulse Oximetry (O2 saturation),chest x-ray3 
 
X3 
 
Electrolytes including PO4 
 
Start of Course6 
 
Optional Observations:  Arms A and B T-LLy ONLY 
(All optional studies require patient consent) 
 
 
 
 
Cell Banking7 
Baseline7 
 
 
Bone Marrow MRD Assessment 
 
End of Induction9 
 
Recommended Observations:  Arms A and B T-LLy ONLY 
PET Scan (Recommended) 
Diagnosis 
End of Induction# 
PET Scan (If + at End 
Induction) 
TPMT and NUDT15 genotype (if 
available) 
 
During Induction  
 

  
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7.3 
Required Clinical, Laboratory and Disease Evaluations Post-Consolidation Therapy: Arm A-
SR and Arm B-SR (T-ALL and T-LLy) 
STUDIES**  
IM (CMTX) 
Delayed Intensification 
Maintenance 
Required Observations: Arms A-SR and B-SR T-ALL and T-LLy 
Hx/PE with VS/Wt (BSA)  
Start of Course 
Start of Course 
Every 4 weeks 
CBC/diff/plts 
Prior to each 
MTX dose 
Weekly 
Every 4 weeks 
CSF cell count & cytospin 
With each IT 
With each IT 
With each IT 
Bilirubin, ALT, creatinine 
Prior to each 
MTX dose 
Day 1, 29 
Prior to each 12 wk cycle 
Thiopurine metabolites  
 
 
As clinically Indicated 1,4 
Required Observations: Patients receiving bortezomib (Arm B-SR) ONLY (T-ALL and T-LLy) 
Pulse Oximetry (O2 saturation) and 
Chest x-ray 
 
X3 
 
Electrolytes including PO4 
 
Start of Course6 
 
Required Observations: T-LLy ONLY 
Chest CT/Chest x-ray2 
 
 
Completion of Therapy2 
Abdomen/Pelvis CT or MRI 
 
 
Completion of Therapy7 
Bone scan5 
 
 
Completion of Therapy 
Diagnostic Biopsy/Cytology8 
 
 
At relapse8 
PET scan# 
 
 
Post-treatment# 
Optional Observations: T-ALL and T-LLy  
Optional Banking/Biology8 
 
 
At relapse8 
1 For patients in whom TPMT and/or NUDT15 genotyping was not previously performed (see Section 5.10). 
2 If patient has CR at end-Induction, no subsequent chest CT is required but a chest x-ray will be performed at end-
Consolidation and end of therapy. If patient has CR at end-Consolidation, a chest x-ray will be performed at end of 
therapy. If patient does not have CR at end-Consolidation, a chest CT will be performed at end of therapy. For patients 
who had PET-CT at diagnosis, a PET-CT can be used instead of standard CT to follow disease response. 
Note: Patients who have NR and have not achieved at least a PR at end-Consolidation are off protocol therapy. 
3 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest 
x-ray documented within 12 hours prior to each dose of bortezomib.  
4 Recommended only for HR-ALL patients during any Maintenance cycle in which 6MP/MTX has been held and restarted 
or in case of persistent ANC elevation and concern for non-compliance (see Section 5.10). 
5 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. A PET scan can 
be used as a substitute for bone scan; however, a bone scan is preferred in patients with bone symptoms.  
6 Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia in some studies. Serum 
phosphorus should be checked at the beginning of Delayed Intensification. See Section 5.2.3 for optional recommendations 
on correction and monitoring. 
7 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no 
repeat scans are required. 
8 T-ALL: Done as part of AALL08B1 or APEC14B1 
8 T-LLy: If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on APEC14B1, submit as part of 
this protocol (see Section 13.6 for details) 
#Patients with post treatment residual masses only 
 
 

  
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7.4 
Required Clinical, Laboratory and Disease Evaluations Post-Consolidation Therapy: Arm A-
IR and Arm B-IR (T-ALL and T-LLy) 
STUDIES**  
IM#1 (HD MTX) 
Delayed Intensification 
IM#2 (CMTX) 
Maintenance 
Required Observations: Arms A-IR and B-IR (T-ALL and T-LLy) 
Hx/PE with VS/Wt (BSA) 
Start of Course 
Start of Course 
Start of Course 
Every 4 weeks 
CBC/diff/plts 
Prior to each MTX 
dose 
Weekly 
Prior to each 
MTX dose 
Every 4 weeks 
CSF cell count & cytospin 
With each IT 
With each IT 
With each IT 
With each IT 
Bilirubin, ALT, creatinine 
Prior to each MTX 
dose 
Day 1, 29 
Prior to each 
MTX dose 
Prior to each 12 
wk cycle 
Thiopurine metabolites 
 
 
 
As clinically 
Indicated 1,2 
Required Observations: Patients receiving bortezomib (Arm B-IR) ONLY (T-ALL and T-LLy) 
Pulse Oximetry (O2 
saturation) and Chest x-ray 
 
X8 
 
 
Electrolytes including PO4  
 
Start of Course6 
 
 
Required Observations: T-LLy ONLY 
Chest CT/Chest x-ray3 
 
 
 
Completion of 
Therapy3 
Abdomen/Pelvis CT or 
MRI 
 
 
 
Completion of 
Therapy4 
Bone scan5 
 
 
 
Completion of 
Therapy 
Diagnostic 
Biopsy/Cytology7 
 
 
 
At relapse7 
PET scan# 
 
 
 
Post-treatment#  
Optional Observations: T-ALL and T-LLy 
Optional Banking/Biology7 
 
 
 
At relapse7 
1For patients in whom TPMT and/or NUDT15 genotyping was not previously performed (see Section 5.10). 
2Recommended only for HR-ALL patients during any Maintenance cycle in which 6MP/MTX has been held and restarted 
or in case of persistent ANC elevation and concern for non-compliance (Section 5.10). 
3Obtain chest CT for all patients at Baseline and at end-Induction. The baseline chest CT may be delayed until the patient 
is stable. If patient has CR at end-Induction, no subsequent chest CT is required but a chest x-ray will be performed at 
end-Consolidation and end of therapy. If patient does not have CR at end-Induction, a chest CT will be performed at end-
Consolidation. If patient has CR at end-Consolidation, a chest x-ray will be performed at end of therapy. If patient does 
not have CR at end-Consolidation, a chest CT will be performed at end of therapy. For patients who had PET-CT at diagnosis, 
a PET-CT can be used instead of standard CT to follow disease response. 
4 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no 
repeat scans are required. 
5 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. . A PET scan can 
be used as substitute for bone scan; however, a bone scan is preferred in patients with bone symptoms. 
6 Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia in some studies. Serum 
phosphorus should be checked at the beginning of Delayed Intensification. See Section 5.2.3 for optional recommendations 
on correction and monitoring. 
7 T-ALL: Done as part of AALL08B1 or APEC14B1 
7 T-LLy: If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on APEC14B1, submit as part of 
this protocol (see Section 13.6 for details) 
8 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 
saturation) and Chest x-ray documented within 12 hours prior to each dose of bortezomib. 
# Patients with post treatment residual masses only 
 
 

  
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7.5 
Required & Optional Clinical, Laboratory and Disease Evaluations for Arm A-VHR and Arm 
B-VHR (T-ALL and T-LLy) 
STUDIES**  
3 HR BFM Blocks 
Delayed 
Intensification 
IM (CMTX) 
Maintenance 
Required Observations: Arms A-VHR and B-VHR 
Hx/PE with VS/Wt (BSA) 
Start of each Block 
Start of Course 
Start of 
Course 
Every 4 weeks 
CBC/diff/plts 
Start of Course & 
every 2 days after 
completion of 
chemotherapy 
Weekly 
Prior to each 
MTX dose 
Every 4 weeks 
CSF cell count & cytospin 
With each IT 
With each IT 
With each IT 
With each IT 
Bilirubin, ALT, creatinine 
Start of Course 
Day 1, 29 
Prior to each 
MTX dose 
Prior to each 12 wk cycle 
T-ALL only: Bone Marrow 
MRD & cytomorphology 
Assessment  
End of 3 HR BFM 
blocks8,9 
 
 
 
Thiopurine metabolites 
 
 
 
As clinically Indicated 1,2 
Required Observations: Patients receiving bortezomib (Arm B-VHR T-ALL and T-LLy) ONLY 
Pulse Oximetry (O2 saturation) 
and CXR3 
 
X10  
 
 
Electrolytes including PO4 
 
Start of Course6 
 
 
Required Observations: T-LLy ONLY 
Chest CT3 
End of 3 HR BFM 
blocks 
 
 
Completion of Therapy3 
Abdomen/Pelvis CT or MRI 
End of 3 HR BFM 
blocks 
 
 
Completion of Therapy4 
Bone scan5 
End of 3 HR BFM 
blocks 
 
 
Completion of Therapy 
Diagnostic Biopsy/Cytology 
(bilateral Bone Marrow aspirate 
and biopsy) 8,9 
End of 3 HR BFM 
blocks if PR or NR 
 
 
At relapse8 
PET scan# 
 
 
 
Post-treatment#  
Optional Observations: T-ALL and T-LLy 
Optional Banking/Biology 8 
 
 
 
At relapse 8 
1For patients in whom TPMT and/or NUDT15 genotyping was not previously performed (see Section 5.10). 
2Recommended only for HR-ALL patients during any Maintenance cycle in which 6MP/MTX has been held and restarted or in case 
of persistent ANC elevation and concern for non-compliance (see Section 5.10). 
3For patients who had PET-CT at diagnosis, a PET-CT can be used instead of standard CT to follow disease response. 
4Reimage if positive at end of consolidation. 
5 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no repeat scans 
are required. A PET scan can be used as substitute for bone scan; however, a bone scan is preferred in patients with bone symptoms. 
6 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. 
7 Bortezomib has been associated with hyponatremia, hypophosphatemia, and hypokalemia in some studies. Serum phosphorus should 
be checked at the beginning of Delayed Intensification. See Section 5.2.3 for optional recommendations on correction and monitoring. 
8 T-ALL: Done as part of AALL08B1 or APEC14B1 
T-LLy: If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on APEC14B1, submit as part of this protocol (see 
Section 13.6 for details) 
9 T-ALL Only. See Section 14.1 for details  
10 Patients who have detectable MRD and/or are not in morphologic remission at the end of 3 HR BFM blocks are removed from 
protocol therapy 
11 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest 
x-ray documented within 12 hours prior to each dose of bortezomib. 
#Patients with post treatment residual masses only 
 

  
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7.6 
Studies Suggested to be Obtained After Stopping Therapy (T-ALL Patients) 
Note: See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org  
1st year  
PE, CBC/diff/platelets q 4 weeks, 
 
 
CXR, BMA, CSF, as clinically indicated* 
2nd year 
PE, CBC/diff/ platelets q 2 months 
 
 
CXR, as clinically indicated* 
3rd year 
PE, CBC/diff/ platelets q 3 months 
CXR, as clinically indicated* 
4th year 
PE, CBC/diff/ platelets q 6 months 
 
 
CXR, as clinically indicated* 
5th year 
PE, CBC/diff/ platelets q 6-12 months 
* Obtain at any point after the end of therapy when it is clinically indicated. 
 
7.7 
Studies Suggested to be Obtained After Stopping Therapy (T-LLy Patients) 
See COG Late Effects Guidelines for recommended post treatment follow-up: 
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. 
 
7.8 
At Relapse 
T-ALL patients who relapse should have samples of bone marrow sent to the Molecular Reference 
Laboratory for cell banking as part of AALL08B1 or Project:EveryChild (APEC14B1, if open for 
ALL relapse specimens). 
 
T-LLy patients who enrolled on APEC14B1: T-LLy patients who relapse should have samples of bone 
marrow sent to the Molecular Reference Laboratory for cell banking as part of Project:EveryChild 
(APEC14B1). 
 
T-LLy patients who did not enroll on APEC14B1: samples should be sent as part of this protocol (See 
Section 13.6) 
 
 
 

  
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8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
8.1 Criteria for Removal from Protocol Therapy 
a) Relapse/ progressive disease 
b) VHR T-ALL who have an M2/M3 marrow and/or detectable MRD at the end of the 3 HR 
Intensification Blocks 
c) VHR T-LLy with biopsy-proven persistent disease and/or morphologically positive bone marrow 
at end of 3 HR Intensification Blocks  
d) Identified to have Ph+ T-ALL* 
e) Identified to have Ph+ T-LLy** 
f) Refusal of further protocol therapy by patient/parent/guardian. 
g) Completion of planned therapy 
h) Physician determines it is in patient’s best interest 
i) Development of a second malignancy 
j) Inevaluable 
k) Adverse events requiring removal from protocol therapy 
 
#As assessed by CT with persistent active disease by biopsy or morphologically positive bone marrow 
at end of 3 HR Intensification Blocks 
 
*Ph+ T-ALL patients are not eligible for post-induction therapy on AALL1231 and should be 
removed from protocol therapy prior to Day 15 of Induction therapy. 
**Ph+ T-LLy patients are not eligible for post-induction therapy on AALL1231 and should be 
removed from protocol therapy prior to or at the end of Induction. 
 
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. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at recurrence) with 
the exception of COG AALL1421, a Phase 2 study of IV pegcrisantaspase, 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 the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design and Endpoints 
This is a randomized Phase III trial, with patients randomized 1:1 to backbone chemotherapy +/- 
bortezomib. Patients will be stratified at enrollment as T-ALL or T-LLy and will be randomized within 
each stratum. 
Primary Endpoint: Comparison of EFS between modified ABFM backbone +/- bortezomib in all 
randomized patients. 
 
Secondary Endpoints:  
(a) To compare EFS and cumulative incidence rates for isolated CNS, isolated bone marrow, and 
combined bone marrow relapse between IR patients on the non-bortezomib containing arm of 
this study (no CRT) with similar patients on AALL0434 (+ CRT) 
(b) To assess toxicities associated with administering modified standard therapy for T-ALL and 
T-LLy, which includes dexamethasone and additional doses of pegaspargase. 

  
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(c) To compare EFS between VHR T-ALL patients treated with HR BFM intensification blocks 
who become MRD negative and those who remain MRD positive at the end of HR Block 3. 
Comparison of EFS between VHR T-LLy patients treated with HR BFM intensification 
blocks who have PR or CR with those who do not respond (NR). 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Based on accrual rates observed on AALL0434, this study is projected to accrue around 250/year T-
ALL and 75/year T-LLy patients. This study is expected to accrue up to a maximum of 1400 patients 
over a 4.4 year period with a minimum follow up of 3 years, adjusting for ineligible and inevaluable 
patients, patient withdrawals, and losses due to other reasons. 
 
Projected distribution of accrual by risk group: 
Standard Risk (SR) T-ALL: 40-50% of T-ALL patients; 
Intermediate Risk (IR) T-ALL: 35-50% of patients; 
Very High Risk (VHR) T-ALL: 10-15% of patients; 
SR T-LLy: 65% of T-LLy patients; 
IR T-LLy: 25% of T-LLy patients; and, 
VHR T-LLy: <10% of T-LLy patients. 
 
9.3 
Statistical Analysis Methods 
 
9.3.1 
Power Calculation for Phase 3 Bortezomib Primary End-point: 
With 1200 eligible, evaluable patients randomized to the +/- bortezomib arms, there is 90.5% 
power to detect improvement in 4-year EFS from 85% to 90% with an alpha of 0.05, using a 
one-sided log rank test (HR =0.6483) (comparison of the two EFS curves). There is sufficient 
power to detect a difference if the baseline EFS is different from the projected 85%. A baseline 
4 year-EFS of 80% would allow detection of an improvement to 85% (HR=0.7283), with 
power of 82.1%; and there is 83.4% power to detect an improvement in EFS from 88% to 
92% (HR=0.6523). Interim monitoring for efficacy and futility will be performed. 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 using the method of Freidlin and Korn. The lower 
boundaries are based on repeated testing of the alternative hypothesis at the 0.05 level (1-
sided). The comparative analyses of regimen outcome will occur at approximately 20%, 40%, 
60%, 80% and 100% of the projected combined EFS event horizon (217 events assuming 
baseline EFS rate of 85%) for the overall randomized group. 
 
9.3.1.1 Amendment #6 (05/29/2019) 
The COG DSMC recommended permanent closure of the study to accrual during the 
spring 2019 meeting; primarily due to concerns about the impact the positive results 
from AALL0434 for the nelarabine randomization could have on the conduct and 
interpretability of AALL1231. With the permanent closure to accrual as of 05/24/2019, 
this study will not have the required number of randomized patients (+/- Bortezomib) 
to have sufficient power to meet the primary objective. Last patient was randomized in 
November 2017. Per the recommendation of the DSMC, final analyses comparing EFS 
for the randomized arms, will be conducted based on the 3/31/2020 database freeze. 
   
9.3.2 Secondary End-points: 
Power calculation for CNS therapy changes primary end-point: The risk group definitions 
on this proposed study are different than AALL0434, and EOC MRD data will not be available 
on many AALL0434 patients. In order to determine if eliminating CRT and the multiple 
backbone modifications affect EFS and relapse rates, similar populations must be compared. 

  
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Any subject on either trial who is all of the following: [<9.99 years old, initial WBC 
<50,000/mm3, day 29 MRD <0.1%, CNS1, testicular disease negative, not steroid pretreated] 
will be eliminated from the analysis, because they did not receive CRT on 0434 and will not 
receive CRT on AALL1231. We will also eliminate any subject on either trial who is an 
induction failure (M3 marrow on day 29) or CNS3 because they would have received CRT on 
0434 and will still get CRT on AALL1231. Outcomes (EFS) for the remaining patients (about 
49% of all T-ALL patients) on both studies will be compared. It is important not only to 
compare CNS relapse rates but also to compare BM, combined BM and CNS, and total relapse 
rates, because the elimination of prophylactic CRT may change the distribution of relapse, but 
not change overall relapse rate. Cumulative incidence rates for isolated CNS, isolated marrow, 
and combined marrow relapses will be monitored for these patients and compared with that 
seen for similar patients on AALL0434. Assuming approximately 584 patients (as identified 
by our definitions earlier excluding various subgroups) in 0434 meet these criteria and 
received CRT, there will be around the same number of patients who meet these criteria on 
this study and will not be getting CRT. Outcomes on AALL0434 are blinded at this time, 
hence the table below gives the power and detectable differences in cumulative incidence rates 
assuming a range of baseline rates on AALL0434 for the different types of relapse (isolated 
CNS, isolated marrow, combined marrow+CNS) for the above monitoring, using a one-sided 
log-rank test with a 5% significance level. Interim monitoring will be done using an alpha x 
(time)2 spending function with 5 looks occurring at 20%, 40%, 60%, 80%, and 100% 
information. 
 
Comparison of 2-year 
cumulative incidence rates on 
AALL0434 vs. AALL1231 
Hazard ratio 
Total 
expected 
events 
Power 
1.5% vs. 4% 
2.7 
32 
81% 
2% vs. 4.7% 
2.38 
39 
80% 
2.5% vs. 5.5% 
2.23 
47 
81% 
3% vs. 6.2% 
2.1 
54 
81% 
3.5% vs. 6.8% 
1.98 
60 
80% 
 
Evaluation of the modified backbone: Event-free survival (EFS) of patients treated on the 
control arm (no bortezomib) of AALL1231 will be compared with the EFS and OS of patients 
treated on the control arm (no nelarabine and Capizzi MTX with PEG-ASP arm) of the 
previous study AALL0434. Safety data will also be compared between the two arms. 
 
Evaluation of HR blocks:  
The proportion of VHR T-ALL patients with EOC MRD ≥0.1% who become MRD negative 
(MRD undetectable) after the three high-risk BFM blocks of therapy, will be estimated. EFS 
for these patients (who continue on chemotherapy) will be compared with those who continue 
to have detectable MRD and who may receive other treatment options including HSCT. It is 
anticipated that there will be about 100 – 120 VHR T-ALL patients accrued on this study. 
With this, the proportion who become MRD negative after the HR blocks can be estimated 
with a maximum standard error of 5%. It is projected that 80% of patients will become MRD 
negative after the HR blocks. With small numbers, the comparison of EFS between the two 
groups above will be essentially descriptive. 
 
There will be a total of about 25 to 30 VHR T-LLy patients on study. Comparison of EFS 
between VHR T-LLy patients treated with HR BFM intensification blocks who are PR or CR 
with those who do not respond (NR) will essentially be descriptive due to small patient 
numbers. 
 

  
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9.3.3 
Interim Monitoring 
 
Induction Mortality. It is expected that a small percentage of patients will experience 
treatment related mortality (TRM) during induction. It is possible that induction mortality may 
increase based on the modifications that include dexamethasone, an additional dose of PEG-
ASP, and +/- bortezomib randomization. Induction deaths on the two randomized arms will 
be closely monitored. The induction mortality rate on UKALL 2003 was 2.4% for patients 
treated with the anthracycline containing induction, dexamethasone at 6mg/m2/day, and an 
extra dose of pegaspargase on day 18. This TRM rate is quite similar to that seen in other 
recent studies using a four-drug induction regimen, including AIEOP-BFM ALL 2000 (2% 
on dexamethasone-containing arm) and COG AALL0232 (2.16% for AYA pts vs. 1.67% for 
younger pts.46,47,51 Due to the changes in induction compared to previous trials, the overall 
induction death rate will be closely monitored. All patients enrolled on study who receive 
induction will be included in this monitoring. Assuming a ‘null’ induction mortality rate of 
2.5%. A Pocock boundary (truncated at 3 standard deviations) with 7 interim looks (after first 
100 patients and then after every 200 patients enrolled, up to the first 1000 patients). The 
probability of crossing the boundary at any time when the true induction mortality rate is 2.5% 
is 10%.  The boundary is given in the table below. If the boundary is crossed, the study will 
be temporarily closed for review of deaths and possible modifications to therapy. 
 
Sample size 
Number of induction deaths 
to trigger concern (Pocock 
boundary, alpha = 10%) 
Percent of induction deaths 
that trigger concern (Pocock 
boundary, alpha = 10%) 
100 
7 
7.0% 
200 
11 
5.5% 
400 
17 
4.25% 
600 
23 
3.83% 
800 
29 
3.63% 
1000 
35 
3.50% 
1200 
41 
3.42% 
 
The induction death rates on the two randomized arms will also be compared and monitored 
closely for increased rates on the bortezomib arm. The induction death rates will be monitored 
using a Pocock type boundary (truncated at 3 standard deviations) to provide a greater chance 
of stopping early if the death rate looks excessive, using a one-sided test with an alpha of 10%. 
There will be 6 planned looks after every 200 patients randomized to the two arms. With this 
plan, there is 80% power to detect a difference if the induction death rates on the two arms are 
2% vs. 4% or 3% vs. 5%.  Since the induction regimen using dexamethasone and the addition 
of bortezomib, is hoped to result in some potential improvement in EFS, the above monitoring 
rule for induction deaths needs always to be considered in conjunction with EFS results (i.e., 
a slightly increased induction death rate would possibly be acceptable if the observed early 
EFS results looked promising). 
 
Grade 4-5 infections. It is expected that a percentage of patients will experience Grade 4-5 
infections. It is possible that Grade 4-5 infections may increase based on the modifications 
during induction that include dexamethasone, an additional dose of PEG-ASP, and +/- 
bortezomib randomization and during DI that include an additional dose of PEG-ASP and +/- 
bortezomib randomization. In AALL0232, 84.8% of subjects had a grade 3-5 infection during 
protocol therapy; however, only 13.7% had a grade 4 infection and 1.5% had a grade 5 infection 
(AALL0232, Study Progress Report, September 30 2011). The overall grade 4+ infection rate 
together with other toxicities of concern, among all patients will be estimated every six months 
at the time of interim monitoring to the COG Data Safety Monitoring Committee (DSMC). If 
the rate seems excessive compared to that seen on earlier studies (AALL0232, AALL0434), 

  
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the data will reviewed for possible modifications to therapy. In addition, the grade 4+ infection 
rates will be compared between the two randomized arms (+/- bortezomib). Significant 
differences will be brought to the attention of the COG DSMC for review and possible therapy 
modifications. 
 
Osteonecrosis. It is expected that a modest percentage of patients will experience 
osteonecrosis (ON). The reported rates of osteonecrosis vary widely between studies and 
increased incidence occurs with older age and female gender. Three-year ON rates on CCG-
1882 were 14.2% +/- 1.3% for children greater than 10 years of age.180 On CCG-1961, the 5-
year ON incidence rates were 9.9% +/-1.5% and 20% +/- 4.3% for the 10 to 15 and 16 to 21 
year age groups, respectively.181 On AALL0232, the rates in children over 10 years were 
17.2% for patients randomized to receive dexamethasone and 12.6% on the prednisone arm.182 
On the St Jude Total XV ALL trial, the cumulative incidence of symptomatic ON (grade 2-4) 
was 14.6% +/- 1.6%.183 Finally, on UKALL 2003 the rate of ON in intermediate risk patients 
of all ages, which included most of the T-ALL patients, was 9.4% (Vora, personal 
communication). As of February 2013, AALL0434 had a total of 85/1406 (6%) grade 2-3 
osteonecrosis reported. There were no reports of grade 4 ON.   It is possible that osteonecrosis 
rates may increase based on the increased use of dexamethasone and extra doses of PEG-ASP. 
The incidence of grade 2-4 symptomatic osteonecrosis will be closely monitored on the trial. 
Very detailed information is captured on osteonecrosis with a specific case report form on the 
COG ALL trials and will also be done for this study. Rates of osteonecrosis will be 
summarized overall, and by age-group and gender in the biannual study progress reports and 
reviewed by the study committee. Any indication of an increase in rates will be reviewed 
closely and reported to the COG DSMC for review and possible therapy modifications. 
 
Targeted Toxicities (Bortezomib). Peripheral neuropathy and pulmonary toxicity are of 
special concern with bortezomib treatment, although these toxicities are more commonly 
found in adults than children. Both of these will be closely monitored and reported to the 
DSMC for biannual review and on an ad hoc basis as required for judging the safety of 
bortezomib. In addition, the specific dose modifications and supportive care guidelines are 
provided in Section 5.2. 
 
Adverse Event Monitoring 
The study will be monitored to ensure that bortezomib is feasible and does not result in 
excessive toxicities or death during induction or DI. In addition, the study will be monitored 
to ensure changes in the backbone do not result in excessive toxicities. As described above, 
specific monitoring rules will be followed for TRM, grade 4-5 infections, osteonecrosis, 
peripheral neuropathy, and pulmonary toxicity. The incidence rates of the following key 
adverse events (in addition to any Grade 4 non hematologic toxicities) will be estimated across 
all patient subgroups on this trial. 
 
1. CNS hemorrhage requiring medical intervention (Grade 2 and higher) 
2. GI bleed requiring operative or interventional radiology intervention (Grade 3 and 
higher) 
3. Pancreatitis requiring medical intervention (Grades 2 and higher) 
4. Transient ischemic attacks (All grades) 
6. Stroke (All grades) 
7. Encephalopathy (Grade 3 and higher) 
8. Neuropathy; motor or sensory, interfering with ADL (Grade 3 and higher)* 
9. Seizure (Grade 2 and higher) 
10. Allergic reaction (Grade 3 and higher) 
11. Ileus (Grade 3 and higher) 

  
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12. Mucositis/stomatitis; functional (Grade 3 and higher) 
13. Bilirubin (Grade 3 and higher) 
14. Thrombosis (Grade 3 and higher) 
15. Hyponatremia (Grade 3 and higher) 
16. Hypophosphatemia (Grade 3 and higher) 
17. Osteonecrosis (Grade 2 and higher) 
 
9.4 
Gender and Minority Accrual Estimates 
Based on the distribution derived from AALL0434, the gender and minority distribution of the study 
population is expected to be: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* These totals must agree 
 
9.5 
Correlative Studies  
 
9.5.1 
Minimal Residual Disease Determination at Serial Time Points During Therapy 
Patients with newly diagnosed T-ALL will have MRD measured in the bone marrow (BM) at 
the end of the first block of Induction therapy (Day 29). Those patients (~50%) with MRD 
levels <0.01% in BM at Day 29 will be considered Standard Risk and assigned to the least 
intensive cytotoxic therapy. For the remaining patients (~50%), MRD will be assessed in BM 
at the end of Consolidation (EOC) therapy. Those with MRD <0.1% (~40%) will be 
considered Intermediate Risk and receive intermediate intensity therapy. The remainder 
(~10%) will be considered Very High Risk and receive intensified therapy followed by an 
additional MRD assessment with those positive for MRD taken off study. Specimens from all 
patients will also be assayed at study entry in order to define an abnormal phenotype that will 
facilitate detection of MRD. 
 
Part of the diagnostic immunophenotyping at study entry will include the marginal cost for 
early thymic precursor (ETP) sub classification, a subset whose outcome is an important 
secondary endpoint of the study. Early studies suggested patients with ETP ALL do poorly, 
but more recent data suggest the prognosis may not be dire (see Section 2.2 for background 
and rationale on ETP ALL). It is critical to understand whether or not ETP phenotype 
independently predicts outcome in T-ALL. Multivariate analysis will be performed to 
determine if ETP ALL is an independent predictor of poor outcome based on MRD rates at 
End Induction and End of Consolidation. Preliminary data suggest ETP represents 12.4% of 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
57 
144 
201 
Not Hispanic or Latino 
320 
879 
1199 
Ethnic Category: Total of all subjects 
377 
1023 
*1400 
Racial Category 
 
American Indian or Alaskan Native 
1 
6 
7 
Asian 
22 
56 
78 
Black or African American 
64 
148 
212 
Native Hawaiian or other Pacific Islander 
5 
8 
13 
White 
285 
805 
1090 
Racial Category: Total of all subjects 
377 
1023 
*1400 

  
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T-ALL in AALL0434, yielding 118 ETP patients of the 952 T-ALL anticipated on 
AALL1231. There are few data available to predict the proportion of ETP+ patients that will 
have MRD <0.1% at EOC. Overall, we expect that ~10% of T-ALL patients will have MRD 
≥0.1% at EOC while ~90% will have MRD <0.1%. Given the known higher percentage of 
end induction MRD+ patients among the ETP+ subset, we hypothesize that ~50% of ETP+ 
patients (n=59) will have MRD ≥0.1% at EOC (5-fold higher rate than MRD-negative), while 
~50% (n=59) will have MRD <0.1%. If the 4-year EFS of these ETP+, EOC MRD <0.1% 
patients is ~50% or better, it would suggest that ETP patients can be risk stratified based on 
MRD alone (unless there is a specific therapy available for ETP patients). However, if this 
assumption is incorrect and ETP+ patients with MRD <0.1% at EOC have an EFS < 50%, it 
would suggest that MRD alone cannot be used to risk stratify these patients and alternative 
strategies (stem cell transplant in CR1 or other novel therapies) should be pursued for all ETP 
patients. Hence, we will see if the lower limit of the 95% confidence interval for the 4-year 
EFS estimate for ETP+, EOC MRD <0.1% patients exceeds 50%. With a sample size of 59 
ETP+, EOC MRD < 0.1% cases (assuming no censoring before 4 years), the lower bound on 
an exact 95% CI for 4-year EFS will exceed 50% with at least 86% probability (=Prob[number 
event free at four years is at least 38]) if the true 4-year EFS is at least 70%. The EFS will also 
be compared between ETP+, EOC MRD<0.1% versus ETP+, EOC MRD>0.1%. Due to small 
numbers (59 patients in each group), this comparison will essentially be descriptive. 
 
Patients with T-LLy will have the level of marrow involvement assessed at diagnosis to 
facilitate risk stratification into Standard and Intermediate risk groups. T-LLy patients will 
also be assessed for MRD at Day 29, as this study will enroll more T-LLy patients than any 
to date and offers a unique opportunity to establish risk factors for this understudied patient 
population. We hypothesize that T-LLy patients with <0.01% MRD at End of Induction will 
have the best outcome, consistent with existing data in T-ALL. No data exist on the frequency 
of marrow MRD following therapy for T-LLy, although the frequency of marrow involvement 
at diagnosis > 0.01% is 66% in AALL0434. Assuming that about 80% of T-LLy patients will 
have MRD < 0.01% at End of Induction, this yields roughly 198 T-LLy patients on this study 
with MRD<0.01% and 50 patients with MRD>0.01%. Assuming an overall 4-year EFS of 
80% for T-LLy, there is over 99% power to detect a difference in EFS between the two MRD 
groups (90% vs. 40% 4-year EFS, HR=0.1155). There is over 98% power to detect a 
difference in EFS if the EFS rates are 85% and 60% in the two groups (HR=0.3181). 
 
Additional statistical details are included in Appendix XI. 
 
9.5.2 
Evaluating Mechanisms of Bortezomib Response and Mechanisms of Bortezomib 
Resistance in T- ALL 
Statistical analysis, including sample sizes are included in Appendix XII. 
 
 
9.5.3 
Identifying Biomarkers and Mechanisms of Chemotherapy Resistance and Response in T-
ALL, Focusing on ETP ALL 
Statistical analysis, including sample sizes are included in Appendix XII. 
 
 
 
 

  
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10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE)  
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity 
and performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Additionally, 
toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 as 
referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to version 5.0). 
 
10.2 
T-ALL and T-LLy: Relapse 
Any recurrence of disease whether in marrow or extramedullary. Relapse should be 
histopathologically/biopsy confirmed. 
 
10.2.1 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 < 5 WBC/μL, a second CSF evaluation is required within 2-4 
weeks. While identification of a leukemic clone in CSF by flow cytometry (CD2, CD3, CD34, 
or the same T-cell immunophenotypic markers that were identified at diagnosis) 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 a diagnosis of CNS relapse. 
 
10.2.2 Testicular Relapse 
Must be documented by testicular biopsy, if not associated with a marrow relapse. 
 
10.2.3 Bone Marrow Relapse 
Patients with an M3 marrow at any point after achieving remission. 
 
10.2.4 Combined extramedullary and Bone Marrow Relapse 
Patients with a CNS or testicular relapse and a M2 or M3 marrow. 
 
10.3 
T-ALL: Response 
See definitions in Section 3.3. 
 
10.4 
T-LLy: Response  
These criteria are derived from published international consensus guidelines.184,185  
 
Prior to therapy: Patients will have a bilateral bone marrow biopsies and aspirate, CT of the neck, 
chest, abdomen and pelvis, CXR, and, if indicated, a bone scan. On Day 29 patients will have a repeat 
CT of chest and CT of areas of active disease at diagnosis (neck, abdomen, and/or pelvis), CXR and 
if positive at diagnosis a bone scan. Patients with morphologic evidence of bone marrow disease at 
diagnosis will repeat the bilateral bone marrow aspirates and biopsies (>5-25% blasts by morphology) 
at Day 29. At end of consolidation, patients not in a CR at the end of Induction will have repeat CT 
imaging of active sites of disease and if positive at end of Induction a bone scan. Patients with 
morphologic evidence of bone marrow disease (>5-25% blasts by morphology) at end of Induction 
will repeat the bilateral bone marrow aspirates and biopsies at the end of consolidation. VHR patients 
will have repeat imaging at the end of 3 HR BFM blocks of sites demonstrating active disease at the 
end of consolidation. Patients with morphologic evidence of bone marrow disease at end of 
consolidation will have a repeat bilateral bone marrow aspirates and biopsies at the end of the 3 HR 
BFM blocks. 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 and for VHR patients if there are residual 
masses at the end of the 3 HR BFM blocks. 

  
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Of note, if a PET scan is obtained at baseline, PET imaging should be continued with subsequent 
response assessment until patient no longer has PET-avid disease. A bone scan is the preferred method 
to follow bone disease however, PET scan can be used as a substitute for a bone scan in patients with 
bone symptoms. For patients who had a PET-CT at diagnosis, a PET-CT can be used instead of a 
regular CT to follow disease response. 
 
10.4.1 Complete Response (CR) 
Defined as disappearance of all detectable clinical evidence of disease from all sites as 
determined by physical examination and appropriate imaging studies. Lymph nodes must have 
decreased to less or equal 1.5cm. Any macroscopic nodules in any organs detectable by CT 
should be gone. Bone marrow aspirate/biopsy must be morphologically normal. MRD will be 
sent on D29 on those patients consenting but will not be used in clinical decision making on 
this study. 
 
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/CT 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. 
 
10.4.2 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. 
 
In patients with a positive PET scan prior to therapy, the post-treatment PET must be positive 
in at least one previously involved site. No new lesions. 
 
10.4.3 Stable Disease (SD) / No response (NR) 
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 post-treatment CT or PET. 
 
10.4.4 Relapsed/Progressive Disease (PD) 
Greater than 25% 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. 
 
 
 
 

  
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Certain adverse events must be reported in an expedited manner to allow 
for timelier monitoring of patient safety and care. The following sections provide information about 
expedited reporting. 
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) whether the patient has received 
an investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) 
of the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND). In some instances, the investigational agent may be available commercially, but is 
actually being tested for indications not included in the approved package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. The NCI, rather than a commercial distributor, may on some occasions distribute 
commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
• Concurrent administration: When an investigational agent is used in combination with a 
commercial agent, the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
• Sequential administration: When a study includes an investigational agent and a commercial 
agent on the same study arm, but the commercial agent is given for a period of time prior to 
starting the investigational agent, expedited reporting of adverse events which occur prior 
to starting the investigational agent would follow the guidelines for commercial agents. Once 
therapy with the investigational agent is initiated, all expedited reporting of adverse events 
follow the investigational agent reporting guidelines. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI requires that 
AEs be submitted according to the timeframes in the AE reporting tables assigned to the protocol, 
using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. A 
Serious Adverse Event (SAE) is any adverse drug event (experience) occurring at any dose that results 
in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part of 
routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 

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

  
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The NCI requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe 
the event: 
• 
Leukemia secondary to oncology chemotherapy 
• 
Myelodysplastic syndrome 
• 
Treatment related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) must also be 
reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportF
orm.pdf, needs to be completed and faxed along with any additional medical information to 
(301) 897-7404. The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of the 
CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in an 
expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the “Pregnancy, puerperium and 
perinatal conditions” SOC. 
 
There is a possibility that the sperm of male patients treated on studies involving 
possible teratogenic agents may have been damaged. For this reason, pregnancy in 
partners of men on study needs be reported and followed in the same manner as 
a patient pregnancy. 
 
Pregnancy needs to be followed until the outcome is known. If the baby is born with 
a birth defect or anomaly, then a second CTEP-AERS report is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.”  Any Pregnancy loss 
should be be reported expeditiously, as Grade 4 “Pregnancy loss” under the 
“Pregnancy, puerperium and perinatal conditions” SOC. Do NOT report a 
pregnancy loss as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during the first 28 
days after birth”, should be reported expeditiously as Grade 4, “Death neonatal” 
under the “General disorders and administration” SOC, when the death is the 
result of a patient pregnancy or pregnancy in partners of men on study. Do NOT 
report a neonatal death resulting from a patient pregnancy or pregnancy in partners 

  
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of men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs 
 
11.5.1 
Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an AE, when 
possible it is to be documented as “Course Zero” using CTCAE terminology and grade. An 
expedited AE report is not required if a patient is entered on a protocol with a pre-existing 
condition (e.g., elevated laboratory value, diarrhea). The baseline AE must be re-assessed 
throughout the study and reported if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must reassess the 
event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event to 
determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities existing at 
baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between treatment 
cycles/courses. 
 
ROUTINE reporting: The AE must be reported only once unless the grade becomes more 
severe in a subsequent course. If the grade becomes more severe the AE must be reported 
again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade becomes more 
severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy and then 
reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent cycle/course 
must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent cycle/course 
does not require CTEP-AERS reporting unless: 
1) 
The grade increases OR 
2) 
Hospitalization is associated with the recurring AE. 
 
 
 
 

  
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11.6 
Exceptions to Expedited Reporting 
 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and Potential Risks 
(CAEPR) that contains a list of events that are considered expected for CTEP-AERS reporting 
purposes. (Formerly referred to as the Agent Specific Adverse Event List (ASAEL).) 
 
AEs listed on the SPEER should be reported expeditiously by investigators to the NCI via 
CTEP-AERS ONLY if they exceed the grade of the event listed in parentheses after the event. 
If the CAEPR is part of a combination IND using multiple investigational agents and has an 
SAE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is listed as 
expected. The exception or acceptable reporting procedures will be specified in the protocol. 
The protocol specific guidelines supersede the NCI Adverse Event Reporting Guidelines. 
These special situations are listed under the CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the primary 
responsibility for AE identification, documentation, grading, and assignment of attribution to the 
investigational agent/intervention. It is the responsibility of the treating physician to supply the 
medical documentation needed to support the expedited AE reports in a timely manner. 
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine reporting. 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within the 
study database. 
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be submitted 
electronically to NCI via CTEP-AERS at: https://eapps-ctep.nci.nih.gov/ctepaers. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be made to 
the NCI for agents supplied under a CTEP IND by telephone call to (301)897-7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned in must be 
entered into the electronic CTEP-AERS system by the original submitter of the report at the site.  
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the event, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted within 
7 calendar days of the investigator learning of the event.  
• 
Any event that results in a persistent or significant incapacity/substantial disruption of the 

  
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ability to conduct normal life functions, or a congenital anomaly/birth defect, or is an IME, 
which based upon the medical judgment of the investigator may jeopardize the patient and 
require intervention to prevent a serious AE, must be reported via CTEP-AERS if the event 
occurs following investigational agent administration.  
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of possible, 
probable, or definite to an agent/intervention under an NCI IND/IDE requires expedited 
reporting within 24 hours. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 1) whether 
the patient has received at least one dose of an investigational agent on this study; 2) the characteristics 
of the adverse event including the grade (severity), the relationship to the study therapy (attribution), 
and the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 
4) whether or not hospitalization or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (e.g., H & P, admission and/or 
notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to the NCI. NOTE: 
English is required for supporting documentation submitted to the numbers listed below in 
order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under a CTEP 
IND to: (301) 897-7404. 
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax # (310) 640-9193; 
email: COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE 
within 30 Days of the Last Administration of the Investigational Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. This 
 
does not include hospitalizations that are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
 
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.  
 

  
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Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special Situations as 
Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
• 
All Grade 3-Grade 5 pulmonary toxicities (with the exception of laryngitis) must be reported as SAEs. 
Sites are required to complete the patient Medidata/Rave screens on-line within 24 hours of any 
Grade 3-5 pulmonary toxicity. 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not require 
expedited reporting. 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway 
 
The following are expedited reporting requirements for adverse events experienced by patients on 
study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B. 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who have NOT 
received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy With 
a Commercial Agent or Within 30 Days1 
 
 

  
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Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution. Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent that can be attributed (possibly, probably, or 
definitely) to the agent and is not due to cancer recurrence must be reported via CTEP-
AERS. 
 
 
11.12 Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on the COG case 
report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within the 
study database. For this study, routine reporting will include all toxicities reported via CTEP-AERS 
and all Grade 4 and higher nonhematologic Adverse Events as well as the following specific toxicities: 
 
1. CNS hemorrhage requiring medical intervention (Grade 2 and higher) 
2. GI bleed requiring operative or interventional radiology intervention (Grade 3 and higher) 
3. Pancreatitis requiring medical intervention (Grades 2 and higher) 
4. Transient ischemic attacks (All grades) 
6. Stroke (All grades) 
7. Encephalopathy (Grade 3 and higher) 
8. Neuropathy; motor or sensory, interfering with ADL (Grade 3 and higher)* 
9. Seizure (Grade 2 and higher) 
10. Allergic reaction (Grade 3 and higher) 
11. Ileus (Grade 3 and higher) 
12. Mucositis/stomatitis; functional (Grade 3 and higher) 
13. Bilirubin (Grade 3 and higher) 
14. Thrombosis (Grade 3 and higher) 
15. Hyponatremia (Grade 3 and higher) 
16. Hypophosphatemia (Grade 3 and higher) 
17. Osteonecrosis (Grade 2 and higher) 
 
*Please use Balis scale (Section 5.13.6) grading for neuropathy (motor or sensory).  
 
See Section 5.2 for identification, management and reporting of bortezomib-related toxicities.  
 
12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data 
will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 
31 and October 31. This is not a responsibility of institutions participating in this trial. 

  
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12.2 
CTA/CRADA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as “Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of its 
own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 

  
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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13.0 
PATHOLOGY GUIDELINES FOR T-LLy 
 
13.1 
Pathology Goals 
To provide accurate diagnosis and classification of pediatric lymphoblastic lymphoma through central 
pathologic review of morphology and immunophenotypic data. This study is limited to T-cell 
lymphoblastic lymphoma (Stages II-IV). The central review will employ the 2008 World Health 
Organization (WHO) Lymphoma Classification98 to facilitate concordance in diagnosis and correlate 
morphologic, immunophenotypic and cytogenetic data. 
 
NOTE: Tissue for central review is strongly encouraged but not required for enrollment. The 
distinction between T-ALL and T-LLy is based on morphology on bone marrow aspirate as 
determined by local institutions and not by central MRD. Bilateral bone marrow aspirates and biopsies 
are strongly preferred but not required for study eligibility.  A unilateral bone marrow aspirate for 
morphology and for central MRD bone marrow assessment are required to be eligible. 
 
13.2 Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
 
13.2.1 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 13.1). Submit 
representative tissue sections for fixation including at least one block with 10% buffered 
formalin. 
 

  
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Figure 13.1 
 
13.2.2 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 one cell block should be prepared with specification of the fixative utilized and the 
time in fixative 
 
 
13.3 
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: paraffin section 
immunohistochemistry, 
frozen 
section 
immunohistochemistry, 
cytocentrifuge 
(cytospin) 
immunocytochemistry, and flow cytometry. 
 
For eligibility in this study, an extensive panel of antibodies should be employed for 
immunophenotypic evaluation. This can be done on snap frozen tissue by immunohistochemistry, and 
body fluid/cytology specimens by flow cytometry or cytocentrifuge (cytospin) immunocytochemistry. 
This panel of antibodies is listed as follows: 
 
T-Cell: CD1a, CD2, CD3, CD4, CD5, CD7, CD8. 
B-Cell: CD19, CD20, Kappa, Lambda. 
Myeloid: CD13, CD14, CD33. 
Other: CD10, CD25, CD34, CD45, TdT. 
 
The method of TdT evaluation should be specified (i.e. flow cytometry, immunofluorescence, 
immunohistochemistry). 
 
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 

  
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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, CD5, CD19, CD79a and TdT. If specimen is 
limited to paraffin embedded tissue only, a preferred panel of antibodies should include at least: 
CD45RO (UCHL-1), CD79a, and TdT. If additional antibodies that may be utilized in paraffin 
embedded tissue are available at the primary institution, the panel may include: CD3 (polyclonal), 
CD43 (Leu22), CD22, PAX599,100, and CD45RA (4KB5). If immunophenotyping studies are not 
available locally, the case may be sent as a consultation case for evaluation including 
immunophenotyping studies to Dr. Rodney Miles (see address in Section 13.5.6). 
 
13.4 
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. 
 
13.5 
Retrospective Central Pathology Review 
 
13.5.1 Requested Materials 
Materials to be submitted for retrospective pathology review to the COG Biopathology Center 
include the following: 
• 
Initial diagnostic material prior to therapy 
• 
Specimens demonstrating relapse of lymphoma at any time 
• 
Specimens from residual masses demonstrating residual lymphoma or complete 
response to therapy 
• 
A copy of all final pathology reports (see details in Section 13.5.1d) 
• 
Pathology Data Collection Form 
• 
AALL1231 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 13-1. 
 
a.) 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 13.5.4). For cytology 
specimens, a paraffin block may be available as a cell block preparation (see Section 
13.5.1.5). 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). 
 
b.) 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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c.) 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. 
 
d.) Pathology Reports 
A copy of all pathology reports on each case should be submitted. This should include: 
Final reports of diagnostic biopsy and bone marrow specimens (even if negative) All 
immunophenotyping reports of diagnostic biopsy and bone marrow specimens (if 
available); also include copies of flow cytometry histograms (if available) Results of any 
genotypic studies (i.e. gene rearrangement studies) Results of any cytogenetic (karyotypic) 
analysis 
 
e.) Pathology Data Collection Forms 
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 WHO Lymphoma Classification98 on the data 
collection form. 
 
13.5.2 Transmittal Form 
An AALL1231 specimen transmittal form must be submitted along with the pathology review 
materials. 
 
13.5.3 Biopathology Center Address 
All material submitted for 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) 722-2865 
Fax: (614) 722-2897 
Email:  BPCParaffinTeam@nationwidechildrens.org 
 
* The room number is required. Packages not listing the room number could be denied and returned to 
sender. 
 
13.5.4 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. 
 
13.5.5 Lymphoma Classification 
Morphologic evaluation and classification of the study cases will utilize the criteria described 
in the WHO Lymphoma Classification.98 Eligible pediatric lymphomas will be classified as 
precursor T-cell lymphoblastic lymphoma. 
 
13.5.6 Review Pathologists 
For any questions regarding the pathology protocol, please contact: 
 
Rodney R. Miles, MD PhD 
ARUP Laboratories Hematopathology 
500 Chipeta Way 
Salt Lake City, UT 84108 
Phone: (801) 213-3448   (801) 581-5854 

  
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Email: rodney.miles@path.utah.edu 
 
13.6 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse- for T-LLy patients not 
enrolled on Project:EveryChild (APEC14B1) 
At diagnosis, at least one square centimeter of snap frozen tumor is requested in addition to the material 
required for central review (described in Section 13.5). If more than 1 gram is available, cut tissue into 
1 gram aliquots. Wrap each piece of tissue in a separate piece of foil and snap freeze in vapor phase 
liquid nitrogen (do not submerge the tissue in liquid nitrogen) or cold isopentane. Label the foil with 
either “P” or “M” to designate whether the tissue submitted is primary or metastatic. Place tissue in 
the appropriate zip-lock bag (primary or metastatic) and, using a waterproof marker, label the bag with 
the patient’s BPC number, specimen type and date obtained. Document the anatomic site of collection 
on the transmittal form. Store specimens at -70°C or colder until shipped. Include a transmittal form 
and pathology 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. 
 
13.6.1 Specimen Shipping Instructions 
Specimen Procurement Kits for shipping frozen tumor tissue to the BPC are provided upon 
request. To request a Specimen Procurement Kit, use the following link: 
 
https://ricapps.nationwidechildrens.org/KitManagement/ 
 
Select ‘AALL1231’ from the protocol list to order kits for the submission of frozen tumor 
tissue from T-LLy patients. 
 
Frozen specimens 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 three separate layers of packaging : 
a. Place the tissue in a zip-lock bag. 
b. Place the zip-lock bag in the biohazard diagnostic envelope. Expel as much air 
as possible and seal the envelope securely. 
c. Place the biohazard envelope inside the Tyvek envelope. Expel as much air as 
possible 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 and pathology report inside the compartment. 
 
4. Place the foam 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 Kit Management to print a Federal Express shipping label. A blank adhesive label 
is provided in the Specimen Procurement Kit to use when printing the shipping label. 

  
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Attach the shipping label to the top of the kit. Complete the dry ice label (UN 1845). 
Attach 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 
Phone: (614) 722-2865 
Email: BPCBank@nationwidechildrens.org 
 
* The room number is required. Packages not listing the room number could be denied and 
returned to sender. 
 
 
14.0 
MRD ANALYSIS GUIDELINES AND REQUIREMENTS 
 
14.1 
Minimal Residual Disease- Required and Optional Specimens: T-ALL patients 
The following MRD assessments are required for T-ALL patients. Bone marrow will be collected 
and shipped at the following time points: 
 
• 
Diagnosis (done as part of AALL08B1 or Project:EveryChild) 
• 
*End of Induction 
• 
*End of Consolidation (IR and VHR patients with end of Induction MRD ≥ 0.01%) 
• 
*End of High Risk Block #3 (for VHR T-ALL patients) in order to assess disease 
involvement in the bone marrow and for subsequent risk stratification. 
 
*These samples will be shipped to the COG ALL Reference Flow Cytometry Lab using the 
shipping and handling requirements in Appendix IX. 
 
NOTE: Day 8 peripheral blood MRD is NOT sent on this study 
 
14.2 
Minimal Residual Disease- Required and Optional Specimens: T-LLy Only* 
The following MRD assessments are REQUIRED for T-LLy patients as a part of AALL1231. Bone 
marrow will be collected and shipped at the following time point: 
 
• 
Diagnosis 
 
*NOTE: Only a unilateral specimen should be sent for MRD testing at diagnosis. 
 
The following MRD assessments are OPTIONAL for T-LLy patients as part of AALL1231. Bone 
marrow will be collected and shipped at the following time point to assess whether MRD can predict 
EFS and OS in T-LLy: 
 
• 
**End of Induction 
 
** These samples will be shipped to the COG ALL Reference Flow Cytometry Lab using the 
shipping and handling requirements in Appendix IX. Only a unilateral specimen should be sent 
for MRD testing at end of Induction. 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
Correlative studies are optional, and not required for risk-stratification or treatment 
assignment. These tests are not required for treatment decisions but are essential for advancing 
the field. 

  
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15.1 
Evaluating Mechanisms of Bortezomib Response and Resistance in T-ALL and Identifying  
Biomarkers and Mechanisms of Chemotherapy Resistance and Response in T-ALL, Focusing 
on Early Thymic Precursor (ETP) ALL.   
This optional study is open to all T-ALL patients (Arm A and B and is NOT limited to patients 
receiving bortezomib.). Peripheral blood and bone marrow will be collected. Please check the protocol 
website for updates.  
 
The goal of this study is to understand the mechanisms of bortezomib action and the mechanisms of 
bortezomib resistance and to compare signaling pathway abnormalities between ETP ALL and non-
ETP ALL. Appendix XII provides additional details regarding experimental design. 
 
 
For consenting patients of Arm A and Arm B, we are requesting a pretreatment and end of Induction 
bone marrow sample (peripheral blood can be substituted if >80% blasts), and 4 peripheral blood 
samples. Peripheral blood will be collected at the following time points:  
• 
Pre-treatment 
• 
4-8 hours (ideally at 6 hours) after initiating Induction chemotherapy 
• 
22-26 hours (ideally at 24 hours) after initiating Induction chemotherapy 
• 
End of Induction. 
 
If randomized to the bortezomib-containing arm post-treatment samples are timed relative to first dose 
of bortezomib. 
 
See Appendix X for sample collection, processing, and shipping information for the Horton Lab. 
 
15.2 
OPTIONAL TISSUE BANKING 
 
15.2.1 Studies of Genomic Variation  
There is substantial evidence that both inherited germline constitutional and somatically-
acquired ALL-specific genomic variation may contribute to variations in response186-195 
AALL08B1 and successor study Project:EveryChild (APEC14B1) will serve as the 
mechanism by which materials will be collected and banked for genomic research, all of 
which must be approved by the ALL Biology committee. The AALL08B1 protocol and 
the Project:EveryChild (APEC14B1) protocol and Manual of Procedures include 
information on consent, collection, shipping, processing, analysis, and storage of 
diagnostic samples. The same guidelines and instructions for collection, shipping, 
processing, analysis, and storage will be used for subsequent samples, including End of 
Induction, End of Consolidation, and relapse. 
 
A blood sample at Day 29 is being requested specifically for the purpose of providing 
constitutional (germline) DNA from each 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. 
 
COG maintains an ALL cell bank that includes specimens from legacy CCG and POG 
ALL cell banks, COG ALL classification protocols (AALL03B1 and AALL08B1) and 
specimens collected prospectively from patients enrolled in current trials, including 
Project:EveryChild (APEC14B1). Specimens are available to any qualified investigator, 
from COG and non-COG institutions. Applications are submitted electronically to the 
Chair of the COG ALL Cell Bank Committee and reviewed by the Cell Bank Committee 
following established policies. In general, every effort is made to supply qualified 
investigators with small numbers (10-20) of non-scarce specimens. For large studies and 

  
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particularly those that request scarce specimens (e.g., those from low frequency genetic 
or clinical subsets, relapsed samples or sample sets containing patients of defined 
outcomes), the committee prioritizes the use of samples based on scientific merit to 
ensure adequate supply for future research questions. 
 
Specimens from the COG ALL cell bank are supplied to investigators following 
scientific review and approval of their proposal. Released samples may include vials of 
cryopreserved cells, or aliquots of nucleic acids, depending upon the needs of the 
investigator and the supplies that are available. Following scientific approval, 
investigators must sign a formal letter of collaboration and provide evidence of local IRB 
approval for the proposed laboratory studies. Any proposal that involves greater than 100 
patients must also be approved by CTEP prior to sample release (for banked tissue 
request form, see 
https://members.childrensoncologygroup.org/News/Newsitem.asp?ID=11427). 
The 
samples that are sent to investigators are coded. 
 
 
16.0 
RADIATION THERAPY GUIDELINES 
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). 
 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved COG 
RT facilities (per COG administrative policy 3.9). 
 
16.1 
Cranial Radiation Therapy 
All CRT will be given during the 1st cycle (first 4 weeks) of Maintenance. See the tables below to 
determine which subjects will receive CRT. 
 
T-ALL- Cranial Radiation Therapy 
 
SR 
IR 
VHR 
CNS 1 
none 
none 
CRT (1200 cGy) 
CNS 2 
none 
none 
CRT (1200 cGy) 
CNS 3 
n/a 
CRT (1800 cGy) 
CRT (1800 cGy) 
 
 
T-LLy- Cranial Radiation Therapy 
 
SR 
IR 
VHR 
CNS 1 
none 
none 
none 
CNS 2 
none 
none 
none 
CNS 3 
n/a 
CRT (1800 cGy) 
CRT (1800 cGy) 
 
16.1.1 
Equipment and Calibration 
 
16.1.1.1 
Modality 
X-ray beams with a nominal energy between 4 and 6 MV are permitted. The use 
of IMRT is not permitted in this study. 

  
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16.1.1.2 
Calibration  
Calibrations of therapy units used in this protocol shall be verified by the 
Radiological Physics Center (RPC). 
 
16.1.1.3 
Target Volume 
The target volume consists of the entire brain and meninges, including the frontal 
lobe as well as posterior halves of the globes of the eyes, with the optic disc and 
nerve, extending superior to the vertex and posterior to the occiput. The caudal 
border will be below the skull base at the C2 vertebral level. 
 
The target volume shall be defined by means of CT or conventional simulation. 
Care must be taken to avoid shielding the posterior orbit and cribriform plate. In 
case of conventional simulation, radio-opaque markers should be placed on the 
surface of the fleshy canthus to aid in localizing this point. 
 
16.1.2 Target Dose 
 
16.1.2.1 
Prescription Point 
The prescription point in the cranial volume is at or near the center. For multi-
convergent beams, the prescription point is usually at intersection of the beam 
axes. Note: Regardless of the location of central axis, dose should be prescribed at 
or near the center of the cranial volume (midway between the maximum 
separation). 
 
16.1.2.2 
Dose Definition 
Absorbed dose is specified in centigrays (cGy)-to-muscle. 
 
16.1.2.3 
Tissue Heterogeneity 
No tissue heterogeneity corrections, such as for bone attenuation, will be made. 
 
16.1.2.4 
Prescribed Dose and Fractionation 
Very High Risk T -ALL patients who are CNS 1 or 2 
These patients will receive prophylactic cranial radiation, consisting of a total dose 
of 1200 cGy given in 8 daily fractions of 150 cGy per fraction, administered 
Monday through Friday. 
 
All T-ALL and T-LLy who are CNS3 
All patients who are CNS3 at diagnosis will receive cranial radiation consisting of 
a total dose of 1800 cGy given in 10 daily fractions of 180 cGy per fraction, 
administered Monday through Friday. 
 
16.1.2.5 
Dose Uniformity 
Dose variations in target volume will be within +7%, -5% of prescription-point 
dose. (From ICRU Report 50: small high-dose volumes can be excluded from 
evaluation of dose uniformity but not small low-dose volumes.) 
 
16.1.2.6 
Treatment Interruptions 
No corrections will be made for treatment interruptions less than 7 days. For 
interruptions greater than 7 days, contact the Study Radiation Oncology 
Coordinator. 
 

  
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16.1.3 Treatment Technique 
 
16.1.3.1 
Patient Position 
It is recommended that the patient be treated in supine with immobilization 
appropriate for the child such as a face mask and well-fitting headrest. 
 
16.1.3.2 
Beam Configuration 
The cranial volume is treated with two lateral, equally-weighted photon beams. 
Fields shall extend at least 1 cm beyond periphery of the scalp. 
 
16.1.3.3 
Field Shaping 
Field-shaping will be done with blocks which are at least 5 half-value layers 
(HVLs) thick. Multi-leaf collimators are acceptable. 
 
16.1.2.11 
Eye Protection 
A simple method to minimize lens irradiation, while treating posterior halves of 
eyes, is to let central axes of the horizontal cranial beams go through both orbits. 
The anterior edges of beams are defined by an external block or by an 
independently controlled collimator and meet at a point 1 cm anterior to frontal 
lobe meninges. Shielding blocks cover the anterior halves of eyes and protect nose 
and mouth. Essentially the same geometry can be achieved with by placing central 
axes through center of head by angling lateral fields so rays through the eyes lie 
in the same horizontal plane. It is acceptable to use a parallel-opposed beam-pair, 
without such angling, with shielding blocks that cover the anterior half of 
proximal eye. The dose to contralateral lens will then increase 
 
16.2 
Testicular Radiation 
T-ALL and T-LLy patients with persistent testicular disease at end-Induction should receive radiation 
to the testes during Consolidation. A testicular biopsy should be performed if the clinical findings are 
equivocal. During the first two weeks of Consolidation, testicular radiation therapy will be given at 
2400 cGy in 12 once-daily fractions of 200 cGy. Testicular radiation must be started during 
Consolidation and should be completed before the end of this phase of therapy. Patients with testicular 
leukemia at diagnosis that clinically resolves completely by end-Induction, and those that have 
a negative testicular biopsy at end-Induction will NOT receive testicular radiation. 
 
16.2.1 Equipment and Calibration 
 
16.2.1.1 Modality 
High-energy photon or electron beams are permitted. Selection of energy is 
determined by dose uniformity criterion, and with electrons, lowest possible energy 
should be used to spare tissues outside target volume. IMRT is not permitted in this 
study. 
 
16.2.1.2 Calibration 
Calibrations of therapy machines used in this protocol will be verified by the 
Radiological Physics Center. 
 
16.2.1.3 Target Volume 
The target volume consists of testes in the scrotal sac. (Note: The cremasteric reflex 
may move testes high up in inguinal canal.) The field may be reduced as the 
palpably enlarged mass decreases in size during treatment. 
 

  
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16.2.2 Target Dose 
 
16.2.2.1 
Prescription Point 
Prescription point is at or near center of planning target volume. 
 
16.2.2.2 
Dose Definition 
Absorbed dose is specified as centigrays (cGy)-to-muscle. 
 
16.2.2.3 
Prescribed Dose and Fractionation 
Total dose to prescription point will be 2400 cGy in 12 daily fractions of 200 cGy 
per fraction, administered Monday through Friday. 
 
16.2.2.4 
Dose Uniformity 
Variations of dose within planning target volume will be within +7%, -5% of dose 
to prescription point. The uniformity requirement can be met with electron beam 
of appropriate energy provided bolus is used, which is simplest technique. Bolus 
may also be needed for photon beams to fulfill dose uniformity requirement. (From 
ICRU Report 50: small high-dose volumes can be excluded from evaluation of 
dose uniformity, but not small low-dose volumes.) 
 
16.2.2.5 
Treatment Interruptions 
No corrections will be made for treatment interruptions less than 7 days. For 
interruptions greater than 7 days, contact the Study Radiation Oncology 
Coordinator.  
 
16.2.3 Treatment Technique 
 
16.2.3.1 
Patient Position 
Patient will be treated in supine position. 
 
16.2.3.2 
Field Shaping 
Field shaping can be done with blocks of at least 5 HVLs thick. Multi-leaf 
collimators are acceptable. 
 
16.2.3.3 
Normal Tissue Sparing 
Testes will be supported posteriorly and, if possible, extended caudally in order 
to minimize perineal irradiation. Field shall not be angled towards perineum. The 
penis shall be excluded from field by fixing it to skin over the symphysis pubis. 
 
16.3 
Quality Assurance Documentation 
 
16.3.1 IROC RHODE ISLAND (FORMERLY QARC) Post Treatment Review 
Patients receiving RT on this study will have a review only of the dose delivered. There is no 
on-treatment review and no target volume review. 
Within one week of the completion of radiotherapy, the following data will be submitted: 
 
“RT-2 Radiotherapy Total Dose Record” form. 
Copy of patient’s radiation therapy chart, including prescription, and daily and cumulative 
doses. 
 
16.3.2 Data must be sent to 
 
IROC Rhode Island (formerly QARC) 
Building B, Suite 201 
640 George Washington Highway 

  
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Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
16.3.3 Questions regarding the dose calculations or documentation should be directed to 
 
COG Protocol Dosimetrist 
IROC Rhode Island (formerly QARC) 
Building B, Suite 201 
640 George Washington Highway 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
16.3.4 Questions regarding the radiation therapy section of this protocol should be directed to the 
Study Radiation Oncology Coordinator 
 
Samir I. Patel, MD 
University of Alberta-Stollery Children’s Hospital 
11560 University Avenue 
Edmonton, AB T6L 6J5 
Phone: (780) 432-8518 
Fax: 
(780) 432-8380  
E-mail: samir.patel2@albertahealthservices.ca  
 
16.4 
Definitions of Deviation in Protocol Performance 
 
16.4.1 Minor Deviation 
Dose to prescription point differs from that in protocol between 6% and 10%. 
 
16.4.2 Major Deviation 
Dose to the prescription point differs from that in the protocol by more than 10%. 

 
 
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APPENDIX I: 
THERAPY DELIVERY MAPS – ARM A (T-ALL 
and T-LLy) 
 

 
 
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APPENDIX I-A  
Patients must complete and sign the appropriate informed consent and undergo bortezomib randomization before starting Induction therapy. This Course lasts 5 
weeks (35 days) and 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 lumbar 
puncture (LP)* OR 
Day 1 
May give prior to 
randomization 
 
Note age-based dosing 
a. Hx/PE with VS/Wt (BSA), CBC/diff/plts 
b. Bilirubin (total and direct), ALT, AST 
creatinine 
c. CSF cell count & cytospin2 
d. TPMT and NUDT15 genotype (if 
available) 
e. BM MRD 
f. Performance status 
g. Pregnancy test 
h. BM cytomorphology 
i.  CXR 
j. Cell Banking (optional) 
 
T-LLy Only 
k. Chest CT 
l. Abdomen/pelvis CT (or MRI) 
m. Bone scan 
n. Diagnostic biopsy/cytology4 
o. PET scan  
 
Optional Studies T-ALL ONLY 
Bortezomib Response Study (open to Arms 
A and B): See Section 15.1 for details 
p. PB sample  
q. BM sample  
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
VinCRIStine  
(VCR) 
IV Push 
Over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15 & 22 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
Dexamethasone 
(DEX) 
PO (may be 
given IV) 
3 mg/m2/dose 
BID 
Days 1-28 
(no taper) 
Total daily dose: 6 
mg/m2/day, divided BID 
DAUNOrubicin 
(DAUN) 
IV Push/infusion 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, 15 & 22 
 
PEG aspargase  
(PEG-ASP) 
IV over 1-2 hours 
 
2500 International 
units/m2 x 1 dose 
Days 4 & 18 
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  
(Days 15 & 22 for 
CNS3 ONLY) 
Note age-based doing 
 
Please note CNS3 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
BSA____m 
Date 
Due 
Date 
Given 
Day 
IT ARAC 
____mg 
VCR 
____mg 
DEX 
____mg ____mg 
DAUN 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
-2/-
1/0/LP 
____mg* 
 
 
 
 
 
(a,b,f,g,h,i,j$)@ (k,l,m8,n)4,@ (p)5,^ (e)$ 
 
 
1 
____mg ____mg ____mg 
____mg 
 
 
b,c*, d11,n1,5 
--- 
 
 
 
4 
 
 
 
____IU 
(1 dose) 
 
 
--- 
 
 
 
8 
 
____mg 
____mg 
 
____mg 
a, c 
--- 
 
 
 
15 
 
____mg 
____mg 
 
____mg# a, c#, 
--- 
 
 
 
18 
 
 
 
____IU 
(1 dose) 
 
 
--- 
 
 
 
22 
 
____mg 
____mg 
 
____mg# a, c# 
--- 
 
 
 
29 
 
 
 
 
 
____mg 
a, b,c,e3,h10, (i ,k12,l7,m8,o9) 4 (p,q)5 
 
 
36 
Start next course (Consolidation, Appendix I-B) on Day 36 or when blood count parameters are met (whichever occurs later) 
Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count recovery to 
occur.) 
*On Day 1 OR at the time of diagnostic lumbar puncture (LP) if < than 72 hours from the start of protocol therapy. 
$ T-ALL: Done as part of AALL08B1 or APEC14B1 T-LLy: If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on APEC14B1, submit as 
part of this protocol (see Section 13.6 for details) 
 
#CNS3 patients ONLY 
 
@Baseline  
^ Pre-treatment 
1 For all patients who consent, collect at hours 0, 6 and 24. See Section 15.1 for details. 
2 Obtain with each IT administration  
 
3 Optional for T-LLy. Required for T-ALL         4 T-LLy ONLY 
5T-ALL ONLY 
6 follow-up exams only if baseline demonstrates disease. 
7 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no repeat scans are required. 
8 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. A PET scan can be used as a substitute for bone scans; however, 
a bone scan is preferred in patients with bone symptoms. 
9 PET scan is recommended but not required at baseline. If a PET is obtained at baseline, PET imaging should be continued with subsequent response assessments 
until patient no longer has PET-avid disease. 
10T-LLy: only if positive at diagnosis 
11 To be performed any time during Induction 
12If a PET-CT was obtained at diagnosis, it can be used instead of a regular CT to follow response. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.  
 
 
INDUCTION- Arm A (without bortezomib)  
This Induction course is for patients randomized to treatment on Arm A (no bortezomib) See Section 4.3 for details. 
_________________       ________ 
     Patient name or initials              DOB       
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APPENDIX I-B  
CONSOLIDATION Arm-A  
This Consolidation course is for patients on Arm A. See Section 4.6 for details. 
__________________________       _________________________ 
                Patient name or initials                                                DOB 
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). Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count recovery to 
occur.) Once Consolidation therapy has begun, interruptions for myelosuppression should occur only at Day 29. Patients with T-ALL and persistent testicular 
disease at end-Induction will receive XRT to the testes during Consolidation (a testicular biopsy is required if there is any uncertainty regarding the clinical 
response). Within the first two weeks of Consolidation, testicular radiation therapy will be given at 2400 cGy in 12 once-daily fractions of 200 cGy (See 
Section 16.2). Testicular radiation must be started during Consolidation and should be completed before the end of this phase of therapy. This Course lasts 8 
weeks (56 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 8, 15, 22  
 
Omit Days 15 & 
22 for CNS3 
patients ONLY  
Note age-based dosing 
 
Please note CNS3  
a. Hx/PE with VS/Wt (BSA) 
b. CBC/diff/plts 
c. CSF cell count & 
cytospin2 
d. Bilirubin (total and direct), 
ALT, AST creatinine 
e. Performance Status 
f. BM MRD1,4 
g. Bone Marrow 
cytomorphology 
 
T-LLy Only 
h. Chest CT/CXR 
i. Abdomen/pelvis CT (or 
MRI), Bone scan, PET 
scan 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Cyclophosphamide 
(CPM) 
IV over 
30-
60 minutes 
1000 mg/m2/dose 
Days 1 & 29 
See Section 4.6 for admin 
guidelines 
Cytarabine 
(ARAC) 
IV or 
SubQ 
75 mg/m2/dose 
Days 1-4, 8-11, 
29-32 & 36-39 
 
Mercaptopurine 
(MP) 
PO 
60 mg/m2/dose 
Days 1-14 & 29-
42 
See Section 4.6 and Appendix VI 
for administration guidelines 
VinCRIStine 
(VCR) 
IV Push 
over 
1 min+ 
1.5 mg/m2/dose 
Days 15, 22, 43 & 
50 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
Pegaspargase 
(PEG-ASP) 
IV over  
1-2 hours 
2500 International 
units/m2/dose 
Days 15 & 43 
Administer through the tubing of 
a freely infusing solution of D5W 
or 0.9% NaCl 
T-ALL patients with biopsy proven testicular disease at end-Induction will receive testicular XRT. See Section 4.4 & Section 16.0 
for additional details. 
 
 
 
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APPENDIX I-B  
CONSOLIDATION Arm-A  
This Consolidation course is for patients on Arm A. See Section 4.6 for details. 
__________________________       _________________________ 
                Patient name or initials                                                DOB 
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). Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count recovery to 
occur.) Once Consolidation therapy has begun, interruptions for myelosuppression should occur only at Day 29. Patients with T-ALL and persistent testicular 
disease at end-Induction will receive XRT to the testes during Consolidation (a testicular biopsy is required if there is any uncertainty regarding the clinical 
response). Within the first two weeks of Consolidation, testicular radiation therapy will be given at 2400 cGy in 12 once-daily fractions of 200 cGy (See 
Section 16.2). Testicular radiation must be started during Consolidation and should be completed before the end of this phase of therapy. This Course lasts 8 
weeks (56 days) and this Therapy Delivery Map is on two (2) pages. 
 
Therapy Delivery Map  
 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
IT MTX 
____mg 
CPM 
____mg 
ARAC 
____mg 
MP 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comme
nts 
 
 
 
CNS3 T-ALL  
All other patients  
 
 
 
 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1$ 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
a,b,c,d,e5 
 
 
2 
 
 
 
____mg 
 
 
 
 
 
3 
 
 
 
____mg 
 
 
 
 
 
4 
 
 
 
____mg 
 
 
 
--- 
 
 
 
8 
____mg 
____mg 
 
____mg 
 
 
b,c 
 
 
9 
 
 
 
____mg 
 
 
 
 
 
10 
 
 
 
____mg 
 
 
 
 
 
11 
 
 
 
____mg 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
 
____mg 
 
 
 
____mg 
____IU 
b,c 
--- 
 
 
22 
 
____mg 
 
 
 
____mg 
 
b,c 
--- 
 
 
29 
 
 
____mg 
____mg 
____mg 
 
 
b 
 
 
30 
 
 
 
____mg 
 
 
 
 
 
31 
 
 
 
____mg 
 
 
 
 
 
32 
 
 
 
____mg 
 
 
 
--- 
 
 
 
36 
 
 
 
____mg 
 
 
b 
 
 
37 
 
 
 
____mg 
 
 
 
 
 
38 
 
 
 
____mg 
 
 
 
 
 
39 
 
 
 
____mg 
 
 
 
--- 
 
 
 
43 
 
 
 
 
 
____mg 
____IU 
b 
--- 
 
 
50 
 
 
 
 
 
____mg 
 
b 
--- 
 
 
56 
 
 
 
 
 
 
 
b,g6, (i7,j8)3 
 
 
57 
 
 
 
 
 
 
 
f 1,4 
 
 
 
 
Start next course (Based on Risk Assignment See Section 4.1.2) on Day 57 or when blood count parameters are met (whichever occurs later). 
1 End of Consolidation bone marrow is not performed on SR T-ALL patients. It is REQUIRED for T-ALL patients with end Induction BM 
MRD ≥ 0.01% ONLY  
2 Obtain with each IT administration  
 
3 T-LLy ONLY   
4 T-ALL only 
 
5 Prior to Day 1 therapy 
6 T-LLy: Only if positive at end Induction. See section 7.0 for additional details.  
7If patient has CR at end-Induction perform a CXR. If PR or NR at end-Induction perform a chest CT (If a PET-CT was obtained at diagnosis, 
it can be used instead of a regular CT to follow response) 
8 If baseline is negative, no repeat scans are required. 
$ T-ALL and T-LLy patients with persistent testicular disease at end-Induction should receive radiation to the testes during Consolidation. 
See Section 16.2 for details. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES. 
 
 
 
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THERAPY DELIVERY MAPS – ARM A-SR  (T-ALL and T-
LLy) 
 

 
 
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APPENDIX I-C  
INTERIM MAINTENANCE with CMTX- Arm A-SR 
This IM course is for patients assigned to Arm A-SR. See Section 4.7 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Post-consolidation risk assignment must have been completed as described in Section 4.1. Start when ANC ≥750/L and platelets ≥75,000/l. Patients need 
to meet renal and hepatic function requirements to initiate methotrexate as described in Section 5.10.1, Section 5.10.2, and Section 5.10.3. 
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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
1 Obtain with each IT 
administration 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV infusion 
over 10-15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 21, 
31 & 41 
See Section 4.7 and 
Section 5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
--- 
 
 
11 
____mg 
____mg 
 
 
b* 
--- 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
--- 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
--- 
 
 
41 
____mg 
____mg 
 
 
b* 
--- 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Appendix I-D) on Day 57 or when blood count parameters are 
met (whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
Page 1 of 1 

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 172 
APPENDIX I-D 
 
DELAYED INTENSIFICATION Arm A-SR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-SR (no 
bortezomib) See Section 4.8 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious 
proven or presumed infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 
75,000/µL. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO (may be given IV) 
 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
PEG aspargase 
 (PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT 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 
 
 
____IU 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
____mg 
 
____mg 
 
 
b 
--- 
 
 
15 
____mg 
____mg ____mg 
____mg 
 
 
b 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
____IU 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
b 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
 
 
Page 1 of 2 

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 173 
 
DELAYED INTENSIFICATION Arm A-SR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-SR (no 
bortezomib). See Section 4.8 for details. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 + Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
Administer through the tubing of a 
freely infusing solution of D5W or 
0.9% NaCl 
Cyclophosphamide 
(CPM) 
IV over 30-
60 minutes 
1000 
mg/m2/dose 
Day 29 
See Section 4.8 for administration 
guidelines 
Cytarabine (ARAC) 
IV over 1-30 min or 
SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.8, Section 5.13 & 
Appendix VII 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, 29 & 36 
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
PEG-ASP 
____IU 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
IT MTX 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
____mg 
_____mg 
_____mg 
_____mg 
b,d,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
 
_____mg 
_____mg 
b,c 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b 
--- 
 
 
57 
 
 
 
 
 
 
b 
--- 
 
 
63 
 
 
 
 
 
 
b 
 
 
64 
Start next course (Maintenance, Appendix I-M) on Day 64 or when blood count parameters are met 
(whichever occurs later) 
 
1 Obtain with each IT administration  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
 
Page 2 of 2 

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 174 
 
 
 
 
 
 
 
 
 
 
 
 
 
THERAPY DELIVERY MAPS – ARM A-IR  (T-ALL and T-
LLy) 
 

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 175 
APPENDIX I-E  
INTERIM MAINTENANCE #1 with HDMTX- Arm A-IR 
This IM course is only for patients randomized to Arm A-IR. See Section 4.10 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients receive this block immediately after consolidation and must meet all of the following criteria: Post-consolidation risk assignment must have been 
completed as described in Section 4.1. Start when ANC ≥750/L and platelets ≥75,000/l. Patients need to meet renal and hepatic function 
requirements to initiate methotrexate as described in Section 5.9.1, Section 5.9.2, and Section 5.9.3. This Course lasts 8 weeks (56 days) 
and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High-Dose Methotrexate 
(HD MTX) 
IV over 24 
hours 
5000 mg/m2/dose 
Days 1, 15, 29 & 
43 
See Section 5.9 & Appendix 
IV for administration 
guidelines.  
Note: 2 stage administration 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
42, 48, and 54 
hours after the 
start of the HD 
MTX infusion 
See Section 5.9 and Appendix 
IV for HD MTX Infusion and 
Leucovorin rescue guidelines. 
VinCRIStine (VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose 
Days 1, 15, 29 & 
43 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
Mercaptopurine (MP) 
PO 
25 mg/m2/dose 
Days 1-56 
See Section 4.10, Section 
5.11and Appendix VI 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 & 29 
Deliver within 6 hours of the 
start of IV MTX (hr -6 to 
+6) 
 
Note age-based dosing 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due Date 
Given 
Day 
HD MTX 
____mg 
LCV 
VCR 
____mg 
MP 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
 
____mg 
____mg 
____mg 
a,b*,c 
 
 
2 
 
 
 
 
 
 
 
3 
 
____mg$ 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
--- 
 
 
 
15 
____mg 
 
____mg 
 
b* 
 
 
16 
 
 
 
 
 
 
 
17 
 
____mg$ 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
--- 
 
 
 
29 
____mg 
 
____mg 
____mg 
b*,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
____mg$ 
 
 
 
 
 
32 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
34 
 
 
 
 
 
--- 
 
 
 
43 
____mg 
 
____mg 
 
b* 
 
 
44 
 
 
 
 
 
 
 
45 
 
____mg$ 
 
 
 
 
 
46 
 
 
 
 
 
 
47 
 
 
 
 
 
--- 
 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Appendix I-F) on Day 57 or when blood count parameters are met (whichever occurs later). 
1 Obtain with each IT administration 
 
 
*To be performed prior to each dose of methotrexate 
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.
Page 1 of 1 

 
 
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 AALL1231 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 176 
APPENDIX I-F  
 
DELAYED INTENSIFICATION Arm A-IR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-IR (no 
bortezomib) See Section 4.8 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious 
proven or presumed infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 
75,000/µL. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO (May be given IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT 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 
 
 
____IU 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
____mg 
 
____mg 
 
 
b 
--- 
 
 
15 
____mg 
____mg ____mg 
____mg 
 
 
b 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
____IU 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
b 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE 
GUIDELINES. 
 
 
 
Page 1 of 2 

 
 
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 AALL1231 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 177 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43, & 50 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
Cyclophosphamide 
(CPM) 
IV over 30-60 min 1000 
mg/m2/dose 
Day 29 
See Section 4.8 for administration 
guidelines 
Cytarabine 
(ARAC) 
IV over 1-30 min or 
SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine 
(TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.8, Section 5.13 & 
Appendix VII for administration 
guidelines 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
_____mg 
____mg 
_____mg 
_____mg 
b,d,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
_____mg 
 
_____mg 
b,c 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b 
--- 
 
 
57 
 
 
 
 
 
 
b 
--- 
 
 
63 
 
 
 
 
 
 
b 
 
 
64 
Start next course (IM #2 CMTX, APPENDIX I-G) on Day 64 or when blood count parameters are met 
(whichever occurs later) 
1 Obtain with each IT administration 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES. 
DELAYED INTENSIFICATION Arm A-IR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-IR (no bortezomib) 
See Section 4.8  for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Page 2 of 2 

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 178 
APPENDIX I-G  
 
INTERIM MAINTENANCE #2 with CMTX- Arm A-IR  
This IM course is for patients randomized to Arm A-IR. See Section 4.7 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. Patients need to meet renal and 
hepatic function requirements to initiate methotrexate as described in Section 5.10. 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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV 
infusion over 10-
15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 
21, 31 & 41 
See Section 4.7 and Section 
5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 2500 International units/m2/dose Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
--- 
 
 
11 
____mg 
____mg 
 
 
b* 
--- 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
--- 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
--- 
 
 
41 
____mg 
____mg 
 
 
b* 
--- 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Maintenance Appendix I-M) on Day 57 or when blood count parameters are met 
(whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
 
Page 1 of 1 

 
 
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 AALL1231 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 179 
 
 
 
 
 
 
 
 
 
 
 
 
THERAPY DELIVERY MAPS – ARM A-VHR (T-ALL and 
T-LLy)  
 

 
 
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 AALL1231 
Version Date: 5/29/19  
 
 
 
 
 
 
Page 180 
APPENDIX I-H  
 
Intensification Block (1) – Arm A-VHR 
This course is only for patients randomized/assigned to treatment on Arm A-VHR. See Section 4.11 for details 
_____________________      ___________________ 
     Patient name or initials                     DOB 
T-ALL patients who are M2 or M3 at the end of Consolidation should proceed directly to Intensification Block 1 without waiting for count recovery or MRD results to proceed. 
Patients receive this block immediately after consolidation and must meet all of the following criteria: Post-consolidation risk assignment must have been completed as 
described in Section 4.1. T-ALL only:  Begin Intensification Block #1 after collection of end of consolidation bone marrow for MRD, when ANC ≥750/L and platelets 
≥75,000/l, and organ function requirements are met as defined in Sections 5.9.1, 5.9.2, and 5.9.3, or whichever occurs later. T-LLy only: Start when ANC ≥750/L and platelets 
≥75,000/l. This Cycle lasts 21 days and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone 
(DEX) 
PO (May be 
given IV) 
10 mg/m2/dose BID 
1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
High dose methotrexate 
(HD-MTX) 
IV 
5000 mg/m2/dose 
Day 1 
See Section 5.9 & Appendix IV for 
administration guidelines 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
Days 3-4 
Minimum of 3 doses given at 42, 48, and 54 hours 
after the start of the HD MTX infusion See Section 
5.9 and Appendix IV for HD MTX Infusion and 
Leucovorin rescue guidelines. 
VinCRIStine (VCR) 
IV push over 1 
min+ 
1.5 mg/m2/dose 
Days 1 & 6 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose of 2 mg 
Cyclophosphamide 
(CPM) 
IV over 1-
6 hours 
200 mg/m2/dose Q12 
hrs x5 doses 
Days 2-4 
See Section 4.11 for administration 
guidelines 
High dose cytarabine 
(ARAC) 
IV over 3 hours 2000 mg/m2/dose 
Q12 hrs x2 doses 
Day 5 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 2500 International 
units/m2/dose 
Day 6  
Administer 3 hours after completion of the second 
HD-AraC infusion through the tubing of a freely 
infusing solution of D5W or 0.9% NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 1 
Note age-based dosing 
 
Delivery within 6 hrs of IV MTX infusion 
Filgrastim (G-CSF) 
SubQ 
5 mcg/kg/dose 
Daily beginning 
on Day 7 
Continue until WBC > 3000/µL  
Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg 
IV MTX 
____mg 
LCV 
____mg$ 
VCR 
____mg 
CPM 
____mg 
ARAC 
____mg 
PEG-ASP 
____IU 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
G-CSF 
____mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
1 
 ___mg 
___mg 
____mg 
 
____mg 
 
 
 
____mg (MTX) 
____mg     (HC) 
____mg (ARAC) 
 
a,b,c,d 
 
 
2 
___mg 
___mg 
 
 
 
____mg 
___mg 
 
 
 
 
 
 
 
3 
___mg 
___mg 
 
____mg$ 
 
____mg 
___mg 
 
 
 
 
 
 
 
4 
___mg 
___mg 
 
 
____mg 
 
 
 
 
 
 
 
5 
___mg 
___mg 
 
 
 
 
____mg 
___mg 
 
 
 
 
 
 
6 
 
 
 
____mg 
 
 
____IU 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
____mcg 
b* 
 
 
21 
Start next course (Intensification Block 2 Appendix I-I) on Day 22 or when blood count parameters are met (whichever occurs later). 
1 Obtain with each IT administration  
 
*Every 2 days after completion of chemotherapy until count recovery 
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
Page 1 of 1 

 
 
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Page 181 
APPENDIX I-I  
 
Start Day 1 when ANC ≥750/L and platelets ≥75,000/L. This Cycle lasts 21 days and this Therapy Delivery Map is on one (1) page. 
 
 
 
Intensification Block (2) -Arm A-VHR 
This course is only for patients randomized to treatment on Arm A-VHR .See Section 4.12 for 
details.  
_____________________      ___________________ 
     Patient name or initials                     DOB 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) PO (May be given IV) 10 mg/m2/dose BID 
1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
High dose 
methotrexate (HD-
MTX) 
IV over 24 hours 
5000 mg/m2/dose 
Day 1 
See Section 5.9 & Appendix IV 
for administration guidelines 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
Days 3-4 
Minimum of 3 doses given at 42, 48, 
and 54 hours after the start of the HD 
MTX infusion See Section 5.9 and 
Appendix IV for HD MTX Infusion 
and Leucovorin rescue guidelines. 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1 & 6 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
Mesna 
IV 
300 mg/m2/dose Hour 0, 4, 
and 8 from start of each 
ifosfamide infusion 
Days 2-4 
Hydration following ifosfamide 
administration: If patient stops 
methotrexate hydration for 
whatever reason, need to continue 
until 12 hours post ifosfamide 
infusion.  
Ifosfamide (IFOS) 
IV over 1 hr 
800 mg/m2/dose Q12 hours 
x5 doses 
Days 2-4 
Suggested hydration: Administer 3000 
mL/m2/day (125 mL/m2/hr) using fluid 
containing 0.45% NaCl or 0.9% NaCl. 
Achieve urine specific gravity < 1.010 
and urine output > 3 mL/kg/hr prior to 
start of ifosfamide 
Start immediately after HD-MTX 
DAUNOrubicin 
(DAUN) 
IV Push/infusion 
Over 1-15 min 
30 mg/m2/dose 
Day 5 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 6 
Administer through the tubing of a 
freely infusing solution of D5W or 
0.9% NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 1 
Note age-based dosing 
 
Delivery within 6 hrs of IV MTX 
infusion 
Filgrastim (G-CSF) 
SubQ 
5  mcg/kg/dose 
Daily beginning 
on Day 7 
Continue until WBC > 3000/µL 
Page 1 of 2 

 
 
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Page 182 
 
Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg  
IV 
MTX 
____mg 
LCV 
___mg$ 
VCR 
____mg 
MESNA 
IFOS 
____mg 
DAUN 
____mg 
PEG-
ASP 
____IU 
IT  
MTX 
____mg 
IT  
HC 
____mg 
IT 
ARAC 
____mg 
G-CSF 
____mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
___mg 
___mg ____mg 
 
____mg 
 
 
 
 
____mg ____mg ____mg 
 
a,b,c,d 
 
 
2 
___mg 
___mg 
 
 
 
____mg 
___mg 
____mg 
____mg 
___mg 
____mg 
____mg 
___mg 
 
 
 
 
 
 
 
 
 
3 
___mg 
___mg 
 
____mg$ 
 
____mg 
___mg 
____mg 
____mg 
___mg 
____mg 
____mg 
___mg 
 
 
 
 
 
 
 
 
 
4 
___mg 
___mg 
 
 
____mg 
___mg 
____mg 
 
____mg 
 
 
 
 
 
 
 
 
 
 
5 
___mg 
___mg 
 
 
 
 
 
____mg 
 
 
 
 
 
 
 
 
6 
 
 
 
____mg 
 
 
 
____IU 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
____mcg 
b* 
 
 
 
21 
Start next course (Intensification Block 3 Appendix I-J) on Day 22 or when blood count parameters are met (whichever occurs 
later). 
1 Obtain with each IT administration  
 
 
*Every 2 days after completion of chemotherapy until count recovery  
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
Intensification Block (2) -Arm A-VHR 
This course is only for patients randomized to treatment on Arm A-VHR .See Section 4.12 for 
details.  
_____________________      ___________________ 
     Patient name or initials                     DOB 
Page 2 of 2 

 
 
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Page 183 
APPENDIX I-J  
 
Start Day 1 when ANC ≥ 750/L and platelets ≥ 75,000/L. HR3 lasts 21 days. This Cycle lasts 21 days and this Therapy Delivery Map is 
on one (1) page. 
Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg  
ARAC 
____mg 
ETOP 
____mg 
PEG-
ASP 
____IU 
IT  
MTX 
____mg 
IT  
HC 
____mg 
IT 
ARAC 
____mg 
G-CSF 
___mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
1 
 ___mg 
___mg 
____mg 
____mg 
 
 
 
 
 
 
a,b,d 
 
 
2 
___mg 
___mg 
____mg 
____mg 
 
 
 
 
 
 
 
 
 
3 
___mg 
___mg 
 
____mg 
___mg 
 
 
 
 
 
 
 
 
4 
___mg 
___mg 
 
____mg 
___mg 
 
 
 
 
 
 
 
 
5 
___mg 
___mg 
 
____mg 
 
____mg 
____mg 
____mg 
 
c 
 
 
6 
 
 
 
____IU 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
___mcg 
 
 
 
 
21 
 
 
 
 
 
 
 
 
T-ALL: b*, e 
T-LLy: b*, i, (f,g,h)2 
Start next course (Delayed Intensification Appendix I-K) on Day 22 or when blood count parameters are met (whichever occurs later). 
1 Obtain with each IT administration  
 
2 See Section 7.0 for details 
*Every 2 days after completion of chemotherapy until count recovery 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.
Intensification Block (3) Arm A-VHR 
This course is only for patients randomized to treatment on Arm A-VHR. See Section 
4.13 for details. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone 
(DEX) 
PO (May be given 
IV) 
10 mg/m2/dose BID Days 1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine, 
 
T-ALL ONLY 
e. BM MRD 
 
T-LLy ONLY: 
f. Chest CT/CXR2 
g. Abdomen/pelvis CT 
(or MRI)2 
h. Bone scan2 
i. Diagnostic biopsy/ 
cytology 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
High dose cytarabine 
(ARAC) 
IV over 3 hours 
2000 mg/m2/dose 
Q12 hours x 4 
doses 
Days 1-2 
 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Q12 hours x5 doses 
Days 3-5 
See Section 4.13 for 
administration guidelines 
Pegaspargase  
(PEG-ASP) 
 IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 6 
Administer through the 
tubing of a freely infusing 
solution of D5W or 0.9% 
NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC 
dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 5 
Note age-based dosing 
 
Filgrastim (G-CSF) 
SubQ 
5  mcg/kg/dose 
Daily beginning on Day 7 
Continue until WBC 
> 3000/µL  
Page 1 of 1 

 
 
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Page 184 
APPENDIX I-K  
 
DELAYED INTENSIFICATION- Arm A-VHR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-VHR (no 
bortezomib). See Section 4.8 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients receive this block immediately after HR Intensification 3 and must meet all of the following criteria: VHR T-ALL Post-HR Intensification Block 3 
MRD was completed and demonstrated undetectable MRD as described in Section 4.13 Start 7 days after collection of HR Intensification Block 3 bone 
marrow for MRD or when ANC ≥750/L and platelets ≥75,000/l, whichever occurs later. VHR T-LLy: Post-HR Intensification Block 3 disease evaluation 
was completed and demonstrated a radiographic CR OR a radiographic PR and a biopsy showing no residual disease as described in Section 10.4 Start when 
ANC ≥750/L and platelets ≥75,000/l All patients: Once Delayed Intensification has begun, it may be interrupted for myelosuppression (ANC ≤ 750/µL 
and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the remainder of the therapy should not 
be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious proven or presumed infection and 
resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 75,000/µL. This Course lasts 9 weeks 
(63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO (May be given IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36  
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT 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 
 
 
____IU 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
____mg 
 
____mg 
 
 
b 
--- 
 
 
15 
____mg 
____mg ____mg 
____mg 
 
 
b 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
____IU 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
b 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE 
GUIDELINES. 
 
 
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DELAYED INTENSIFICATION- Arm A-VHR (without bortezomib)  
This Delayed Intensification course is for patients randomized to treatment on Arm A-VHR (no 
bortezomib). See Section 4.8 for details.  
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15,43, & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count 
& cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
Cyclophosphamide 
(CPM) 
IV over 30-
60 minutes 
1000 
mg/m2/dose 
Day 29 
See Section 4.8 for 
administration guidelines 
Cytarabine (ARAC) 
IV over 1-30 
minutes or SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.8, Section 5.13 & 
Appendix VII for administration 
guidelines 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
_____mg 
____mg 
_____mg 
_____mg 
 
b,d,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
_____mg 
 
_____mg 
b,c 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b 
--- 
 
 
57 
 
 
 
 
 
 
b 
--- 
 
 
63 
 
 
 
 
 
 
b 
 
 
64 
Start next course (IM CMTX, APPENDIX I-L) on Day 64 or when blood count parameters are met (whichever 
occurs later) 
1 Obtain with each IT administration 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES. 
 
 
Page 2 of 2 

 
 
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 AALL1231 
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Page 186 
 
APPENDIX I-L  
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. Patients need to meet renal and 
hepatic function requirements to initiate methotrexate as described in Section 5.10 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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV 
infusion over 10-
15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 
21, 31 & 41 
See Section 4.7 and Section 
5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 2500 International units/m2/dose Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
--- 
 
 
11 
____mg 
____mg 
 
 
b* 
--- 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
--- 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
--- 
 
 
41 
____mg 
____mg 
 
 
b* 
--- 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Maintenance, Appendix I-M) on Day 57 or when blood count parameters are met 
(whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
 
INTERIM MAINTENANCE (CMTX) – Arm A-VHR  
This IM course is for patients randomized to Arm A-VHR. See Section 4.7 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Page 1 of 1 

 
 
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Page 187 
 
 
 
 
 
 
 
 
 
 
 
 
 
THERAPY DELIVERY MAP – MAINTENANCE ARM A  
(T-ALL and T-LLy) 
 

 
 
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Page 188 
APPENDIX I-M 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL. Only Mercaptopurine and PO Methotrexate will 
be interrupted for myelosuppression as outlined in Section 5.11. This Cycle lasts 12 weeks (84 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, 29 & 57 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE with VS/Wt 
(BSA) 
b. 
CBC/diff/plts 
c. 
CSF cell count & 
cytospin1 
d. 
Bilirubin, ALT, 
creatinine 
e. 
Thiopurine metabolites- 
as clinically indicated 
f. 
Optional 
Banking/Biology 
 
T-LLy ONLY: 
g. 
Chest CT/CXR 
h. 
Abdomen/pelvis CT (or 
MRI) 
i. 
Bone scan 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO (May be 
given IV) 
3 mg/m2/dose  
Days 1-5, 29-33 & 57-61 
Total daily dose: 
6 mg/m2/day, divided BID 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose 
Days 1-84 
See Section 4.14, Section 
5.11 and Appendix VI for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose 
weekly 
Days 8, 15, 22, 29@, 36, 43, 50, 57, 64, 71 
& 78 
 
@NOTE: Omit Day 29 of Cycles 1- 4 for 
SR T-ALL and T-LLy patients and cycles 
1- 2 for IR T-ALL and T-LLy patients 
See Section 5.11 for 
suggested starting 
dose based on TPMT and 
NUDT15 status (if available) 
 
Please note Day 29 
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 
 
&Day 29 of Cycles 1- 4 for SR T-ALL and 
T-LLy patients ONLY.  
 
Day 29 of Cycles 1-2 IR T-ALL and T-
LLy patients ONLY 
Note age-based dosing 
 
Please note Day 29 
Enter Cycle # ________  
Ht_____________cm 
 
Wt____________kg 
 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
_____mg 
DEX 
___mg ___mg 
MP 
____mg 
PO MTX 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1$ 
_____mg 
___mg ___mg 
____mg 
 
____mg 
a,b,c,d 
--- 
 
 
 
5 
 
 
 
 
--- 
 
 
 
8 
 
 
____mg 
 
 
--- 
 
 
 
15 
 
 
____mg 
 
 
--- 
 
 
 
22 
 
 
____mg 
 
 
--- 
 
 
 
29 
_____mg 
___mg ___mg 
____mg@ 
____mg& 
a,b,c 
--- 
 
 
 
33 
 
 
 
 
--- 
 
 
 
36 
 
 
____mg 
 
 
--- 
 
 
 
43 
 
 
____mg 
 
 
--- 
 
 
 
50 
 
 
____mg 
 
 
--- 
 
 
 
57 
_____mg 
___mg ___mg 
____mg 
 
a,b 
--- 
 
 
 
61 
 
 
 
 
--- 
 
 
 
64 
 
 
____mg 
 
 
--- 
 
 
 
71 
 
 
____mg 
 
 
--- 
 
 
 
78 
 
 
____mg 
 
 
--- 
 
 
 
84 
 
 
 
 
f5 (g4,h3,i3)2# 
 
 
85 
Begin next cycle on Day 85 regardless of counts and repeat until two years (for T-ALL girls and all T-LLy pts, regardless of gender) and 
three years (for T-ALL boys) from the start of Interim Maintenance (see Section 4.14). Only MP & PO MTX will be interrupted for 
myelosuppression during subsequent Maintenance cycles as outlined in Section 5.11. 
1 Obtain with each IT administration 
 
2 T-LLy ONLY  
 
3 If baseline is negative, no repeat scans are required. 
4 If CR at end-Consolidation perform a CXR; If PR or NR at end-Consolidation perform chest CT  
5 Collect ONLY if the patient relapses. T-ALL: as a part of AALL08B1 (or APEC14B1 if available to ALL patients) T-LLy: submit via APEC14B1 (if 
enrolled). 
$RADIATION THERAPY (T-ALL:IR CNS3 and all VHR patients, T-LLy:CNS3 only) See Section 16.0 
# Only collect at the completion of therapy. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES.  
 
MAINTENANCE- Arm A 
This Maintenance course is for Arm A. See Section 4.14 for details  
_____________________       _______________ 
            Patient name or initials                   DOB 
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APPENDIX II: THERAPY DELIVERY MAPS – ARM B  (T-ALL 
and T-LLy) 
 

 
 
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APPENDIX II-A  
 
INDUCTION- Arm B (with bortezomib) 
This induction is for all patients randomized to treatment on Arm B (with bortezomib). See Section 4.5 for 
details.  
________________   ______________ 
    Patient name or initials                        DOB 
Patients must complete and sign the appropriate informed consent and undergo bortezomib randomization before starting Induction therapy. 
This Course lasts 5 weeks (35 days) and this Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bortezomib (BOR) 
IND#58443  
IV push over 3-5 
seconds 
1.3 mg/m2/dose 
Days 1, 4, 8 & 11 
At least 72 hours must 
have elapsed between 
doses.  
a. Hx/PE with VS/Wt 
(BSA) CBC/diff/plts 
b. Bilirubin (total and 
direct), ALT, AST 
creatinine 
c. CSF cell count & 
cytospin2 
d. Electrolytes including 
PO4 
e. TPMT and NUDT15 
genotype (if available) 
f. BM MRD 
g. Performance status 
h. Pregnancy test 
i. BM cytomorphology 
j. CXR 
k. Pulse oximetry & Chest 
CXR 7 
l. Cell banking 
T-LLy only 
m. Chest CT 
n. Abdomen/pelvis CT (or 
MRI) 
o. Bone scan 
p. Diagnostic biopsy/ 
cytology 
q. PET scan 
Optional Studies T-ALL ONLY 
Bortezomib Response Study 
(open to Arms A and B): See 
Section 15.1 for details 
r. PB sample (optional) 
s. BM sample (optional) 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
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 lumbar 
puncture (LP)* OR Day 
1 
May give prior to 
randomization 
 
Note age-based dosing 
VinCRIStine (VCR) 
IV Push 
Over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15 & 22 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
Dexamethasone 
(DEX) 
PO (May be given IV) 
 
3 mg/m2/dose 
BID 
Days 1-28 
(no taper) 
Total daily dose: 6 
mg/m2/day, divided BID 
DAUNOrubicin 
(DAUN) 
IV Push/infusion 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, 15 & 22 
 
Pegaspargase  
(PEG-ASP) 
IV over 1-2 hours 
 
2500 International 
units/m2/dose 
Day 4 and 18 
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  
(Days 15 & 22 for 
CNS3 ONLY) 
Note age-based doing 
 
Please note CNS3 
 
 
 
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INDUCTION- Arm B (with bortezomib) 
This induction is for all patients randomized to treatment on Arm B (with bortezomib). See Section 4.5 for 
details. 
________________   ______________ 
    Patient name or initials                        DOB 
 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
BOR 
____mg 
IT ARAC 
____mg 
VCR 
____mg 
DEX 
____mg ____mg 
DAUN 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
-2/-1/0/LP* 
 
____mg 
 
 
 
 
 
(a,b,d,g,h,i,j, m, n, o, 
p)4@ (r)5,^ (f, l)$ 
 
 
1 
____mg 
____mg 
____mg ____mg ____mg 
 
 
a,b,c*,d, e11,k7,q4 
--- 
 
 
 
4 
____mg 
 
 
 
____IU 
(1 dose) 
 
k7 
--- 
 
 
 
8 
____mg 
 
____mg 
____mg 
 
____mg 
a,c, k7 
--- 
 
 
 
11 
____mg 
 
 
 
 
 
k7 
--- 
 
 
 
15 
 
 
____mg 
____mg 
 
____mg# 
a,c#, 
--- 
 
 
 
18 
 
 
 
 
____IU 
(1 dose) 
 
 
--- 
 
 
 
22 
 
 
____mg 
____mg 
 
____mg# 
a,c# 
--- 
 
 
 
29 
 
 
 
 
 
 
____mg a,b,c,f3,i1, (j,m,n9,o 10, 
q12)4  (r, s)5 
 
 
36 
Start next course (Consolidation, Appendix II-B) on Day 36 or when blood count parameters are met (whichever occurs later). 
Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count recovery to 
occur.) 
*On Day 1 OR at the time of diagnostic lumbar puncture (LP) if < than 72 hours from the start of protocol therapy.  
^Pre –treatment   
$ T-ALL: Done as part of AALL08B1 or APEC14B1 T-LLy: If enrolled on APEC14B1, submit as a part of APEC14B1. If not enrolled on 
APEC14B1, submit as part of this protocol (see Section 13.6 for details) 
#CNS3 patients ONLY 
@Baseline 
 
 
1 T-LLy: only if positive at diagnosis 
 
2 Obtain with each IT administration 
3 Optional for T-LLy. Required for T-ALL  
4 T-LLy ONLY  
5 T-ALL ONLY 
6 To be collected at hours 0, 6 and 24 relative to the first dose of bortezomib. See Section 15.1 for details 
7 Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest x-ray 
documented within 12 hours prior to each dose of bortezomib. 
8 follow-up exams only if baseline demonstrates disease 
9 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no repeat scans are 
required. 
10 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. 
11 To be performed any time during Induction 
12 PET scan is recommended but not required at baseline. If a PET is obtained at baseline, PET imaging should be continued with subsequent 
response assessments until patient no longer has PET-avid disease. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES. 
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Page 192 
APPENDIX II-B  
 
CONSOLIDATION Arm-B  
This Consolidation course is for patients on Arm B. See Section 4.6 for details. 
________________   ______________ 
    Patient name or initials                        DOB 
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). Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count 
recovery to occur.) Once Consolidation therapy has begun, interruptions for myelosuppression should occur only at Day 29. Patients with T-
ALL and persistent testicular disease at end-Induction will receive XRT to the testes during Consolidation (a testicular biopsy is required if 
there is any uncertainty regarding the clinical response). Within the first two weeks of Consolidation, testicular radiation therapy will be given 
at 2400 cGy in 12 once-daily fractions of 200 cGy (See Section 16.2). Testicular radiation must be started during Consolidation and should 
be completed before the end of this phase of therapy. This Course lasts 8 weeks (56 days) and this Therapy Delivery Map is on one (2) pages. 
DRUG 
ROUTE DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 8, 15, 22  
 
Omit Days 15 & 
22 for CNS3 
patients ONLY  
Note age-based dosing 
 
Please note CNS3  
a. 
Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
c. CSF cell count & 
cytospin2 
d. Bilirubin (total and direct), 
ALT, AST creatinine 
e. Performance Status 
f. BM MRD1,4 
g. Bone Marrow 
cytomorphology 
 
T-LLy Only 
h. Chest CT/CXR 
i. Abdomen/pelvis CT (or 
MRI), Bone scan, PET 
scan 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Cyclophosphamide 
(CPM) 
IV over 
30-
60 minutes 
1000 mg/m2/dose Days 1 & 29 
See Section 4.6 for admin 
guidelines 
Cytarabine 
(ARAC) 
IV or 
SubQ 
75 mg/m2/dose 
Days 1-4, 8-11, 29-
32 & 36-39 
 
Mercaptopurine 
(MP) 
PO 
60 mg/m2/dose 
Days 1-14 & 29-42 See Section 4.6 and Appendix VI 
for administration guidelines 
VinCRIStine 
(VCR) 
IV Push 
over 
1 min+ 
1.5 mg/m2/dose 
Days 15, 22, 43 & 
50 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
Pegaspargase 
(PEG-ASP) 
IV over  
1-2 hours 
2500 
International 
units/m2/dose 
Days 15 & 43 
Administer through the tubing of 
a freely infusing solution of D5W 
or 0.9% NaCl 
T-ALL patients with biopsy proven testicular disease at end-Induction will receive testicular XRT. See Section 4.4 & Section 16.0 
for additional details. 
 
 
 
 
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CONSOLIDATION Arm-B  
This Consolidation course is for patients on Arm B. See Section 4.6 for details. 
________________   ______________ 
    Patient name or initials                        DOB 
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). Patients with Day 29 marrow M2 or M3 or MRD >5% should start as soon as possible (not wait for Day 36 or count 
recovery to occur.) Once Consolidation therapy has begun, interruptions for myelosuppression should occur only at Day 29. Patients with T-
ALL and persistent testicular disease at end-Induction will receive XRT to the testes during Consolidation (a testicular biopsy is required if 
there is any uncertainty regarding the clinical response). Within the first two weeks of Consolidation, testicular radiation therapy will be given 
at 2400 cGy in 12 once-daily fractions of 200 cGy (See Section 16.2). Testicular radiation must be started during Consolidation and should 
be completed before the end of this phase of therapy. This Course lasts 8 weeks (56 days) and this Therapy Delivery Map is on one (2) pages. 
 
Therapy Delivery Map  
 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
IT MTX 
____mg 
CPM 
____mg 
ARAC 
____mg 
MP 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comme
nts 
 
 
 
CNS3 T-ALL  All other patients  
 
 
 
 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1$ 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
a,b,c,d,e5 
 
 
2 
 
 
 
____mg 
 
 
 
 
 
3 
 
 
 
____mg 
 
 
 
 
 
4 
 
 
 
____mg 
 
 
 
--- 
 
 
 
8 
____mg 
____mg 
 
____mg 
 
 
b,c 
 
 
9 
 
 
 
____mg 
 
 
 
 
 
10 
 
 
 
____mg 
 
 
 
 
 
11 
 
 
 
____mg 
 
 
 
--- 
 
 
 
15 
 
____mg 
 
 
 
____mg 
____IU 
b,c 
--- 
 
 
22 
 
____mg 
 
 
 
____mg 
 
b,c 
--- 
 
 
29 
 
 
____mg 
____mg 
____mg 
 
 
b 
 
 
30 
 
 
 
____mg 
 
 
 
 
 
31 
 
 
 
____mg 
 
 
 
 
 
32 
 
 
 
____mg 
 
 
 
--- 
 
 
 
36 
 
 
 
____mg 
 
 
b 
 
 
37 
 
 
 
____mg 
 
 
 
 
 
38 
 
 
 
____mg 
 
 
 
 
 
39 
 
 
 
____mg 
 
 
 
--- 
 
 
 
42 
 
 
 
 
 
 
 
 
 
43 
 
 
 
 
 
____mg 
____IU 
b 
--- 
 
 
50 
 
 
 
 
 
____mg 
 
b 
--- 
 
 
56 
 
 
 
 
 
 
 
b, g6, (h7,i8)3 
 
 
57 
 
 
 
 
 
 
 
f 1,4 
 
Start next course (Based on Risk Assignment. See Section 4.1.2) on Day 57 or when blood count parameters are met (whichever occurs later). 
1 End of Consolidation bone marrow is not performed on SR T-ALL patients. It is REQUIRED for T-ALL patients with end Induction BM 
MRD ≥ 0.01% ONLY 
2 Obtain with each IT administration  
 
3 T-LLy ONLY   
4 T-ALL only 
 
5 Prior to Day 1 therapy 
6 T-LLy: Only if positive at end Induction. 
7If patient has CR at end-Induction perform a CXR. If PR or NR at end-Induction perform a chest CT 
8 If baseline is negative, no repeat scans are required.  
$ T-ALL and T-LLy patients with persistent testicular disease at end-Induction should receive radiation to the testes during Consolidation. 
See Section 16.2 for details. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE 
CARE GUIDELINES. 
 
 
 
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THERAPY DELIVERY MAPS – ARM B-SR  (T-ALL and T-
LLy) 
 

 
 
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APPENDIX II-C  
 
INTERIM MAINTENANCE with CMTX- Arm B-SR 
This IM course is for patients or assigned to Arm B-SR. See Section 4.7 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. Patients need to meet renal and 
hepatic function requirements to initiate methotrexate as described in Section 5.10. 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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV 
infusion over 10-
15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 
21, 31 & 41 
See Section 4.7 and Section 
5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 2500 International units/m2/dose Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
--- 
 
 
11 
____mg 
____mg 
 
 
b* 
--- 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
--- 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
--- 
 
 
41 
____mg 
____mg 
 
 
b* 
--- 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Appendix II-D) on Day 57 or when blood count parameters are 
met (whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
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APPENDIX II-D  
 
DELAYED INTENSIFICATION Arm B-SR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-
SR (with bortezomib). See Section 4.9 for details 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious 
proven or presumed infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 
75,000/µL. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bortezomib (BOR) 
IND#58443 
IV push over 3-5 seconds 1.3 mg/m2/dose 
Days 1, 4, 15 & 18 
At least 72 hours must have 
elapsed between doses.  
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes including 
PO4 
f. Pulse Oximetry (O2 
saturation) and CXR- 
Patients who develop 
respiratory signs or 
symptoms as defined 
in Section 5.2.2 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 + Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
Dexamethasone 
(DEX) 
PO (May be given IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1,29 & 36 
Note age-based dosing 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
BOR 
____mg 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
Studies 
Comments 
 
 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
 
 
 
1 
____mg 
____mg 
____mg ____mg 
____mg 
 
_____mg 
a,b,c,d,e, f* 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
____mg 
 
 
____IU 
 
f* 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
____mg 
 
____mg 
 
 
b 
--- 
 
 
15 
____mg 
____mg 
____mg ____mg 
____mg 
 
 
b, f* 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
____mg 
 
 
____IU 
 
f* 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
b 
 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
* Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest x-ray documented 
within 12 hours prior to each dose of bortezomib. 
 
 
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DELAYED INTENSIFICATION Arm B-SR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-SR 
(with bortezomib). See Section 4.9 for details 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes 
including PO4 
f. Pulse Oximetry 
(O2 saturation) 
and CXR- Patients 
who develop 
respiratory signs 
or symptoms as 
defined in Section 
5.2.2 
1 Obtain with each 
IT administration 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
Cyclophosphamide 
(CPM) 
IV over 30-
60 minutes 
1000 
mg/m2/dose 
Day 29 
See Section 4.9 for 
administration guidelines 
Cytarabine  
(ARAC) 
IV over 1-30 min or 
SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine  
(TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.9, Section 5.13 
& Appendix VII for 
administration guidelines 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
_____mg 
____mg 
_____mg 
_____mg 
b,d,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
_____mg 
 
_____mg 
b,c 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b 
--- 
 
 
57 
 
 
 
 
 
 
b 
--- 
 
 
63 
 
 
 
 
 
 
b 
 
 
64 
Start next course (Maintenance, Appendix II-M) on Day 64 or when blood count parameters are met (whichever 
occurs later) 
 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
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Page 198 
 
 
 
 
 
 
 
 
 
 
 
THERAPY DELIVERY MAPS – ARM B-IR  (T-ALL and T-
LLy) 
 

 
 
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Page 199 
APPENDIX II-E  
 
INTERIM MAINTENANCE #1 with HDMTX- Arm B-IR 
This IM course is only for patients randomized to Arm B-IR. See Section 4.10 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients receive this block immediately after consolidation and must meet all of the following criteria: Post-consolidation risk assignment must have been 
completed as described in Section 4.1. Start when ANC ≥750/L and platelets ≥75,000/l. Patients need to meet renal and hepatic function requirements to 
initiate methotrexate as described in Section 5.9.1, Section 5.9.2, and Section 5.9.3 This Course lasts 8 weeks (56 days) and this Therapy Delivery 
Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High-Dose Methotrexate 
(HD MTX) 
IV over 24 
hours 
5000 mg/m2/dose 
Days 1, 15, 29 & 
43 
See Section 5.9 & Appendix IV 
for administration guidelines 
Note: 2 stage administration 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
42, 48, and 54 
hours after the 
start of the HD 
MTX infusion 
See Section 5.9 and Appendix 
IV for HD MTX Infusion and 
Leucovorin rescue guidelines. 
VinCRIStine (VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose 
Days 1, 15, 29 & 
43 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
Mercaptopurine (MP) 
PO 
25 mg/m2/dose 
Days 1-56 
See Section 4.10, Section 5.11 
and Appendix VI 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 & 29 
Deliver within 6 hours of the 
start of IV MTX (hr -6 to +6) 
 
Note age-based dosing 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
HD MTX 
____mg 
LCV 
VCR 
____mg 
MP 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
 
____mg 
____mg 
____mg 
a,b*,c 
 
 
2 
 
 
 
 
 
 
 
3 
 
____mg$ 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
--- 
 
 
 
15 
____mg 
 
____mg 
 
b* 
 
 
16 
 
 
 
 
 
 
 
17 
 
____mg$ 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
--- 
 
 
 
29 
____mg 
 
____mg 
____mg 
b*,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
____mg$ 
 
 
 
 
 
32 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
34 
 
 
 
 
 
--- 
 
 
 
43 
____mg 
 
____mg 
 
b* 
 
 
44 
 
 
 
 
 
 
 
45 
 
____mg$ 
 
 
 
 
 
46 
 
 
 
 
 
 
47 
 
 
 
 
 
--- 
 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Appendix II-F) on Day 57 or when blood count parameters are met (whichever occurs later). 
1 Obtain with each IT administration 
 
*To be performed prior to each dose of methotrexate 
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.
Page 1 of 1 

 
 
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Page 200 
APPENDIX II-F 
 
DELAYED INTENSIFICATION Arm B-IR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-IR 
(with bortezomib). See Section 4.9 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious 
proven or presumed infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 
75,000/µL. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bortezomib (BOR) 
IND#58443 
IV push over 3-5 seconds 1.3 mg/m2/dose 
Days 1, 4, 15 & 18 
At least 72 hours must have 
elapsed between doses.  
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes 
including PO4 
f. Pulse Oximetry (O2 
saturation) and 
CXR- Patients 
who develop 
respiratory signs 
or symptoms as 
defined in Section 
5.2.2 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
Dexamethasone 
(DEX) 
PO (May be given IV) 
 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
Pegaspargase 
 (PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
BOR 
____mg 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
Studies 
Comments 
 
 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
 
 
 
1 
____mg 
____mg 
____mg ____mg 
____mg 
 
_____mg 
a,b,c,d,e, f* 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
____mg 
 
 
____IU 
 
f* 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
____mg 
 
____mg 
 
 
b 
--- 
 
 
15 
____mg 
____mg 
____mg ____mg 
____mg 
 
 
b, f* 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
____mg 
 
 
____IU 
 
f* 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
b 
 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
1 Obtain with each IT administration 
 
^ To be performed prior to first dose of bortezomib 
*Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest x-ray 
documented within 12 hours prior to each dose of bortezomib. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE 
GUIDELINES. 
 
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Page 201 
DELAYED INTENSIFICATION Arm B-IR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-IR 
(with bortezomib). See Section 4.9 for details 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes including 
PO4 
f. Pulse Oximetry (O2 
saturation) and CXR- 
Patients who develop 
respiratory signs or 
symptoms as defined 
in Section 5.2.2 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36 
Note age-based dosing 
Cyclophosphamide 
(CPM) 
IV over 30-
60 minutes 
1000 
mg/m2/dose 
Day 29 
See Section 4.9 for 
administration guidelines 
Cytarabine  
(ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine  
(TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.9, Section 5.13 & 
Appendix VII for administration 
guidelines 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
_____mg 
____mg 
_____mg 
_____mg 
b, c,d,e 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
_____mg 
 
_____mg 
b,c,e 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b,e 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b,e 
--- 
 
 
57 
 
 
 
 
 
 
b,e 
--- 
 
 
63 
 
 
 
 
 
 
b,e 
 
 
64 
Start next course (IM#2 , APPENDIX II-G) on Day 64 or when blood count parameters are met (whichever 
occurs later) 
 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE 
GUIDELINES. 
Page 2 of 2 

 
 
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Page 202 
APPENDIX II-G  
 
INTERIM MAINTENANCE #2 with CMTX- Arm B-IR  
This IM course is for patients randomized to Arm B-IR. See Section 4.7 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. Patients need to meet renal and 
hepatic function requirements to initiate methotrexate as described in Section 5.10. 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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV 
infusion over 10-
15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 
21, 31 & 41 
See Section 4.7 and Section 
5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over1-2 hours 2500 International units/m2/dose Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
--- 
 
 
11 
____mg 
____mg 
 
 
b* 
--- 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
--- 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
--- 
 
 
41 
____mg 
____mg 
 
 
b* 
--- 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Maintenance Appendix II-M) on Day 57 or when blood count parameters are met 
(whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
 
 
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Page 203 
 
 
 
 
 
 
 
 
 
 
 
THERAPY DELIVERY MAPS – ARM B-VHR (T-ALL and 
T-LLy) 
 

 
 
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Page 204 
APPENDIX II-H  
 
Intensification Block (1) - Arm B-VHR 
This course is only for patients randomized to treatment on Arm B-VHR. See Section 
4.11 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
T-ALL patients who are M2 or M3 at the end of Consolidation should proceed directly to Intensification Block 1 without waiting for count 
recovery or MRD results to proceed. Patients receive this block immediately after consolidation and must meet all of the following criteria: 
Post-consolidation risk assignment must have been completed as described in Section 4.1. T-ALL only: Begin Intenstification Block #1 after 
collection of end of consolidation bone marrow for MRD. when ANC  ≥750/μL and platelets ≥75,000/μl, and organ function requirements 
are met as definded in Sections 5.9.1, 5.9.2, and 5.9.3, or whichever occurs later. T-LLy only: Start when ANC ≥750/μL and platelets 
≥75,000/μl. This Cycle lasts 21 days and this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) 
PO (May be 
given IV) 
 
10 mg/m2/dose BID 
1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. 
Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
High dose 
methotrexate (HD-
MTX) 
IV 
5000 mg/m2/dose 
Day 1 
See Section 5.9 & Appendix IV for 
administration guidelines 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
Days 3-4 
Minimum of 3 doses given at 42, 48, and 54 
hours after the start of the HD MTX infusion See 
Section 5.9 and Appendix IV for HD MTX 
Infusion and Leucovorin rescue guidelines. 
VinCRIStine (VCR) 
IV push over 1 
min+ 
1.5 mg/m2/dose 
Days 1 & 6 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
Cyclophosphamide 
(CPM) 
IV over 1-
6 hours 
200 mg/m2/dose 
Q12 hrs x5 doses 
Days 2-4 
See Section 4.11 for administration 
guidelines 
High dose cytarabine 
(ARAC) 
IV over 3 
hours  
2000 mg/m2/dose 
Q12 hours x 2 doses 
Day 5 
 
Pegaspargase 
(PEG-ASP) 
 IV over 1-2 
hours 
2500 International 
units/m2/dose 
Day 6 
Administer 3 hours after completion of the 
second HD-AraC infusion through the tubing of a 
freely infusing solution of D5W or 0.9% NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 1 
Note age-based dosing 
 
Delivery within 6 hrs of IV MTX infusion 
Filgrastim (G-CSF) 
SubQ 
5 mcg/kg/dose 
Daily beginning on 
Day 7 
Continue until WBC > 3000/µL  
 
 
 
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Page 205 
Intensification Block (1) - Arm B-VHR 
This course is only for patients randomized to treatment on Arm B-VHR. See Section 
4.11 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg 
IV 
MTX 
____mg 
LCV 
VCR 
____mg 
CPM 
____mg 
ARAC 
____mg 
PEG-ASP 
____IU 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
G-CSF 
____mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
___mg 
___mg 
____mg 
 
____mg 
 
 
 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
a,b,c,d 
 
 
2 
___mg 
___mg 
 
 
 
____mg 
___mg 
 
 
 
 
 
 
 
3 
___mg 
___mg 
 
____mg$ 
 
____mg 
___mg 
 
 
 
 
 
 
 
4 
___mg 
___mg 
 
 
____mg 
 
 
 
 
 
 
 
5 
___mg 
___mg 
 
 
 
 
____mg 
___mg 
 
 
 
 
 
 
6 
 
 
 
____mg 
 
 
____IU 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
____mcg 
b* 
 
 
 
21 
Start next course (Intensification Block 2 Appendix II-I) on Day 22 or when blood count parameters are met (whichever 
occurs later). 
*Every 2 days after completion of chemotherapy until count recovery 
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
 
Page 2 of 2 

 
 
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Page 206 
APPENDIX II-I 
Start Day 1 when ANC ≥750/μL and platelets ≥75,000/μL. This Cycle lasts 21 days and this Therapy Delivery Map is on one (1) page. 
 
 
 
Intensification Block (2) Arm B-VHR 
This course is only for patients randomized to treatment on Arm B-VHR. See Section 4.12 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) PO (May be given IV) 
 
10 mg/m2/dose BID 
1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
High dose 
methotrexate (HD-
MTX) 
IV 
5000 mg/m2/dose 
Day 1 
See Section 5.9 & Appendix IV for 
administration guidelines 
Leucovorin (LCV) 
PO/IV 
15 mg/m2/dose 
Days 3-4 
Minimum of 3 doses given at 42, 48, and 
54 hours after the start of the HD MTX 
infusion See Section 5.9 and Appendix IV 
for HD MTX Infusion and Leucovorin 
rescue guidelines. 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1 & 6 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
Mesna 
IV 
300 mg/m2/dose 
Hour 0, 4, and 8 
from start of each 
ifosfamide infusion 
Days 2-4 
Hydration following ifosfamide 
administration: If patient stops 
methotrexate hydration for whatever 
reason, need to continue until 12 
hours post ifosfamide infusion.  
Ifosfamide (IFOS) 
IV over 1 hr 
800 mg/m2/dose 
Q12 hours x5 
doses 
Days 2-4 
Suggested hydration: Administer 
3000 mL/m2/day (125 mL/m2/hr) 
using fluid containing 0.45% NaCl or 
0.9% NaCl. Achieve urine specific 
gravity < 1.010 and urine output > 3 
mL/kg/hr prior to start of ifosfamide 
Start immediately after HD-MTX 
DAUNOrubicin 
(DAUN) 
IV Push/infusion 
Over 1-15 min 
30 mg/m2/dose 
Day 5 
 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 6 
Administer through the tubing of a 
freely infusing solution of D5W or 
0.9% NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC 
dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 1 
Note age-based dosing 
 
Delivery within 6 hrs of IV MTX 
infusion 
Filgrastim (G-CSF) 
SubQ 
5 mcg/kg/dose 
Daily beginning on Day 7 Continue until WBC > 3000/µL  
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Page 207 
 
Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg 
IV MTX 
____mg 
LCV 
VCR 
____mg 
MESNA 
____mg 
IFOS 
____mg 
DAUN 
____mg 
PEG-ASP 
____IU 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
G-CSF 
____mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
 ___mg 
____mg 
____mg 
 
____mg 
 
 
 
 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
a,b,c,d 
 
 
2 
___mg 
____mg 
 
 
 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
 
 
 
 
 
3 
___mg 
____mg 
 
____mg$ 
 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
 
 
 
 
 
4 
___mg 
____mg 
 
 
____mg 
____mg 
____mg 
 
____mg 
 
 
 
 
 
 
 
5 
___mg 
____mg 
 
 
 
 
 
____mg 
 
 
 
 
 
 
6 
 
 
 
____mg 
 
 
 
____IU 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
____mcg 
b* 
 
 
 
21 
 
Start next course (Intensification Block 3 Appendix II-J) on Day 22 or when blood count parameters are met 
(whichever occurs later). 
*every 2 days after completion of chemotherapy until count recovery 
$Please document the number of doses of leucovorin administered 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
 
 
Intensification Block (2) Arm B-VHR 
This course is only for patients randomized to treatment on Arm B-VHR. See Section 4.12 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Page 2 of 2 

 
 
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Page 208 
 
APPENDIX II-J 
 
This Cycle lasts 21 days and this Therapy Delivery Map is on one (1) page. Start Day 1 when ANC ≥ 750/μL and platelets ≥ 75,000/μL. HR3 lasts 21 days. 
 Enter Cycle # ________  
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
DEX 
___mg  
ARAC 
____mg 
ETOP 
____mg 
PEG-ASP 
____IU 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
G-CSF 
___mcg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
1 
 ___mg 
____mg 
____mg 
____mg 
 
 
 
 
a,b,d 
 
 
2 
___mg 
____mg 
____mg 
____mg 
 
 
 
 
 
 
 
3 
___mg 
____mg 
 
____mg 
____mg 
 
 
 
 
 
 
4 
___mg 
____mg 
 
____mg 
____mg 
 
 
 
 
 
 
5 
___mg 
____mg 
 
____mg 
 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
c 
 
 
6 
 
 
 
____IU 
 
 
 
 
 
7 
 
 
 
 
 
___mcg 
 
 
 
 
21 
 
 
 
 
 
 
T-ALL: b*e 
T-LLy: b*,i, (f,g,h)2 
 
 
 
Start next course (Delayed Intensification Appendix II-K) on Day 22 or when blood count parameters are met 
(whichever occurs later). 
 
1 Obtain with each IT administration 
*every 2 days after completion of chemotherapy until count recovery 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
Intensification Block (3) Arm B-VHR 
This course is only for patients randomized to treatment on Arm B-VHR. See Section 
4.13 for details.  
____________________________ 
Patient name or initials 
____________________________ 
DOB 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexamethasone (DEX) PO (May be given IV) 
 
10 mg/m2/dose 
BID 
1-5 
Total daily dose: 
20 mg/m2/day, divided BID 
a. 
Hx/PE with 
VS/Wt (BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
 
T-ALL ONLY 
e. BM MRD 
 
T-LLy ONLY: 
f. 
Chest CT/CXR2 
g. 
Abdomen/pelvis 
CT (or MRI)2 
h. 
Bone scan2 
i. 
Diagnostic 
biopsy/cytology4 
 
 
2 See Section 7.0 for 
details 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
High dose cytarabine 
(ARAC) 
IV 
2000 
mg/m2/dose Q12 
hours x 4 doses 
Days 1-2 
 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Q12 hours x5 
doses 
Days 3-5 
See Section 4.13 for 
administration guidelines 
Pegaspargase  
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 6 
Administer through the tubing 
of a freely infusing solution of 
D5W or 0.9% NaCl 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX and HC 
dosing: 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
ARAC dosing: 
Age (yrs) Dose 
1 – 1.99 
16 mg 
2 – 2.99 
20 mg 
3 – 8.99 
24 mg 
≥ 9 
30 mg 
Day 5 
Note age-based dosing 
 
Filgrastim (G-CSF) 
SubQ 
5 mcg /kg/dose 
Daily beginning on Day 7 
Continue until WBC 
> 3000/µL  
Page 1 of 1 

 
 
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Page 209 
APPENDIX II-K  
DELAYED INTENSIFICATION- Arm B-VHR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-VHR (with 
bortezomib). See Section 4.9 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients receive this block immediately after HR Intensification 3 and must meet all of the following criteria: VHR T-ALL Post-HR Intensification Block 3 MRD was completed 
and demonstrated undetectable MRD as described in Section 4.13 Start 7 days after collection of HR Intensification Block 3 bone marrow for MRD or when ANC ≥750/L and 
platelets ≥75,000/l, whichever occurs later. VHR T-LLy: Post-HR Intensification Block 3 disease evaluation was completed and demonstrated a radiographic CR OR a 
radiographic PR and a biopsy showing no residual disease as described in Section 10.4 Start when ANC ≥750/L and platelets ≥75,000/l All patients: Once Delayed 
Intensification has begun, it may be interrupted for myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the Day 1 therapy or Day 29 
cyclophosphamide has been given, the remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for 
patients with serious proven or presumed infection and resumed when the signs of infection have abated. Hold Day 29 chemotherapy until ANC ≥ 750/µL and platelets ≥ 
75,000/µL. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bortezomib (BOR) 
IND#58443 
IV push over 3-5 seconds 1.3 mg/m2/dose 
Days 1, 4, 15 & 18 
At least 72 hours must 
have elapsed between 
doses.  
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes including 
PO4 
f. Pulse Oximetry (O2 
saturation) and 
CXR- Patients who 
develop respiratory 
signs or symptoms 
as defined in Section 
5.2.2 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
Dexamethasone 
(DEX) 
PO (May be given IV) 
 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 1-15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
 
Pegaspargase 
 (PEG-ASP) 
IV over 1-2 hours 
2500 International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 & 36  
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
BOR 
____mg 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
Studies 
Comments 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
____mg 
____mg ____mg 
____mg 
 
_____mg 
a,b,c,d,e, f* 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
____mg 
 
 
____IU 
 
f* 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
____mg 
 
____mg 
 
 
b 
 
 
 
15 
____mg 
____mg 
____mg ____mg 
____mg 
 
 
b, f* 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
____mg 
 
 
____IU 
 
f* 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
b 
This therapy delivery map continues on the next page with Day 29. 
1 Obtain with each IT administration 
* Patients who develop respiratory signs or symptoms as defined in Section 5.2.2 should have pulse oximetry (02 saturation) and Chest x-
ray documented within 12 hours prior to each dose of bortezomib. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES. 
Page 1 of 2 

 
 
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Page 210 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts  
c. CSF cell count & 
cytospin1 
d. Bilirubin, ALT, 
creatinine 
e. Electrolytes including 
PO4 
f. Pulse Oximetry (O2 
saturation) and CXR- 
Patients who develop 
respiratory signs or 
symptoms as defined 
in Section 5.2.2 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 
2500 
International 
units/m2/dose 
Day 4, 18, & 43 
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 1, 29 &36 
Note age-based dosing 
Cyclophosphamide 
(CPM) 
IV over 30-
60 minutes 
1000 
mg/m2/dose 
Day 29 
See Section 4.9 for 
administration guidelines 
Cytarabine (ARAC) 
IV over 1-30 min or 
SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 29-42  
See Section 4.9, Section 5.13 & 
Appendix VII for 
administration guidelines  
 
Therapy Delivery Map   
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
CPM 
____mg 
ARAC 
_____mg 
TG 
_____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
_____mg 
____mg 
_____mg 
_____mg 
b,d,c 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
--- 
 
 
 
36 
 
 
_____mg  
 
_____mg 
b,c 
 
 
37 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
44 
 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
b 
--- 
 
 
57 
 
 
 
 
 
 
b 
--- 
 
 
63 
 
 
 
 
 
 
b 
 
 
64 
Start next course (IM CMTX, APPENDIX II-L) on Day 64 or when blood count parameters are met (whichever 
occurs later) 
 
1 Obtain with each IT administration 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE 
GUIDELINES. 
 
 
DELAYED INTENSIFICATION- Arm B-VHR (with bortezomib) 
This Delayed Intensification (DI) course is for patients randomized to treatment on Arm B-VHR 
(with bortezomib). See Section 4.9 for details 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Page 2 of 2 

 
 
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Page 211 
APPENDIX II-L  
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. Patients need to meet renal and 
hepatic function requirements to initiate methotrexate as described in Section 5.10. 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 of 2 mg 
a. Hx/PE with VS/Wt 
(BSA) 
b. CBC/diff/plts 
Bilirubin, ALT, 
creatinine 
c. CSF cell count & 
cytospin1 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Methotrexate 
(CMTX) 
IV push over 2-5 
mins or IV 
infusion over 10-
15 mins 
Starting dose is 100 mg/m2 
escalate by 50 mg/m2/dose 
 
Days 1, 11, 
21, 31 & 41 
See Section 4.7 & Section 
5.10 for details 
Pegaspargase 
(PEG-ASP) 
IV over 1-2 hours 2500 International units/m2/dose Days 2 & 22 
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 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a,b*,c 
 
 
2 
 
 
____IU 
 
 
 
 
 
11 
____mg 
____mg 
 
 
b* 
 
 
 
21 
____mg 
____mg 
 
 
b* 
 
 
22 
 
 
____IU 
 
 
 
 
 
31 
____mg 
____mg 
 
____mg 
b*,c 
 
 
 
41 
____mg 
____mg 
 
 
b* 
 
 
 
56 
 
 
 
 
 
 
 
57 
Start next course (Maintenance Appendix II-M) on Day 57 or when blood count parameters are met 
(whichever occurs later). 
1 Obtain with each IT administration 
*To be performed prior to each dose of methotrexate 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR 
SUPPORTIVE CARE GUIDELINES. 
 
 
INTERIM MAINTENANCE (CMTX) – Arm B-VHR 
This IM course is for patients randomized to Arm B-VHR. See Section 4.7 for details 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
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THERAPY DELIVERY MAP – MAINTENANCE ARM B  
(T-ALL and T-LLy) 
 

 
 
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Page 213 
APPENDIX II-M 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL. Only Mercaptopurine and PO Methotrexate will 
be interrupted for myelosuppression as outlined in Section 5.11. This Cycle lasts 12 weeks (84 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, 29 & 57 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE with VS/Wt (BSA) 
b. 
CBC/diff/plts 
c. 
CSF cell count & 
cytospin1 
d. 
Bilirubin, ALT, creatinine 
e. 
Thiopurine metabolites- as 
clinically indicated 
f. 
Optional Banking/Biology 
 
T-LLy ONLY: 
g. 
Chest CT/CXR 
h. 
Abdomen/pelvis CT 
i. 
Bone scan 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Dexamethasone 
(DEX) 
PO (May be 
given IV) 
3 mg/m2/dose  
Days 1-5, 29-33 & 57-61 
Total daily dose: 
6 mg/m2/day, divided BID 
Mercaptopurine 
(MP) 
PO 
75 mg/m2/dose 
Days 1-84 
See Section 4.14, Section 
5.11 and Appendix VI for 
administration guidelines 
Methotrexate 
(MTX) 
PO 
20 mg/m2/dose 
weekly 
Days 8, 15, 22, 29@, 36, 43, 50, 57, 
64, 71 & 78 
 
@NOTE: Omit Day 29 of Cycles 1- 4 for 
SR T-ALL and T-LLy patients and cycles 
1- 2 for IR T-ALL and T-LLy patients 
see Section 5.11 for suggested 
starting 
dose based on TPMT and 
NUDT15 status (if available) 
 
Please note Day 29 
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 
 
&Day 29 of Cycles 1- 4 for SR T-
ALL and T-LLy patients ONLY.  
 
Day 29 of Cycles 1-2 IR T-ALL and 
T-LLy patients ONLY 
Note age-based dosing 
 
Please note Day 29 
Enter Cycle # ________  
Ht_____________cm 
 
Wt____________kg 
 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
_____mg 
DEX 
___mg ___mg 
MP 
____mg 
PO MTX 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1$ 
_____mg 
___mg ___mg 
____mg 
 
____mg 
a,b,c,d 
--- 
 
 
 
5 
 
 
 
 
--- 
 
 
 
8 
 
 
____mg 
 
 
--- 
 
 
 
15 
 
 
____mg 
 
 
--- 
 
 
 
22 
 
 
____mg 
 
 
--- 
 
 
 
29 
_____mg 
___mg ___mg 
____mg@ 
____mg& 
a,b,c 
--- 
 
 
 
33 
 
 
 
 
--- 
 
 
 
36 
 
 
____mg 
 
 
--- 
 
 
 
43 
 
 
____mg 
 
 
--- 
 
 
 
50 
 
 
____mg 
 
 
--- 
 
 
 
57 
_____mg 
___mg ___mg 
____mg 
 
a,b 
--- 
 
 
 
61 
 
 
 
 
--- 
 
 
 
64 
 
 
____mg 
 
 
--- 
 
 
 
71 
 
 
____mg 
 
 
--- 
 
 
 
78 
 
 
____mg 
 
 
--- 
 
 
 
84 
 
 
 
 
f5 (g4,h3,i3)2# 
 
 
85 
Begin next cycle on Day 85 regardless of counts and repeat until two years (for T-ALL girls and all T-LLy pts, regardless of gender) and three 
years (for T-ALL boys) from the start of Interim Maintenance (see Section 4.14). Only MP & PO MTX will be interrupted for myelosuppression 
during subsequent Maintenance cycles as outlined in Section 5.11 
1 Obtain with each IT administration  
2 T-LLy ONLY  
 
3 If baseline is negative, no repeat scans are required. 
4 If CR at end-Consolidation perform a CXR; If PR or NR at end-Consolidation perform chest CT at completion of Maintenance therapy. 
5 Collect ONLY if the patient relapses. T-ALL: as a part of AALL08B1 (or APEC14B1 if available to ALL patients) T-LLy: submit via APEC14B1 
(if enrolled). 
$RADIATION THERAPY (T-ALL:IR CNS3 and all VHR patients, T-LLy:CNS3 only) See Section 16.0 
# Only collect at the completion of therapy. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES
MAINTENANCE- Arm B 
This Maintenance course is for Arm B. See Section 4.14 for details 
_________________________     _______________ 
Patient name or initials                    DOB 
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Page 214 
APPENDIX III: YOUTH INFORMATION SHEETS  
INFORMATION SHEET REGARDING RESEARCH STUDY AALL1231 FOR PATIENTS 
WITH T-ALL 
(for children from 7 through 12 years of age) 
 
A Study of Bortezomib in Children with Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) 
  
1. We have been talking with you about a type of cancer called T-lymphoblastic leukemia or T-ALL. T-
ALL is a type of cancer that only affects T-cells (a special kind of cell of your immune system). T-cell 
ALL 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 T-ALL. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are trying to 
learn more about how to treat T-ALL. We will do this by comparing 2 ways to treat T-ALL. Some of 
the children and teens in this study will get the usual treatment for T-ALL. Some of the children and 
teens will get the usual treatment plus a drug called bortezomib. In this study bortezomib is 
experimental, but is approved by the FDA to treat other conditions. The chemotherapy you get will be 
decided by chance, like flipping a coin for “heads” or “tails”. We don’t know which way is better. That 
is why we are doing this study. 
 
3. Children and teens that are part of this study will be treated with chemotherapy. Chemotherapy is a 
type of medicine that destroys cancer cells. 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 T-
ALL is responding to treatment. 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 keeping the cancer away 
for as long as possible, but we don’t know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called ‘risks’. The risks to you from this study are 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. 
It is also possible that your treatment plan may increase the side effects of treatment without improving 
the chances of getting rid of the cancer for as long as possible.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if there 
are ways to tell how the cancer will respond to treatment. Almost all of these samples will be taken 
when other standard blood tests and bone marrow tests are done. If there is any blood or bone marrow 
left over from tests done for this study, we would like to save them for other research tests in the future. 
You can still take part in this study even if you do not allow us to collect the extra blood or bone marrow 
samples or save the leftover samples for research.  
 

 
 
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Page 215 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL1231 FOR PATIENTS 
WITH T-ALL 
(for teens from 13 through 17 years of age) 
 
A Study of Bortezomib in Children with Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL)  
 
1. We have been talking with you about a type of cancer called T-lymphoblastic leukemia or T-ALL. 
T-ALL is a type of cancer that only affects T-cells (a special kind of cell of your immune system). 
T-cell ALL 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 T-ALL. A research study is 
when doctors work together to try out new ways to help people who are sick. In this study, we are 
trying to learn more about how to treat T-ALL. We will do this by comparing 2 ways to treat T-
ALL. Some of the children and teens in this study will get the usual treatment for T-ALL. Some of 
the children and teens will get the usual treatment plus a drug called bortezomib. In this study 
bortezomib is experimental, but is approved by the FDA to treat other conditions. The 
chemotherapy you get will be decided by chance, like flipping a coin for “heads” or “tails”. We 
don’t know which way is better. That is why we are doing this study. 
 
3. Children and teens that are part of this study will be treated with chemotherapy. Chemotherapy is 
a type of medicine that destroys cancer cells. 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 T-ALL is responding to treatment. 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 keeping the cancer 
away for as long as possible, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called ‘risks’. The risks to you from this study are 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. It is also possible that adding bortezomib to your treatment plan may increase the 
side effects of treatment without improving the chances of getting rid of the cancer for as long as 
possible. Adding bortezomib to your treatment plan could also reduce how well your treatment 
works. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if 
there are ways to tell how the cancer will respond to treatment. Almost all of these samples will be 
taken when other standard blood tests and bone marrow tests are done. If there is any blood or bone 
marrow left over from tests done for this study, we would like to save them for other research tests 
in the future. You can still take part in this study even if you do not allow us to collect the extra 
blood or bone marrow samples or save the leftover samples for research.  
 

 
 
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Page 216 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL1231 FOR PATIENTS 
WITH T-LLy 
(for children from 7 through 12 years of age) 
A Study of Bortezomib in Children with Newly Diagnosed T-Lymphoblastic Lymphoma (T-LLy) 
 
1. We have been talking with you about a type of cancer called T-lymphoblastic lymphoma or  
T-LLy. T-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 become cancerous when a subject has lymphoma. 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 T-LLy. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are trying to 
learn more about how to treat T-LLy. We will do this by comparing 2 ways to treat T-LLy. Some of 
the children and teens in this study will get the usual treatment for T-LLy. Some of the children and 
teens will get the usual treatment plus a drug called bortezomib. In this study bortezomib is 
experimental, but is approved by the FDA to treat other conditions. The chemotherapy you get will be 
decided by chance, like flipping a coin for “heads” or “tails”. We don’t know which way is better. That 
is why we are doing this study. 
 
3. Children and teens that are part of this study will be treated with chemotherapy. Chemotherapy is a 
type of medicine that destroys cancer cells. 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 T-
LLy is responding to treatment. 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 keeping the cancer away 
for as long as possible, but we don’t know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called ‘risks’. The risks to you from this study are 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. 
It is also possible that your treatment plan may increase the side effects of treatment without improving 
the chances of getting rid of the cancer for as long as possible.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if there 
are ways to tell how the cancer will respond to treatment. Almost all of these samples will be taken 
when other standard blood tests and bone marrow tests are done. If there is any blood or bone marrow 
left over from tests done for this study, we would like to save them for other research tests in the 
future. You can still take part in this study even if you do not allow us to collect the extra blood or 
bone marrow samples or save the leftover samples for research.  
 

 
 
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Page 217 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL1231 FOR PATIENTS 
WITH T- LLy 
(for teens from 13 through 17 years of age) 
 
A Study of Bortezomib in Children with Newly Diagnosed T-Lymphoblastic Lymphoma (T-LLy) 
 
1. We have been talking with you about a type of cancer called T-lymphoblastic lymphoma or  
T-LLy. T-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 become cancerous when a subject has 
lymphoma. 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 T-LLy. A research study is 
when doctors work together to try out new ways to help people who are sick. In this study, we are 
trying to learn more about how to treat T-LLy. We will do this by comparing 2 ways to treat T-
LLy. Some of the children and teens in this study will get the usual treatment for T-LLy. Some of 
the children and teens will get the usual treatment plus a drug called bortezomib. In this study, 
bortezomib is experimental, but is approved by the FDA to treat other conditions. The 
chemotherapy you get will be decided by chance, like flipping a coin for “heads” or “tails”. We 
don’t know which way is better. That is why we are doing this study. 
 
3. Children and teens that are part of this study will be treated with chemotherapy. Chemotherapy is 
a type of medicine that destroys cancer cells. 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 T-LLy is responding to treatment. 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 keeping the cancer 
away for as long as possible, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called ‘risks’. The risks to you from this study are 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. It is also possible that adding bortezomib to your treatment plan may increase the 
side effects of treatment without improving the chances of getting rid of the cancer for as long as 
possible. Adding bortezomib to your treatment plan could also reduce how well your treatment 
works. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if 
there are ways to tell how the cancer will respond to treatment. Almost all of these samples will 
be taken when other standard blood tests and bone marrow tests are done. If there is any blood or 
bone marrow left over from tests done for this study, we would like to save them for other 
research tests in the future. You can still take part in this study even if you do not allow us to 
collect the extra blood or bone marrow samples or save the leftover samples for research.  

 
 
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Version Date: 5/29/19  
 
 
 
 
 
 
Page 218 
Draw 24-hr MTX level 
& Creatinine 
 
MTX <150 µM 
MTX >150 µM 
or 
Cr > 125% baseline 
Draw 36-hr MTX level++ 
(& Creatinine) 
MTX >3 µM 
MTX >10 µM 
Consider glucarpidase 
Increase hydration 
to 200 mL/m2/hr 
Draw MTX level (& Creatinine) 
at Hr 42++ & Hr 48 
Continue standard hydration 
(i.e. @ 125 mL/m2/hr) 
MTX <3 µM 
Hr 42 ≤1 µM 
  
Hr 48 ≤0.4 µM 
LCV 15 mg/m2 at 
hrs 42, 48, & 54, 
then stop LCV 
 
- No further MTX 
levels required 
LCV 15 mg/m2 at 
hrs 42, 48, & 54 and 
continue q6hrs until 
MTX level < 0.1 
µM 
 
- Repeat MTX 
levels q12-24 hrs 
Hr 42 = 10-19.9 µM 
  
Hr 48 = 6-9.9 µM 
Hr 42 = 20-200 µM 
  
Hr 48 = 10-100 µM 
Hr 42 >200 µM 
   
Hr 48 >100 µM 
Hr 42 = 1.01-9.9 µM 
 
Hr 48 = 0.41-5.9 µM 
LCV 15 mg/m2 
starting at hr 42 and 
continue q3hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
LCV 100 mg/m2 
starting at hr 42 and 
continue q6hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
LCV 1000 mg/m2 
starting at hr 42 and 
continue q6hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
++ 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 ≤1 and/or 
≤ 0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine output remains satisfactory. 
Consider repeat 
MTX level to r/o 
contamination. 
Increase 
hydration while 
awaiting result  
APPENDIX IV: HIGH-DOSE METHOTREXATE FLOWCHART 
(Please refer to Section 5.9 for complete details; all levels are timed from the start of the 
HDMTX infusion) 
 
 
 
 
 
 

 
 
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APPENDIX V: CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical references. 
 
 
CYP3A4 substrates  
Strong 
Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil4,5   
amiodarone4 
aprepitant/fosaprepitant5 
benzodiazepines 
bortezomib 
brentuximab 
budesonide5 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
glucocorticoids2 
conivaptan5 
crizotinib 
cyclosporine4 
cyclophosphamide  
dapsone 
darifenacin5 
darunavir 
dasatinib5 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine4 
erlotinib 
esomeprazole 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
fosaprepitant 
gefitinib 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors5 
ifosfamide 
imatinib 
indinavir5 
irinotecan  
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
conivaptan 
delavirdine 
grapefruit3 
grapefruit juice3 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
atazanavir 
cimetidine 
conivaptan 
crizotinib 
cyclosporine  
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fluvoxamine 
fosamprenavir 
fosaprepitant 
grapefruit3 
grapefruit 
juice3 
imatinib 
mifepristone 
nilotinib 
verapamil 
alprazolam 
amiodarone  
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
ciprofloxacin 
cyclosporine 
fluvoxamine 
isoniazid 
nicardipine 
propofol 
quinidine 
sertraline 
tacrolimus 
ranolazine 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
echinacea 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids2 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 

 
 
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ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam 
modafinil 
monteleukast 
nefazodone 
nilotinib 
nisoldipine5 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quetiapine5 
quinidine  
saquinavir5 
sildenafil 
simvastatin5 
sirolimus4,5 
sunitinib 
tacrolimus4,5 
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vinca alkaloids 
zolpidem 
1Certain fruits and fruit juices (star fruit, Seville oranges, pomegranate, ginko, goldenseal) may inhibit 
CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 6.5 and 6.9 regarding use of corticosteroids. 
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and 
is concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates 
 
 
 

 
 
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Page 221 
 
APPENDIX VI: MERCAPTOPURINE DOSING TABLE 
Note: The Mercaptopurine dosing nomograms in this appendix only apply to the tablet formulation. 
 
 
MERCAPTOPURINE 25 mg/m2 
 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly 
Dose 
0.36 - 0.49 
½ tab / d x 3 
75 mg/wk 
0.50 - 0.64 
½ tab / d x 4 
100 mg/wk 
0.65 - 0.78 
½ tab / d x 5 
125 mg/wk 
0.79 - 0.92 
½ tab / d x 6 
150 mg/wk 
0.93 – 1.07 
½ tab / d x 7 
175 mg/wk 
1.08 – 1.21 
1 tab / d x 1; ½ tab / d x 6 
200 mg/wk 
1.22 – 1.35 
1 tab / d x 2; ½ tab / d x 5 
225 mg/wk 
1.36 – 1.49 
1 tab / d x 3; ½ tab / d x 4 
250 mg/wk 
1.50 – 1.64 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
1.65 – 1.78 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
1.79 – 1.92 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
1.93 – 2.07 
1 tab / d x 7 
350 mg/wk 
2.08 – 2.21 
1½ tab / d x 1; 1 tab / d x 6 
375 mg/wk 
2.22 - 2.35 
1½ tab / d x 2; 1 tab / d x 5 
400 mg/wk 
2.36 – 2.49 
1½ tab / d x 3; 1 tab / d x 4 
425 mg/wk 
2.50 – 2.64 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
2.65 – 2.78 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
2.79 – 2.92 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
2.93 – 3.00* 
1½ tab / d x 7 
525 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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Page 222 
MERCAPTOPURINE 60 mg/m2 
 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly 
Dose 
0.33 - 0.38 
½ tab / d x 6 
150 mg/wk 
0.39 - 0.44 
½ tab / d x 7 
175 mg/wk 
0.45 - 0.50 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.51 - 0.56 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.57 - 0.62 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.63 - 0.68 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.69 - 0.74 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.75 - 0.80 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.81 - 0.86 
1 tab / d x 7 
350 mg/wk 
0.87 - 0.92 
1 tab / d x 6; 1½ tab / d x 1 
375 mg/wk 
0.93 - 0.98 
1 tab / d x 5; 1½ tab / d x 2 
400 mg/wk 
0.99 - 1.04 
1 tab / d x 4; 1½ tab / d x 3 
425 mg/wk 
1.05 - 1.10 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
1.11 - 1.16 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
1.17 - 1.22 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
1.23 - 1.27 
1½ tab / d x 7 
525 mg/wk 
1.28 - 1.33 
1½ tab / d x 6; 2 tab / d x 1 
550 mg/wk 
1.34 - 1.39 
1½ tab / d x 5; 2 tab / d x 2 
575 mg/wk 
1.40 - 1.45 
1½ tab / d x 4; 2 tab / d x 3 
600 mg/wk 
1.46 - 1.51 
2 tab / d x 4; 1½ tab / d x 3 
625 mg/wk 
1.52 - 1.57 
2 tab / d x 5; 1½ tab / d x 2 
650 mg/wk 
1.58 - 1.63 
2 tab / d x 6; 1½ tab / d x 1 
675 mg/wk 
1.64 - 1.69 
2 tab / d x 7 
700 mg/wk 
1.70 - 1.75 
2 tab / d x 6; 2½ tab / d x 1 
725 mg/wk 

 
 
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1.76 - 1.81 
2 tab / d x 5; 2½ tab / d x 2 
750 mg/wk 
1.82 - 1.87 
2 tab / d x 4; 2½ tab / d x 3 
775 mg/wk 
1.88 - 1.93 
2½ tab / d x 4; 2 tab / d x 3 
800 mg/wk 
1.94 - 1.99 
2½ tab / d x 5; 2 tab / d x 2 
825 mg/wk 
2.00 - 2.05 
2½ tab / d x 6; 2 tab / d x 1 
850 mg/wk 
2.06 - 2.11 
2½ tab/ d x 7 
875 mg/wk 
2.12 - 2.17 
2½ tab/ d x 6; 3 tab / d x 1 
900 mg/wk 
2.18 - 2.23 
2½ tab/ d x 5; 3 tab / d x 2 
925 mg/wk 
2.24 - 2.29 
2½ tab/ d x 4; 3 tab / d x 3 
950 mg/wk 
2.30 - 2.35 
3 tab/ d x 4; 2½ tab / d x 3 
975 mg/wk 
2.36 - 2.41 
3 tab/ d x 5; 2½ tab / d x 2 
1000 mg/wk 
2.42 - 2.47 
3 tab/ d x 6; 2½ tab / d x 1 
1025 mg/wk 
2.48 - 2.52 
3 tab/ d x 7 
1050 mg/wk 
2.53 - 2.58 
3 tab/ d x 6; 3½ tab / d x 1 
1075 mg/wk 
2.59 - 2.64 
3 tab/ d x 5; 3½ tab / d x 2 
1100 mg/wk 
2.65 - 2.70 
3 tab/ d x 4; 3½ tab / d x 3 
1125 mg/wk 
2.71 - 2.76 
3½ tab/ d x 4; 3 tab / d x 3 
1150 mg/wk 
2.77 - 2.82 
3½ tab/ d x 5; 3 tab / d x 2 
1175 mg/wk 
2.83 - 2.88 
3½ tab/ d x 6; 3 tab / d x 1 
1200 mg/wk 
2.89 - 2.94 
3½ tab/ d x 7 
1225 mg/wk 
2.95 - 3.00 
3½ tab/ d x 6; 4 tab / d x 1 
1250 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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Page 224 
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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Page 225 
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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Page 226 
APPENDIX VII: THIOGUANINE DOSING TABLE 
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 

 
 
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2.31 – 2.35 
3½ tab / d x 7 
980 mg/wk 
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 VIII: STAGING CLASSIFICATION OF CHILDHOOD NON-HODGKIN 
LYMPHOMA 
Modified from Murphy [Seminars in Oncology (1980) 7; 332-339] 
 
Stage 
Criteria for Extent of Disease 
 
Localized 
 
I 
A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of 
mediastinum or abdomen 
 
 
II 
A single tumor (extranodal) with regional node involvement 
 
 
Disseminated 
 
III 
Two single tumors (extranodal) on opposite sides of the diaphragm. 
 
Two or more nodal areas above and below the diaphragm. 
 
All primary intra-thoracic tumors (mediastinal, pleural, thymic) 
 
All extensive primary intra-abdominal disease. 
 
All paraspinal or epidural tumors, regardless of other tumor site(s) 
 
 
IV 
Any of the above with initial CNS and/or bone marrow involvement 
 
Enumeration of Number of Regions of Nodal Involvement 
Each of these twenty regions is counted separately for purposes of determining number of sites of involvement.  
 
Peripheral Regions 
Right neck; cervical, supraclavicular, occipital, and pre-auricular 
Left neck; cervical, supraclavicular, occipital, and pre-auricular 
Right infraclavicular 
Left infraclavicular 
Right axilla and pectoral 
Left axilla and pectoral 
Right epitrochlear and brachial 
Left epitrochlear and brachial 
 
 
 

 
 
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APPENDIX IX: MINIMAL RESIDUAL DISEASE-SAMPLE SHIPPING REQUIREMENTS 
MRD samples will be shipped to the COG ALL Reference Flow Cytometry Lab using the shipping and 
handling requirements below. 
 
Samples are to be shipped to Dr. Brent Wood at the University of Washington, Flow Cytometry Laboratory. 
The AALL1231 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. Because clinical 
recommendations will be made on these samples, always include the patient’s name, birth date and COG 
number on any sample submitted. This is a CLIA requirement. COG ALL Reference Laboratories may be 
unable to analyze specimens if adequate patient identifiers are not provided. 
 
Samples for the Reference Laboratories are to be 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 following link: 
 
https://ricapps.nationwidechildrens.org/KitManagement/ 
 
Select ‘AALL08B1’ from the protocol list to order the shipping tubes required for MRD samples. 
 
Bone Marrow Collection Procedures for Reference Laboratories: 
a. Collect 1-2 ml of BM from the 1st pull into a syringe and transfer the specimen immediately into 
the 15 mL shipping media conical tube with RPMI/EDTA. Collection of marrow volumes beyond 
2 ml or use of marrow other than the 1st pull will result in hemodilution and may effect quantitation 
of MRD. 
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 enhanced in the shipping media 
tubes. 
c. 1-2 mL of BM will be sufficient for analysis either at diagnosis or following therapy. 
 
16.1.2 Sample Shipping 
Bone marrow samples for MRD studies will be shipped to one place: 
 
Western Flow Cytometry Reference Laboratory 
Brent Wood, MD, PhD 
Seattle Cancer Care Alliance 
Hematopathology Laboratory, Room G7-800 
825 Eastlake Ave. E. 
Seattle, WA 98109-1028 
Phone: 206-288-7060 
FAX: 206-288-7127 
 
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 TWO PATIENT IDENTIFIERS, INCLUDING THE NAME AND THE COG 

 
 
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NUMBER. IN ADDITION, AN AALL1231 SPECIMEN TRANSMITTAL FORM AVAILABLE IN 
RAVE SHOULD ALWAYS BE SUBMITTED WITH EACH SAMPLE. 
 
Call Reference Laboratories 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 
 
 
 
 

 
 
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APPENDIX X: EVALUATING MECHANISMS OF BORTEZOMIB RESPONSE AND 
RESISTANCE IN T-ALL AND IDENTIFYING BIOMARKERS AND MECHANISMS OF 
CHEMOTHERAPY RESISTANCE AND RESPONSE IN T-ALL, FOCUSING ON ETP ALL 
Eligible samples: 
 
All pre-treatment bone marrow samples from both arms of the study (Arm A and Arm B) are eligible. 
Peripheral blood samples should be sent to the Horton lab only if the patient samples meet the following 
criteria: 
 
Eligible patients must have an initial absolute blast count of at least 1000 lymphoblasts/µL. To calculate 
the absolute blast percentage, multiply the total WBC by the % peripheral blasts: 
 
(WBC)(% blast)(1000) = absolute blast count/µL 
 
As an example, if the patient has a WBC of 10 and 50% blasts, the absolute blast count is:  
(10)(.5)(1000) = 5000/µL 
 
If the initial % blasts is unknown, send peripheral blood samples only if the total WBC is more than 10,000 
cell/L and notify the Horton lab of the % blast as soon as available (contact information provided below). 
 
Samples must be received by the Horton lab no later than 72h after collection. Bone marrow and 
peripheral blood samples can be batched if they will arrive within 72h. If samples will not arrive within 
72h, please send the bone marrow separately from peripheral blood samples. Day 1 peripheral blood 
samples should be shipped together. The Horton lab can accept Saturday shipments if we are contacted 
ahead of time. Please contact Gaye Jenkins or other Horton lab representative (832-824-4676) for 
alternative address and shipping information for Saturday delivery. 
 
Sample collection time points: 
 
 
On -study 
 Day 1, Hour 0 
Day 1, Hour 6 
Day 1, Hour 24 End of 
Induction 
Bone 
Marrow 
(Induction 
only)  
5 mL* 
(peripheral 
blood can be 
substituted if 
>80% blasts) # 
 
 
 
5 ml* 
(peripheral 
blood can be 
substituted if 
>30% blasts) 
Peripheral 
Blood 
(Induction 
only) 
 
5 mL* 
(before start of 
systemic 
chemotherapy) 
 
 
5 mL*  
(6h following 
the start of 
systemic 
chemotherapy) 
5 mL* 
(24h following 
the start of 
systemic 
chemotherapy) 
5 mL*  
(same day as 
end of 
induction  
bone marrow) 
# If the blast count is <80% and bone marrow is not available, please call Dr. Horton or 
Gaye Jenkins to discuss on a case-by-case basis.  
 
*Sample Collection:  
 
1. Bone marrow: send in heparin or ACDA tube (ACDA preferred). Can also be sent diluted 1:1 in 
shipping media. Do not send bone marrow samples in Cell Save tubes. 
 

 
 
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2. Peripheral blood: For all Day 1 samples, Collect 5 mL sample into the CellSave tubes (3 mL) and 
heparin tubes (2 mL).  Collect sample into collection tubes directly, do not transfer a heparinized sample 
into the Cell Save tube; the Cell Save fixative will not work if the sample has already been heparinized. 
Either lithium heparin or sodium heparin is acceptable. Do not use lithium heparin PST (plasma 
separator tubes). End-of Induction samples should be sent in heparin tubes only. 
 
Shipping Note: Samples collected on Saturday and Sunday can be shipped Monday for Tuesday arrival. 
See below for information on obtaining and shipping samples in ThermoSafe containers. 
 
Specimen Requirements: 
Store samples in refrigerator until shipment. 
CellSave tubes will be provided by the Horton lab to each institution. 
To obtain more CellSave tubes, contact the Horton lab at the numbers provided below. 
If the CellSave tubes are not available, submit entire 5 mL sample in heparin tubes. Note that the sample 
integrity is greatly enhanced by the use of CellSave tubes. 
 
• Each sample should be clearly labeled to include the 6 digit COG number as well as the 4 digit treatment 
accession number; study number (AALL1231), date and time sample was drawn. 
 
On the AALL1231 Specimen Transmittal Form in the Medidata/Rave system record the exact time and 
date that the sample is drawn along with the exact start time for administration of systemic chemotherapy. 
Please note the WBC and % blasts on the specimen transmittal form. 
Please include a copy of the AALL1231 specimen transmittal form and institutional immunophenotype 
report with the sample submission to the laboratory. Please also fax a copy of the institutional 
immunophenotype report to FAX #: (832) 825-1206. 
 
Note: it is acceptable for blood to be collected from a central line. 
 
Shipping Requirements:  
Prior to sample collection, please contact Dr. Horton at (832) 824-4269 or Gaye Jenkins/Horton lab at (832) 
824-4676 for ThermoSafe shipping containers. These containers maintain biology samples at a constant 
temperature and are recommended, but not required, for biology sample shipment. Shipment of peripheral 
blood samples should not be delayed for receipt of shipping containers. 
 
If Thermo-Safe shipping container is not available: 
• Place collection tubes in a primary container. Wrap each collection tube separately to protect from 
breakage during shipment. Place the container in a Styrofoam box. 
• Please place an ice pack in the primary container. During the non-winter months (April-October) add 
additional ice packs to the Styrofoam box to assure the samples stays cold during shipment. 
• Package sample as appropriate for biologic material. 
 
For all samples, including those in ThermoSafe containers: 
Include a large ice pack in the ThermoSafe containers. 
• Include a copy of the submitted (in Rave) AALL1231 Specimen Transmittal Form with each shipment. 
• If possible, please send a copy of the bone marrow immunophenotype report with the first 
peripheral blood sample. If this is not possible, please send the report that day via fax (832-825-1206) 
or email to Dr. Horton at tmhorton@txccc.org and Gaye Jenkins at gnjenkin@txccc.org (Please strip 
unnecessary identifiers) 

 
 
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• Ship the sample by Federal Express Priority Overnight delivery to: 
 
Dr. Terzah Horton c/o Gaye Jenkins 
Feigin Center, Suite 760.01 
1102 Bates St. 
Baylor College of Medicine 
Houston, TX  77030 
832-824-4676 
 
FedEx account # 296621072 
Add air bill comment: TCH CC# 3332 
 
• Notify Gaye Jenkins or Horton lab representative prior to shipment of the sample. Phone: (832) 824-
4676. Please email the Fed-Ex tracking number to the email addresses above if prior notification is not 
possible. 
• If possible, do not ship samples for delivery on a weekend or holiday. Please contact the Horton lab for 
special instructions if samples are collected on a Friday. 
 
 
 
 

 
 
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Appendix XI: Minimal Residual Disease (MRD): Description and Characterization of Assay 
Description of populations for testing 
Patients with newly diagnosed T-ALL will have MRD measured in the bone marrow (BM) at the end of 
the first block of Induction therapy (Day 29). Those patients (~50%) with MRD levels < 0.01% in BM at 
Day 29 will be considered Standard Risk and assigned to the least intensive cytotoxic therapy. For the 
remaining patients (~50%), MRD will be assessed in BM at the end of Consolidation (EOC) therapy. Those 
with MRD < 0.1% (~40%) will be considered Intermediate Risk and receive intermediate intensity therapy. 
The remainder (~10%) will be considered Very High Risk and receive intensified therapy followed by an 
additional MRD assessment with those positive for MRD taken off study. Specimens from all patients will 
also be assayed at study entry in order to define an abnormal phenotype that will facilitate detection of 
MRD. 
 
Part of the diagnostic immunophenotyping at study entry will include the marginal cost for early thymic 
precursor (ETP) subclassification, a subset having a poor outcome70 and whose outcome is an important 
secondary endpoint of the study. Data from AIEOP-BFM 2000 suggest that while ETP ALL is often 
associated with poor prognosis, it may not be an independent risk factor for poor outcome, as most patients 
with ETP ALL who do poorly are identifiable by poor response to chemotherapy (PPR, Induction failure, 
or MRD positivity).38 It is critical to understand whether or not ETP phenotype independently predicts 
outcome in T-ALL as these patients may need alternative therapy or HSCT for cure. Multivariate analysis 
will be performed to determine if ETP ALL is an independent predictor of poor outcome based on MRD 
rates at end Induction and end of Consolidation. Preliminary data suggest ETP represents 12.4% of T-ALL 
in AALL0434, yielding 118 ETP patients of the 952 T-ALL anticipated on AALL1231. There are few data 
available to predict the proportion of ETP+ patients that will have MRD < 0.1% at EOC. Overall, we expect 
that ~10% of T-ALL patients will have MRD ≥ 0.1% at EOC, while ~90% will have MRD <0.1%. Given 
the known higher percentage of end of Induction MRD+ patients among the ETP+ subset, we hypothesize 
that ~50% of ETP+ patients (n=59) will have MRD ≥ 0.1% at EOC (5-fold higher rate than MRD-negative), 
while ~50% (n=59) will have MRD <0.1%. If the 4-year EFS of these ETP+, EOC MRD <0.1% patients is 
~50% or better, it would suggest that ETP patients can be risk stratified based on MRD alone (unless there 
is a specific therapy available for ETP patients). However, if this assumption is incorrect and ETP+ patients 
with MRD < 0.1% at EOC have an EFS < 50%, it would suggest that MRD alone cannot be used to risk 
stratify these patients and alternative strategies (stem cell transplant in CR1 or other novel therapies) should 
be pursued for all ETP patients. Hence, we will see if the lower limit of the 95% confidence interval for the 
4-year EFS estimate for ETP+, EOC MRD < 0.1% patients exceeds 50%. 
 
Patients with T-LLy will have the level of marrow involvement assessed at diagnosis to facilitate risk 
stratification into Standard and Intermediate risk groups. All T-LLy patients will also be assessed for MRD 
at Day 29, as this study will enroll more T-LLy patients than any to date and offers a unique opportunity to 
establish risk factors for this understudied patient population. We hypothesize that T-LLy patients with 
<0.01% MRD at end of Induction will have the best outcome, consistent with existing data in T-ALL. No 
data exist on the frequency of marrow MRD following therapy for T-LLy, although the frequency of 
marrow involvement at diagnosis > 0.01% is 66% in AALL0434. Assuming that about 80% of T-LLy 
patients will have MRD < 0.01% at end of Induction, this yields roughly 198 T-LLy patients on AALL1231. 
This will enable us to estimate the 4-year EFS for MRD negative T-LLy patients with a maximum standard 
error of 3.6%. 
 
Laboratory for MRD Testing 
The MRD studies will be performed solely in the flow cytometry laboratory located in the Hematopathology 
Laboratory at the University of Washington in Seattle directed by Dr. Brent Wood. This laboratory has 
more than 5 years of experience performing this assay on nearly 1,400 pediatric patients enrolled on the 

 
 
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ongoing COG T-ALL trial AALL0434. In addition, for the past 8 years this laboratory has generated MRD 
results used for risk assignment on COG frontline B-lineage ALL trials for more than 10,000 pediatric 
patients. 
 
Technical description of the assay 
Analyte and platform: The assay detects leukemic cells at high sensitivity against a background of normal 
peripheral blood or marrow cells using multiparameter flow cytometry. It is based on the principle that 
leukemic cells express cellular antigens at levels that differ from those seen in normal cells.196-198 Cells are 
stained with antibodies that have been previously shown to be informative for this purpose, and that have 
been conjugated to different fluorochromes designed to maximize the resolution between normal and 
abnormal cells. Specifically, the antibody combinations used are: CD16 PB/cCD3 FITC/CD7 PE/CD56 
PE-Cy5/CD5 PE-Cy7/CD38 A594/sCD3 FITC/CD45 APC-H7 and CD8 BV421/CD48 FITC/CD5 
PE/CD34 PE-TR/CD16+56 PE-Cy5/CD3 PE-Cy7/CD4 A594/CD7 APC/CD45 APC-H7 are used to 
identify leukemic cells. Evaluation for ETP type will be performed by using the following antibody 
combination in a single tube for pretreatment samples only: HLA-DR PB, CD7 FITC, CD13+CD33 PE, 
CD117 PE-Cy5, CD34 PE-Cy7, CD38 A594, CD1a APC, CD45 APC-H7. Stained cells are analyzed on a 
LSRII flow cytometer (Becton Dickinson, San Jose, CA). The proportion of leukemic MRD cells is 
expressed as a percentage of T/NK cells in each of the two tubes. An additional tube containing the DNA 
binding dye Syto16 along with CD7 and CD45 is used to calculate the proportion of T/NK cells as a 
percentage of total nucleated cells, which, when combined with results from the other two tubes allows 
computation of MRD as a percent of all nucleated cells. Finally, CD45 and side scatter is used to exclude 
granulocytes from the denominator so that the final value for MRD is expressed as a percent of mononuclear 
cells. By acquiring at least 750,000 events, it is possible to detect leukemic cells with a routine sensitivity 
of 0.01%, better in a subset of cases. This assay is currently used to determine prognostically significant 
thresholds for the on-going AALL0434 clinical trial. 
 
Specimens and processing: Either PB or BM is used for the assays described here. Samples are drawn at 
local institutional sites and sent in anticoagulated tissue culture medium provided to the local institutions 
and processed in most cases within 24 hours of collection. Aliquots of whole PB or BM are stained with 
the combinations of antibodies noted above followed by simultaneous red blood cell lysis with ammonium 
chloride and fixation using a small amount of formaldehyde. Finally the sample is washed once and 
listmode data acquired on the flow cytometry.  
 
Scoring procedures/criteria for positive/cut-points: Listmode data are analyzed in third party software 
using a hierarchical gating strategy with visual interpretation of multiple bivariate dot plots performed by 
Dr. Wood. Leukemic populations identified are analytically isolated from background normal cells using 
Boolean logic and based on the principle that leukemic cells express antigens in a pattern different from 
that seen during normal maturation of that lineage. For patients with T-ALL, the combination of a cut-point 
of < 0.01% leukemic cells in BM at Day 29 after initiation of chemotherapy and <0.1% leukemic cells in 
BM at end of Consolidation will be used to identify patients with a standard risk of relapse. For the 
remaining patients a cut-point of ≥ 0.1% leukemic cells at the end of Consolidation therapy will be used to 
identify patients at very high risk of relapse. Very high-risk patients that remain MRD positive ≥ 0.01% 
after intensification of therapy will be removed from the trial for additional therapy. For patients with T-
LLy, patients with < 1% BM involvement at diagnosis will be considered Standard Risk and those with ≥ 
1% BM involvement at diagnosis will be considered Intermediate or Very High risk depending on CT scan 
at Day 29. Blasts will be scored for ETP type using the published definition,70 i.e. lack of expression of 
CD1a and CD8, expression of one or more of CD13, CD33, CD34, CD117 or HLA-DR, and CD5 
expression 1 log lower than the mature T cells or < 75% positive. 
 
 

 
 
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Background: Minimal Residual Disease (MRD) is known to be a powerful prognostic factor in childhood 
B lineage ALL.36,37,199-205 Only limited data is available for T-ALL, most of it based on relatively small 
numbers of patients using PCR methodology.206-210 The largest and most comprehensive study to date of 
484 pediatric patients38 demonstrates that MRD negativity (< 0.01%) by PCR at end of Induction is the 
most favorable prognostic factor followed by negativity at end of Consolidation (< 0.01%) regardless of 
MRD positivity at end of Induction. The presence of MRD ≥ 0.1% at end of Consolidation is associated 
with an increased risk of relapse. Moreover, patients with T-lymphoblastic lymphoma (T-LLy) who have 
minimal disseminated disease detected by flow cytometry at the time of diagnosis have an adverse 
outcome.211 These studies clearly demonstrate that MRD is prognostically important in T-ALL/T-LLy, 
although confirmation by other large clinical trials is needed. 
 
Flow cytometric approaches to MRD detection in T-ALL have the potential advantage that they are 
informative in the vast majority of cases, including those where T–cell receptor rearrangements are not 
present or not detected by PCR.212 The studies published involve small patient cohorts and largely rely 
either on the expression of immature antigens, e.g. TdT, CD99, CD1a, or CD34, on T cells outside of the 
thymus213-219 or on the absence of surface CD3 expression in the presence of cytoplasmic CD3, an aberrant 
T cell immunophenotype provided NK cells are effectively excluded.215 Although the use of TdT and/or 
CD99 positivity in conjunction with cCD3 is a common strategy, we have shown that following Induction 
chemotherapy down-regulation of both is very common220 and can lead to either underestimation or false 
negative results. The studies that have examined the correlation between MRD detection by Flow cytometry 
or PCR in T-ALL involve small patient cohorts but show a positive correlation between the techniques, 
although to a somewhat lesser degree than for B-ALL41,214,219 perhaps reflecting the reliance of the flow 
cytometric methods used in those studies on inconsistently expressed immature antigens. Taken together, 
the data suggest that MRD in T-ALL can be detected by flow cytometry and that it correlates with PCR 
assays that have been shown to correlate with clinical outcome. 
 
The assay to be employed on AALL1231 is the same as that currently in use on AALL0434 and does not 
rely on the immature antigens TdT or CD99. The assay uses a combination of more broadly expressed T 
cell antigens known to be both differentially expressed and more stable in T-ALL,220 discordant expression 
of surface and cytoplasmic CD3 with NK cell exclusion,215 and decreased to absent expression of CD48. 
The latter has been identified by our group (ASH abstract 2011) as a consistent finding in T-ALL at 
diagnosis that is relatively stable after Induction chemotherapy. This approach improves upon the published 
assays and employs a novel antigen in a high level (8-9 color) context that should improve both sensitivity 
and specificity through exclusion of non-leukemic populations via improved antigenic correlation. 
Reference methods for minimal residual disease assays are not available, consequently determination of 
assay performance characteristics is problematic. Nevertheless, correlation of this flow cytometric assay 
with a PCR-based high-throughput sequencing assay (HTS) shows a high degree of correlation to a level 
of roughly 0.01%, suggesting a sensitivity of 0.01%. Those samples positive at any level by flow cytometry 
show no false positives in comparison with HTS, while flow cytometry negative samples show a single 
false negative just above 0.01% by HTS, suggesting a high degree of specificity above the level of 0.01%. 
Independent enumeration from the two tubes of the flow cytometric assay also shows a high degree of 
correlation without false positives or negatives in either direction, further suggesting a high degree of 
specificity. Given the absence of proficiency testing programs for this assay, blinded samples will be 
exchanged with another laboratory 3 times per year and concordance demonstrated. 
 
Expected population distribution: On AALL0434, this assay has identified that roughly 50% of T-ALL 
patients lack detectable MRD (< 0.01%) at Day 29 in BM, suggesting a group at standard risk for relapse. 
Similarly, on AALL0434 roughly 10% of patients are estimated to have detectable MRD (≥ 0.1%) at the 
end of Consolidation, the only caveat being that on AALL0434 only patients with MRD ≥ 1% at Day 29 
were assessed for MRD at end of Consolidation. The remaining roughly 40% of patients are considered to 
have an intermediate risk of relapse. On AALL0434, ETP patients represent 12.4% of the cohort. For T-

 
 
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LLy, roughly 65% are estimated to have BM involvement <1% at diagnosis and are considered Standard 
Risk with the remaining roughly 35% of patients being Intermediate or Very High risk. 
Cut-point rationale: The Day 29 (0.01%) and end of Consolidation (0.1%) cut-points are the same as those 
that have been shown to be prognostically important at their respective time points in a prior BFM study38 
and are confirmed to be prognostically important in T-ALL in a preliminary review of outcome data from 
AALL0434. For T-LLy, the cut-point of 1% is the same as that currently in use in AALL0434. 
 
Result Access: Results from these analyses will be provided to investigators via the Children’s Oncology 
Group clinical data system, using the identical established procedure already developed to communicate 
results in our frontline trials 
 
Analytical performance: Our flow cytometric assay for minimal residual disease has been used in nearly 
1,000 children with T-ALL enrolled in the on-going AALL0434 COG clinical trial for which outcome is 
not 
yet 
available. 
Consequently, we are not yet 
able to demonstrate the 
relationship of MRD to 
clinical outcome using this 
assay, but will do so when the 
outcome 
data 
is 
made 
available. 
Given 
our 
experience with a B-ALL 
MRD assay of similar design 
that has been shown to be 
highly 
prognostically 
significant 
(unpublished 
from 
AALL0232), 
the 
published data with assays of 
this type to date and the 
correlation of those assays 
with 
prognostically 
significant PCR assays, we 
are confident the assay will 
stratify patients for relapse 
risk. Comparison of this 
assay 
with 
PCR 
as 
a 
surrogate for outcome is not 
easily done, as the PCR 
assays are very labor and 
resource intensive and the 
group does not have access. 
However, we have done a 
limited correlation of this 
assay with a next-generation 
sequencing MRD assay (see 
attached Integrated Assay 
application) showing good correlation down to the range of 0.01% to 0.1% without false positives,221 shown 
in Figure 1.  
 

 
 
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We are unable to assess the precision of this assay in the usual fashion of having multiple replicates because 
the amount of sample available for repeat testing is limited. However, we have taken advantage of the fact 
that we use two different antibody combinations to calculate MRD, and can demonstrate a high degree of 
concordance between the two measurements, as shown in Figure 2. The small subset of mildly discordant 
samples is due the inability of one antibody 
combination to completely define the MRD 
population, which is evident at the time of 
analysis and would not lead to errors in 
reporting. 
 
The success rate of this assay in our hands is 
excellent. Less than 1% of samples received 
give indeterminate results in our assay. We do 
not have any extensive data on any critical 
preanalytical variables that have an impact on 
the performance characteristics of this test. 
Obviously, quality of the marrow initially 
obtained could have an impact if the specimen 
is significantly hemodiluted. While we do not 
have 
any 
direct 
means 
to 
measure 
hemodilution, we can use the proportion of 
nucleated red cells recovered in our sample as 
a surrogate for marrow quality. In preliminary 
analyses for a conceptually similar assay used 
for B-lineage ALL MRD monitoring we were 
unable to demonstrate an outcome difference between patients who lacked MRD but had low levels of 
nRBCs compared to those with high levels, suggesting that hemodilution in routinely obtained samples 
does not cause a significant underestimate of the MRD-positive patient population. 
 
To standardize our ability to define ETP T-ALL, a cohort of cases of possible ETP T-ALL were 
independently reviewed by Dr. Dario Campana, who published the description of the ETP 
immunophenotype, and Dr. Wood. Discordant cases were reviewed and interpretive criteria refined. 
Applying these criteria to 790 cases of ETP from AALL0434 provided a frequency of ETP of 12.4%, which 
agrees very well with published frequency of 12.6%.70 
 
 

 
 
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APPENDIX XII: ADDITIONAL INFORMATION FOR PROPOSED BIOLOGY STUDIES: 
STUDIES OF PROTEASOME ACTIVITY, PROTEOMICS, AND SIGNAL TRANSDUCTION  
Biology Objectives 1.3.2 and 1.3.3 
 
I.   HYPOTHESIS AND BACKGROUND: 
The cornerstone of therapy in acute lymphoblastic leukemia (ALL) is risk stratification of patients based upon 
genetic alterations and minimal residual disease (MRD). While this strategy has proven beneficial in pre-B 
ALL, prognostic associations with genetic aberrations in T-ALL are not sufficiently compelling to contribute 
to risk-adapted therapy, likely due to the significant heterogeneity of mutations in this disease222. The 
AALL1231 clinical trial is testing the novel hypothesis that the addition of proteasome inhibitor therapy to an 
augmented BFM (ABFM) backbone will improve T-ALL event free survival (EFS). Recent data suggests that 
the many genetic subtypes of T-ALL, including the early thymic progenitor (ETP) phenotype, may converge 
on a more limited set of deregulated signaling pathways and cellular processes.223 However, the frequencies 
with which signaling pathways are deregulated, how they impact prognosis, or how they modulate 
chemotherapy responses, are poorly understood. With better understanding and validation, these biochemical 
aberrations could be used clinically to identify patients with a “high risk” molecular signature that would 
benefit from more intensive chemotherapy. 
 
Because DNA mutation analysis and gene expression profiling (GEP) have to date resulted in only modest 
gains in predictive power in T- ALL, we propose using protein analysis methods to understand the biochemical 
underpinnings of T- ALL. Our long-term goal is to identify and validate protein cell stress and/or signaling 
alterations that can be used alone or incorporated with GEP into a single, simple, and robust molecular 
classification system to aid in risk stratification and inform the design of future clinical trials incorporating 
targeted agents.  If successful, the results of this research will move the study forward from an integrated 
study to an integral study that can be incorporated into future T-ALL clinical trials. The overall objective of 
this study is to determine whether proteasome and/or altered signal transduction patterns can identify protein 
expression profiles that predict response to bortezomib-containing therapy or are prognostic of clinical 
outcome.  Based on our strong preliminary data, our central hypothesis is that proteasome alterations, protein 
cell stress activation, and/or the pattern of signaling networks will predict therapy response and allow us to 
identify patients with a “high-risk” protein expression pattern that could benefit from more intense 
chemotherapy. The rationale for this work is that a better understanding of the role of biochemical alterations 
in T-ALL will result in the optimization of simple, robust assays that will aid in pediatric ALL risk stratification 
and personalization of chemotherapy, ultimately improving clinical outcome. We will test our central 
hypothesis with the following specific aims: 
 
Specific Aim 1: To determine if changes in proteasome function or cell stress protein expression patterns can 
predict bortezomib response and drug resistance in T-ALL.  
a) To delineate the mechanisms of bortezomib action and resistance in T-ALL to determine if proteasome 
alterations correlate with clinical response (as measured by minimal residual disease (MRD) or 
outcome (EFS). 
b) To determine if reverse phase protein lysate arrays (RPPA) predict chemotherapy response or 
resistance. 
1. To determine if protein cell stress pathways, such as the unfolded protein response, are active at 
baseline and how activity changes in response to chemotherapy +/- bortezomib, 
2. To define a putative “high risk” protein expression profile that identifies patients receiving either 
standard or intermediate risk therapy that would benefit from the more intense chemotherapy. 
3. To determine if RPPA protein expression profiles correlate with treatment group or T-ALL 
subtypes. 
 

 
 
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Specific Aim 2: To identify biomarkers and mechanisms of chemotherapy resistance and response in T-ALL, 
focusing on ETP-ALL. 
a) To use single cell phosphoflow cytometry (SCPFC) to determine if differences in constitutive 
activation of the MAPK, PI3K/AKT/mTOR, and/or JAK/Stat pathways between ETP and non-ETP T 
cell subtypes will serve as a biomarker of chemotherapy response or resistance.    
b) To determine if augmented NFB signaling predicts response to induction chemotherapy with or 
without bortezomib in ETP and non-ETP T-ALL. 
c) To use RPPA and SCPFC to build and validate multivariate classifiers to predict patient response to 
chemotherapy and determine risk of relapse. 
II. SIGNIFICANCE:  Previous research for prognostic risk factors in pediatric ALL have mostly focused on 
the characterization of genetic abnormalities.224 Many of the new biologic agents being introduced into T-ALL 
therapy, however, directly target protein activation. We expect that the results of this research work will enable 
us to determine if cell stress pathways such as the UPR or altered signaling networks can identify protein 
biomarkers that predict response to induction therapy with Vincristine, Dexamethasone, Asparaginase, 
doxorubicin (VXAD) +/- the proteasome inhibitor (PI) bortezomib. Specifically, our goal is to develop a “high-
risk” protein classifier that identifies patients with a higher risk of relapse in the standard and intermediate risk 
group.  If these patients can be identified with a valid molecular classifier, this could directly result in improved 
therapy and outcome, as higher risk patients would be assigned to more intensive therapy.  There are also 
significant gaps in our understanding of the role of the UPR and other cell stress pathways in response to T-
ALL treatment. Successful completion of the aims described will better define the role of these biochemical 
pathways in response to chemotherapy. Although the primary objective of the clinical trial is to determine if 
bortezomib-containing therapy increases long-term survival, the objective of this work is to develop protein 
expression classifiers that provide useful predictive and prognostic information whether or not bortezomib is 
found to be an effective agent. This contribution will be significant because it will add the predictive power of 
protein alterations to the armamentarium of genetic mutations currently used to assess relapse risk, increasing 
the power of risk stratification and identifying patients most likely to benefit from therapies that target 
deregulated cell signaling pathways in T-ALL.  
 
This research will also have a significant positive impact on future research for three reasons.  First, successful 
completion of this application will define the contribution of alterations in signaling and cell stress proteins to 
treatment outcomes, an objective within the NIH mission to improve the diagnosis and treatment of cancer.  
Second, markers of protein cell stress pathway activation could be used to determine the mechanism of action 
of biologic agents that directly alter protein homeostasis such as proteasome inhibitors (PI) and tyrosine kinase 
inhibitors (TKI) in appropriate T-ALL subgroups. Third, the results of this study could enable the future 
development of simple, robust diagnostic assays testing specific proteins or protein clusters that predict 
response to (VXAD) induction. This will allow for further refinements in risk stratification and, by predicting 
response to VXAD alone or to PI-containing therapy, will lead to the further development of personalized T-
ALL treatment. 
III. INNOVATION: Prior research has demonstrated that mRNA abundance does not always correlate with 
protein expression,225 highlighting a need for new approaches to assess protein signal transduction in multi-
institution trials. There is precedence for this approach. Previous proteomic studies in ALL have utilized 
prospective cohorts to show that proteasome activity is prognostic of clinical outcome (Horton AACR abstract 
2014) and that SCPFC can predict response to therapy in both ALL226,227  and AML228-230. RPPA is also 
predictive of response duration in adult ALL.231 The proposed research is innovative because, with the 
successful completion of these aims, we will demonstrate that RPPA and SCPFC can transition into simple 
robust assays that can be applied to large sample sets in multi-institution clinical trials. The data generated 
from this application will also provide prospective validation of clinical usefulness of the RPPA and SCPFC 
techniques in the setting of a phase 3 clinical trial.  
 

 
 
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Our preliminary data (see below) indicates that RPPA and SCPFC are both feasible and informative in the 
setting of a multi-institutional clinical trial. Proteomic data from either static (RPPA) or dynamic (SCPFC) 
molecular diagnostics, in combination with genomic data, could become key assays for response prediction 
and risk stratification in T-cell ALL where utility of genetic classifiers has been limited. Since gene-expression 
profiling (GEP) data can be combined with protein array data, there also is the potential to develop more in-
depth and robust models of therapy response and relapse risk.232,233 The innovation of this study will be in 
creating the foundation for combined proteome and transcriptome analyses in future trials. 
  
IV. JUSTIFICATION FOR PROSPECTIVE COLLECTION OF FRESH SAMPLES 
Shipping and handling delays are commonplace in multi-institutional clinical trials. Although most samples 
can be shipped overnight, samples are frequently delayed up to 72h over weekends. Although DNA mutation 
analysis and gene expression profiling (GEP) can be performed on frozen samples after shipping, GEP and 
mutation analyses have (to date) limited predictive power in T-ALL.  We propose a broader approach using 
protein analysis methods to understand the biochemical underpinnings of T-ALL. Our long-term goal is to 
develop a simple, robust protein analysis that could either be incorporated with GEP/ mutation analysis, or 
used alone as a complementary tool for risk stratification. 
 
Both of the aims of this study will require prospective collection of fresh lymphoblasts. This has been 
demonstrated for RPPA (see below) prior to the initiation of a similar study in AAML1031. A very similar set 
of experiments was reviewed by both the COG AML Biology committee and by the NCI, which is currently 
providing R01 funding for the project. Although SCPFC can theoretically be performed on banked specimens, 
multiple laboratories (C. Mullighan, J. Dick, D. Teachey, R. Lock, M. Hermiston, and A. Fernando, personal 
communications) have found that T-ALL samples, particularly those of the ETP phenotype, have extremely 
poor viability and yields upon thawing relative to pre-B ALL samples. For example, the yield upon thawing 
of 10 AALL0434 T-ALL samples from the COG tissue bank ranged from 3.8-17.8% (mean 6.94% viable cells, 
equivalent to 0.44 to 2.9x106 cells/vial) (Shimano and Hermiston, unpublished observations; Fig 2A). This is 
in contrast to adequate viability (>70% of samples have >90% viability) when B-ALL are cells thawed from 
the COG tissue bank. Similarly, the Teachey laboratory found that only 30% of banked ETP-ALL cells had 
viability greater than 90% post thaw. While all of these high post-thaw viability samples engrafted successfully 
in Nod Scid Gamma (NSG) mice, none of the remaining 70% of samples with poor post-thaw viability 
engrafted. 
 
Based on these observations and our belief that understanding the biology of ETP and high-risk T-ALL at a 
functional level is critical for identification of protein pathways resulting in chemotherapy resistance, we 
propose to perform these analyses on fresh samples. Since RPPA and SCPFC both require fresh cells, it will 
also provide a unique opportunity to compare these methods and to determine if 1) one of the two is more 
robust in a Phase 3 clinical trial, and 2) if the assays provide complementary information. Use of fresh cells 
will also enable us to achieve our long-term goal of developing a simple, robust protein classifier that can be 
combined with mutation analysis and GEP to aid in risk stratification. The objective of the classifier is to 
identify patients with a “high-risk” molecular signature that have been placed in either the SR or IR risk group, 
thus improving risk stratification and increasing EFS in these groups. Because sample availability has greatly 
limited our ability to study T-ALL biology to date, the use of fresh tissue will enable a comprehensive 
biochemical analysis in both non-ETP and ETP-ALL subtypes. 
 
A. Feasibility of collecting pre-treatment bone marrow samples from multiple sites for SCPFC analysis: 
To evaluate the feasibility of shipping fresh T-ALL cells for SCPFC, Dr. Brent Wood shipped 10 pairs of fresh 
ETP and non-ETP ALL samples (left-over after diagnostic flow cytometric phenotyping and MRD analyses) 
to the Hermiston Lab at UCSF over a six-month period. Even with delays of 72 hours, viability remained 
uniformly good (range 81-98%) and robust signaling responses could be obtained on all samples (Figure 1B). 
Moreover, preliminary data indicates that engraftment rates in NSG mice are quite high (data not shown). 

 
 
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Together, these data indicate that it is feasible to collect pre-treatment samples in the setting of samples 
shipped from multiple sites. 
 
 
 
B. Feasibility of collecting pre-treatment peripheral blood and bone marrow samples from multiple sites 
for RPPA analysis: To test the magnitude of the effect of shipping and handling delays on protein expression, 
we generated two custom protein arrays, one to test the stability of protein expression in heparin tubes (Table 
1 and figure 2A) and a second to test 
protein 
stability 
in 
CellSave 
(CS) 
preservative tubes (Veridex) following 
treatment (Figure 2B). In the first 
analysis, 7 pediatric AML samples were 
processed either on site or after shipment 
by air courier from New York University 
(Horton, manuscript in preparation). 
Shipping was done with peripheral blood 
in heparin tubes and lysates were prepared 
under 5 conditions as shown in Table 1. 
We found that 16 of 18 proteins (Groups 1-3) (Fig. 2A) showed either no change or a decrease in protein 
concentration that could be calibrated if samples were processed within <72h. These data indicate that reliable 
signaling information can be obtained from shipped cells. 
 

 
 
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C. Justification for prospective collection of non-frozen samples in Cell Save preservation tubes for 
RPPA analysis. Using a second patient cohort, the second array compared protein quality of lysates prepared 
from fresh cells versus frozen pellets (Tables 2 and 3). This array was done based on preliminary data in the 
Kornblau lab, using heparin tubes for pre-treatment samples, 
that demonstrating that frozen samples underwent significant 
sample degradation  (Figure 3). This data indicated that 
RPPA lysates must be made with fresh T-ALL samples, 
and that the use of cryopreserved samples would result in 
sample degradation and potentially misleading results. 
 
To determine if collection of fresh material in CS 
tubes alone would be sufficient for sample preservation in 
shipped samples, our second custom RPPA (Tables 2 and 3) 
compared CS tubes with immediate processing to those 
collected before treatment,  6h and 24h after treatment (n=23) 
with and without freezing. Protein expression between groups 
was compared using Student’s t tests analyzing 17 validated 
RPPA antibodies. Although pre-treatment samples showed 
little difference in protein expression after shipping (Table 2, 
left panel) post-treatment samples demonstrated highly 
significant differences (Table 2, right panel).  We then 
compared protein expression shipped in CS tubes without 
freezing (Table 3) where there are only a few significant 
differences between CS samples processed immediately and 
those processed with non-frozen samples (Table 3, right 
panel).  A summary of the statistically post-treatment using fresh lysates are shown in Figure 2B. Based on 

 
 
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these analyses, we concluded that 1) the effects of shipping and time delays <72h should be minimal and should 
not confound protein expression analysis, and 2) CS preservation tubes processed within 72h can protect 
protein expression from changes during shipping. Taken together, these data indicate that RPPA, SCPFC, 
the UPR and other cell stress proteins is both feasible and reliable as long as samples are collected 
prospectively and lysates prepared prior to cryopreservation. 
 
 
 
V.  APPROACH  
   A. Sample collection, sample size and prioritization: The COG AALL1231 study will be a Phase 3 study 
which will randomize  pediatric and adolescent/young adult (AYA) T-cell ALL and T-cell lymphoblastic 
lymphoma (T-LL) patients to receive either standard chemotherapy (modified BFM=VXAD) or standard 
therapy with bortezomib (VXAD-B), with the goal of obtaining 952 eligible, evaluable patients with T-ALL. 
T-LL patients will be excluded from this biology study.  
      Bone marrow (5cc at start of study and 5cc at end of Induction (Day 29) in heparinized tubes) will be 
collected for proteasome and SCPFC analysis. Peripheral blood (PB, 3mL in CS tube, 2 ml in a heparinized 
tube) will be collected for each eligible patient prior to the start of therapy and at 6 hours (h) and 24h following 
start of treatment. One requirement for eligibility for biology studies will be to have an absolute blast count 
(ABC) of at least 1000 cells/µL to have sufficient lymphoblasts for RPPA, SCPFC and proteasome analysis. 
We estimate that approximately 80% of patients will have sufficient PB lymphoblasts based on the historical 
control trial AALL0434.Based on bone marrow collection in AALL07P1 and AAML07P1, we estimate that 
we will receive at least 50% of pretreatment marrows.  Based on the Horton lab collection of similar samples 
on the COG phase 3 AML trial AAML1031, eligible, evaluable and usable peripheral blood were obtained 
from 36% of enrolled patients. Based on the percentage of patients with eligible blasts in PB and collection 
rates from the COG AML study AAML1031, we estimate that we will receive 476 eligible, evaluable, and 
usable bone marrow samples (238/tx group), and 342 PB samples from T-ALL patients (171/treatment (tx) 
group).  This will be the sample size for comparing cellular signaling pathways in treatment groups (VXAD 
+/-B) and in ETP vs. non-ETP patients. 
 
SCPFC will be done from both bone marrow and peripheral blood. Assuming ETP will occur in 12.4% 
of patients, the samples size for ETP and non-ETP will be quite different.  If marrow is received from 50% of 
eligible patients (estimate from AAML1031 and AALL07P1) we will have 476 marrow samples (238/tx group) 
with 59 ETP/417 non-ETP patients (30 ETP/tx group, 208 non ETP/tx group). Although the sample size will 
be smaller, we will also plan to examine changes in PB protein expression in both ETP and non-ETP groups. 
For peripheral blood we will have 342 patients, 42 of which will be ETP and 300 non-ETP. 

 
 
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For assessment of proteasome activity/expression (Priority 2), we will use BM  (pre-treatment and End of 
Induction (Day 29). Proteasome activity will be compared to response to therapy (as determined by End of 
Induction (Day 29) MRD with a cutoff at 0.01%) and EFS at 4 year. For bone marrow samples, the sample 
size is estimated to be 476 (238 Day 29 MRD >=0.01% /238 MRD <0.01%). Changes over time (pre-treatment 
vs. Day 29 bone marrow) will have a sample size of 238 (119/MRD status), accounting for the 50% drop-out 
rate of Day 29 bone marrow compared to pre-treatment bone marrow.  It is likely that we will have sufficient 
sample size to compare baseline proteasome activity by ETP status (59 ETP/ 417 non-ETP).  
UPR studies will be done with peripheral blood, and bone marrow if extra remains (Priority 3). For 
UPR protein analysis, we estimate that 25% of the “UPR patients” will have sufficient material for analysis,234 
resulting in a sample size of 86 patients (43 patients/tx group). 
 
For ease of collection and processing at individual sites, all samples will be sent to the Horton lab where the 
will be divided and subsequently sent to the Hermiston laboratory (Figure 4). The estimate of lymphoblasts 
per samples will vary significantly depending on the absolute blast count of the sample and the processing 
required for analysis (e.g., requirement for cell sorting). As in previous studies, we have limited our blood 
collection volume to 5 mL (2mL heparin, 3mL CS preservation tubes). 
B. Workflow. Figure 4 demonstrates the workflow for sample analysis. WBC number and viability will be 
determined upon receipt of shipped samples using an automated fluorescence cell counter. Cells will then be 
processed as previously described 235 with the addition of non-T cell depletion using magnetic separation prior 
to processing for RPPA lysates proteasome, and 
UPR analysis. Depletion will not be performed 
on heparin samples for SCPFC analysis or (if 
excess sample) for xenograft engraftment.  
Protein pellets and protein lysates will be 
prepared on day of receipt. Because sample 
availability has greatly limited our ability to 
study ETP biology to date, xenografts will be 
established in NSG mice from any leftover cells 
not required for these assays. Any samples 
emerging from these xenografts will be 
deposited in the BioPathology Center to be 
banked for future use. 
Table 4: Prioritization of experiments for peripheral blood and bone marrow collection 
Experiment 
Aim 
Lymphoblast 
# required/a  
Sorti
ng  
Est blood 
volume 
Tube 
typeb 
Timepoint (s) 
Priority 
RPPA 
1 
8x105 
yes 
1-2 mL 
CS 
0h, 6h, 24h 
1 
SCPFC 
1&2 
1x107 
no 
1-2 mL 
Hep 
0h, 6h, 24h 
1 
Proteasome 
expressionc 
1a 
5x106 
yes 
1mL 
CS 
0h, Day 29d 
2 
Proteasome 
activityc 
1a 
3x106 
yes 
1 mL 
Hep 
0h,  Day 29d 
2 
UPR-qRT-
PCR 
1 
2x106 
yes 
0.5 mL 
Hep 
0h, 6h, 24h 
3 
UPR protein 
1a 
1x107 
yes 
1mL 
CS 
0h, 6h, 24h 
3 
a: #= number, sx = sample; b: CS =CellSave preservation tubes (Veridex), c. proteasome assays will be done with 
bone marrow prior to treatment and with bone marrow at the end of Induction (Day 29). 

 
 
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C. Study Team: We have developed a very experienced team of experts with expertise in the areas of focus 
in these correlative studies: David Teachey (T-cell biology), R. Sifers (UPR), S. Kornblau (RPPA), M. 
Hermiston (biochemical analysis in T-ALL) and T. Horton, (protein homeostatis). Dr. Horton has conducted 
several COG clinical trials with bortezomib in relapsed leukemia and lymphoma.235-240 She will combine her 
expertise with specialists in the UPR, RPPA and SCPFC that, as a team, are uniquely placed to evaluate protein 
cell stress pathways within a multi-site clinical trial. We have assembled a statistical team that will be led by 
M. Devidas, head of the COG statistical core.  Protein array analysis and UPR will be done by A. Tsimelzon 
and C. Ahern (Baylor College of Medicine) and K. Coombes (MD Anderson); SCPFC analysis will be done 
by C. Delgado-Martin, M. Hermiston and A. Olshen at UCSF; proteasome analysis will be performed by the 
laboratory of Jacqueline Cloos (VU Medical Center, Amsterdam). Dr. Devidas will review all statistics and 
aid in the correlation of array results with clinical outcome. 
 
D. Specific Aim 1: To determine if changes in proteasome function or cell stress protein expression 
patterns can predict bortezomib response and drug resistance in T- ALL 
1.) Subaim 1a. To delineate the mechanisms of bortezomib action and resistance in T-ALL to determine if 
proteasome alterations correlate with clinical response (Day 29 MRD) or outcome (EFS). 
a. Overview  
Baseline UPR activation is associated with improved 5y-EFS in adults with AML.241 There is also evidence 
that response to PI therapy correlates with UPR activation.242 However, while in vitro studies have shown that 
UPR activation can induce T-ALL cell apoptosis,243-245 UPR activation following T-ALL chemotherapy has 
not been examined in patients. This aim will examine whether baseline UPR activation, or changes that occur 
in the first hours of VXAD +/- bortezomib can determine if induction of UPR effectors can predicts response 
to VXAD +/- bortezomib chemotherapy in T-ALL. As part of our goal of identifying prognostic and predictive 
protein cell stress biomarkers, the objective of this aim will specifically focus on defining the role of the UPR 
in pediatric T-ALL cell apoptosis and the utility of UPR activation as a indicator of chemotherapy response. 
We will test the working hypothesis that activation of the UPR pathway will enhance VXAD-mediated 
apoptosis. Such findings would be of importance, because it will allow, for the first time, the use of UPR 
proteins as predictors of chemotherapy response. 
 
Several prior studies have examined mechanisms of bortezomib action and resistance in pediatric 
leukemia. Three signal transduction pathways 
are of interest based on preliminary data and 
feasibility from our lab and others: 1)  the 
response of the proteasome to proteasome 
inhibitor (PI) therapy,239,246 2) the activation 
of the endoplasmic reticulum (ER)-mediated 
unfolded protein response (UPR), and 3) the 
activation of the NF-κB pathway. 
 
1) 
Overview 
of 
proteasome 
expression and activity in pediatric leukemia: 
Although PI therapy has had encouraging 
results in multiple myeloma and follicular 
large B cell lymhoma, its efficacy is often 
limited by the development of proteasome 
resistance. Although proteasome resistance in 
T-ALL 
can 
result 
from 
proteasome 
mutations,247 they can also correlate with 
change in proteasome capacity.248  The Cloos 
laboratory 
has 
recently 
shown 
that 

 
 
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immunoproteasome activity is higher in T-ALL lymphoblasts than in pre-B cells and AML, both in cell lines 
and in primary patient samples.239 In a recent collaboration between the Cloos and Horton laboratories, we 
discovered that patients having higher immunoproteasome expression were more likely to respond to 
bortezomib, as measured by CR2 after cycle 1 of therapy (see preliminary data below).246 
 
2)  Overview of the unfolded protein response (UPR): Studies have shown that pathways regulating 
cell stress, the ubiquitin-proteasome pathway, and the UPR are integrally linked. Damaged proteins awaiting 
proteasome degradation accumulate in the ER and induce expression of the UPR sensor protein Grp78 (Fig 
5).249,250 Grp78 activates three effector branches of the UPR (Figure 5): the pancreatic kinase like ER kinase 
(PERK)/eIF2-α pathway (left), the IRE1/XBP1 pathway (middle), and the AFT6 pathway (right).243 Phospho 
(P)-eIF2α inhibits global translation, while spliced (s)XBP1 and cleaved (c) AFT6 induce the transcription of 
chaperone proteins that assist with protein folding.251 However, if cellular damage is too extensive for repair, 
UPR effectors (Grp78, IRE1, sXBP1 and CHOP) trigger apoptosis.245,252 
 
3. The role of NF-B activation: NF-B activity was shown to be inhibited in early trials of bortezomib 
in pediatric leukemia.235 Recent data with a larger sample sample size (n=61) collected from patients enrolled 
on both Phase 2 trials of bortezomib in pediatric leukemia (AAML07P1 and AALL07P1) have shown that, 
although NF-B is decreased in many patients, the decrease does not correlate with clinical response. However, 
whether this holds true in T-ALL has not been adressed. Due to the analytic limitations of the NF-B ELISA 
in prior studies, NF-B analysis will be performed using SCPFC in Aim 2b. 
b.  Rationale and preliminary data 
1) Immunoproteasome 
preliminary data: Results from 
Jacqueline Cloos (VU Medical 
Center, 
Amsterdam, 
the 
Netherlands) and the  Horton lab 
have shown that the ratio of 
immunoproteasome 
to 
proteasomes vary widely in 
pediatric leukemia patients and 
that 
increased 
proteasome 
activity 
correlated 
with 
increased 
sensitivity 
to 
PI 
inhibitors 
including 
bortezomib.239 We have expanded this analysis to 
determine if proteasome activity correlated with 
response to bortezomib-containing chemotherapy 
(Figure 6).  Samples collected on the Phase 2 
clinical trials AALL07P1 and AAML07P1 were 
assessed for proteasome activity and expression. 
This study showed, for the first time, that the 
baseline 
ratio 
of 
immunoproteasome 
to 
proteasome expression correlated with response 
to therapy (post-induction CR).246 Patients that 
reached a complete remission (CR) following 
induction, had 2-fold higher ratios of both β5i/β5 
and β1i/β1subunit expression compared to patients 
who did not (p=0.019 and p=0.022). We also 
observed increased ratios of pre-treatment subunit-
 
 
 
 
 
 
 
 
 
 
 
Figure 6:  Ratio of immunoproteasome to proteasome protein subunit expression and 
catalytic activity in patients with CR after induction. 
Figure 7:    UPR 
activation in ALL:  A.  
The UPR chaperone 
Grp78 protein is variably 
expressed at baseline in 
pediatric ALL patients.  
B.  UPR activation (as 
measured by increases in 
the UPR sensor Grp78)  
is seen in both cell lines 
and in some (but not all) 
primary ALL patients 
following VPAD.  + 
control:  RAW cell.  
  

 
 
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specific catalytic activity of β5i/β5 were observed in patients that reached CR (n=10) compared to those who 
did not (n=14). 
 
2) UPR activation: Similar to adult AML, we hypothesize that patients with an intact UPR pathway will 
have a better response to VXAD +/- B,241,253  and that patients sensitive to bortezomib will have robust UPR 
activation following chemotherapy. Preliminary data from the Horton lab shows that baseline UPR activation, 
as determined by Grp78 protein expression, varies widely between ALL samples (Fig 7A) (Horton et. al., 
manuscript in preparation). UPR activation after chemotherapy (VPAD; P = prednisone) was also seen in 1/7 
pediatric ALL patients (Fig 7B). 
 
c. Experimental Design 
Subaim 1a will focus on known candidate signal transduction pathways involved with the response to 
bortezomib. We will evaluate UPR activation using both transcript analysis (qRT-PCR) and protein analysis 
(immunoblots). Although UPR qRT-PCR does not equate with protein expression, it does reflect UPR pathway 
activation and activation of proteins that can trigger apoptosis. It also requires limited cell numbers (2x106) 
and will be done on most eligible patients (in the context of being Priority 3).  Also, qRT-PCR for most UPR 
transcripts can be performed using CS tubes. Although the yield is decreased by approximately 50%, the results 
are similar  (Horton, unpublished results). Based on data from AAML1031, we estimate that 25% of patients 
will have sufficient sample for UPR protein analysis by immunoblot. 
 
1) Determine if there is evidence of baseline UPR activation: Since an overwhelmed UPR can trigger 
apoptosis,252 we hypothesize that baseline induction of the UPR could indicate cell stress and correlate with 
therapy response (MRD) and  clinical outcome (EFS).241 We will assess baseline UPR activation by 
quantitating sXBP1 (an early event in UPR activation), the UPR sensor GRP78, and the UPR terminal effector 
CHOP. Initial assessment will be by qRT-PCR, as this requires the fewest number of cells and can be done on 
all eligible, evaluable, and usable patients (n=342). Baseline GRP78 and CHOP will be compared to normal 
lymphocytes and ALL cell lines. sXBP1 will be the primary measure of baseline UPR activation.  Transcript 
expression will be compared  by response  (MRD) and and outcome (EFS). We expect that baseline UPR 
expression will be more common in treatment responders based on our preliminary data; however, groups will 
also be compared over the first day of treatment to determine if changes over time are more predictive of 
response. 
 
2) Determine if chemotherapy (VXAD+/-B) induces the UPR. In addition to baseline UPR activation, 
we will also assess UPR activation following treatment, allowing us to correlate both baseline and induced 
UPR activation with clinical outcome. UPR effectors (sXBP1,GRP78, CHOP) will be assessed during day 1 
of therapy (0h, 6h, and 24h). Our working hypothesis is that chemotherapy will activate the UPR(i.e. increase 
over time from 0h to 6h or 24h) in some, but not all, patients and that UPR activation will be more pronounced 
in the patients receiving bortezomib-containing chemotherapy.  This is based on our preliminary data (Fig 7) 
a In patients that have evidence of UPR activation following treatment, we will determine which of the three 
UPR pathways is activated. We have optimized 7 antibodies for detection of UPR immunoblots (Grp78, PERK, 
p-eIF2-α, IRE-1, XBP1, CHOP and ATF4)  and 11 primer sets for qRT-PCR quantitation of UPR transcripts 
(above +spliced Xbp1, p-PERK, ATF6, and calreticulin) (Fig 5). We expect that chemotherapy will induce 
UPR transcripts and effector proteins and result in increased spliced (s)Xbp1, an indicator of UPR activation 
and an apoptosis trigger. 
 
3) Assess the prevalence of UPR activation in ETP-ALL: Prior work indicates that baseline UPR 
activation in adult AML is more frequent in high-risk cytogenetic phenotypes such as monosomy 7 and 
del5q.241  However, the extent of UPR activation is unknown in ETP-ALL. We expect that UPR activation will 
be more pronounced in ETP-ALL; however it is possible that only the non-apoptotic pathways (p-eIF2α down-
reguation and chaperone induction) will be common and that effector molecules may not be triggered, as seen 
in Waldenstroms macroglobulinemia.254 This will be assessed by qRT-PCR and (in patients with sufficient 
material) immunoblots. 

 
 
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4) Assess UPR activation by treatment and response groups: Baseline UPR activation, as well as UPR 
induction following chemotherapy, will be stratified by treatment groups.  Our working hypothesis is that 
VXAD+B treated patients will have more sustained activation of protein cell stress pathways, including 
terminal UPR proteins that trigger apoptosis such as Grp78 (through caspase 7), CHOP (through caspase 4), 
and sXbp1 (via JNK).244 We also expect to find that patients responding to therapy (VXAD+/-B)  will have 
evidence of increased sXBP1 transcripts, sustained IRE1 activation, and increased Grp78 and CHOP.244,245,251 
These proteins will be more fully evaluated in the context of other protein cell stress pathways in SA1b. Our 
goal is to develop a protein expression classifier that can predict response to VXAD+/-B, and to determine if 
protein classifiers can also identify SR and IR patients likely to benefit from more intense chemotherapy based 
on their  ‘high-risk” protein signature. 
 
d.) Statistical methods and justification 
 
1) Sample size- Please see Section V for sample size assumptions and justification. 
In addition to determining the effect sizes of assays between treatment groups, we will also compare with early 
response to treatment (MRD) and T-ALL phenotype (ETP vs non-ETP).  For the analysis of data across time 
(0h, 6h and 24h) we do not know a priori the most relevant time points to compare. Short-term differences 
could have returned to baseline by 24h, and may be most accurately estimated by changes between 0h and 6h. 
Long-term reactions would be best measured by 0h-24h comparison.  Complex changes, such as increase at 
6h and decreases by 24h (NF-B) are best measured using all three time points as descriptors. However, for 
simplicity we have provided the affect sizes for changes from 0h to 24h in Table 5. 
Table 5: Effect-size (detectable differences) based on sample size for proteasome activity and UPR* 
1. Proteasome studies 
   (done with BM) 
Samples size 
(max) 
Effect 
size * 
2. UPR  
studies  
Sx. 
Size 
(max) 
Effect 
size * 
Baseline and change (pretx to Day 29) 
in proteasome activity by treatment arm 
(VXLD vs VXLD+B) 
476 (238/tx group)  
238 (119/tx group) 
0.257 
0.365 
Baseline 
PCR-
(BM) by ETP  
476 (59 ETP/ 
417 non-ETP 
0.391 
Baseline and change (pretx to Day 29) 
in proteasome activity by response 
(MRD status) 
476 (238/MRD grp 
238 (119/MRD grp 
0.257 
0.365 
PCR-D1change-
(PB) by ETP 
342 (42 ETP/ 
300 non-ETP 
0.463 
Baseline and change (pretx to Day 29) 
in proteasome activity by ETP status 
(12.4% ETP/ 87.6% non ETP) 
476 (59 ETP/417 
non-ETP 
238 (30 ETP/208 
non ETP) 
0.391 
0.549 
Baseline 
UPR 
protein (PB) 
UPR 
Protein 
change D1 PB 
86 (43/tx grp) 
70 (35/tx grp 
0.611 
0.679 
Assumptions: alpha = 0.05, beta = 0.2.Abbreviations:  tx = treatment, w= with, Day 29  = End induction, PCR = qRT-
PCR. grp= group 
* Effect size = standardized mean difference of either 1) the measurement at baseline, or 2) the change in measurement 
over time as noted. With this effect size, the study will have at least 80% power at 2-sided significance level of 0.05 to 
detect such difference given the corresponding sample size.    
 
Effect sizes in previous studies of the proteasome, the UPR and RPPA have demonstrated that the effect 
sizes listed in Table 5 and Table 6 (below) are smaller than those  needed to detect statistically significant 
differences in prior leukemia studies. 
 
• 
Proteasome expression measurements from pediatric patients enrolled in either AALL07P1 (n=46) or 
AAML07P1 (n-12) showed a 2-fold difference in proteasome subunit expression in those that had 
reached a complete remission (CR) following induction vs. those that had not, for both β5i/β5 and 
β1i/β1 subunit expression (p=0.019 and p=0.022). 

 
 
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• 
A previous UPR study (n=105)238 in adult AML determined that the activation of the UPR, as measured 
by the presence of spliced XPB1, correlated with relapse after CR1 (n=88 sXPB1+, n=17 sXBP1 neg, 
p=0.0182) 
• 
Work with RPPA in adult AML have been able to detect log2 differences of  0.03 and greater (p=0.041,  
n=205). Differences as small as log2 0.01 have been shown to be statistically different in larger data 
sets (n=511).231 
 
2. SubAim 1b. To determine if reverse phase protein lysate arrays (RPPA) predict chemotherapy response or 
resistance. 
1. To determine if protein cell stress pathways, such as the unfolded protein response, are active at 
baseline and how activity changes in response to ABFM chemotherapy +/- bortezomib, 
2. To define a putative “high risk” protein expression profile that identifies patients receiving either 
standard or intermediate risk therapy that would benefit from the more intense chemotherapy. 
3. To determine if RPPA protein expression profiles correlate with treatment group or T-ALL subtypes.  
 
a) Rationale: In Sub-aim 1b, we will use a biochemical approach to identify protein combinations that are 
prognostic in T-ALL. This subaim is more comprehensive than Specific aim 1a, and will use a “candidate 
biomarker approach” to examine proteins previously identified as prognostic in either adult or pediatric acute 
leukemia. 
 
b) Preliminary data: 
1. RPPA feasibility: The Kornblau lab has analyzed one cohort of adult ALL  and two cohorts of adult 
AML using RPPA. The 
first, with 539 samples 
from 258 patients, was 
probed 
with 
51 
antibodies;255 
the 
second, 
with 
747 
samples 
from 
539 
patients, 
was 
probed 
with 231 antibodies.234 A 
subsequent 
array 
for 
adult ALL used 194 
sampes 
with 
131 
antibodies. 
 
These 
studies 
demonstrated 
that there were recurrent 
patterns 
of 
protein 
expression 
that 
correlated with outcome 
(Fig. 6). In the AML, RPPAs proteins constellations correlated with cytogenetic subtype and EFS. In ALL, 
RPPA protein clusters correlated with CR duration. Prelminary analysis of pediatric ALL and AML samples 
is ongoing.  

 
 
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The Kornblau lab recently published an analysis of proteins expression clusters with 180 antibodies, 
using only 150,000 CD34+CD38- AML cells per sample.240  No other currently available technology can 
analyze as many proteins with as little material. RPPA analysis for this patient cohort consisted of 260 
validated antibodies for the proteins involved 
in 25 different protein functional groups (i.e. 
PI3K/AKT, 
JAK/STAT, 
WNT/-catenin, 
UPR, 
apoptosis, 
autophagy, 
cell 
cycle 
regulation integrins and adhesion proteins) that 
are known to be deregulated in acute leukemia, 
or are involved in DNA damage repair.240 The 
Kornblau lab, in collaboration with the K 
Coombes (MDACC statistics) and the Qutub 
laboratory (Rice University) have recently 
developed statistical methodology to generate 
interaction networks from the RPPA datasets 
in combination with known networks from the 
literature, and can map differences in 
expression onto these interactome maps, 
thereby revealing the variations in expression 
that are present between different types of 
leukemia, or alternatively, between different 
treatment or response groups. 
2) 
Antibody 
validation: 
RPPA 
antibodies have gone through extensive testing 
prior to inclusion on the array,234,241,255  
including both analytic validation and assay 
validation 
with 
clinically 
relevant 
samples.256,257 Antibodies validated for RPPA 
use demonstrate specificity of signal and, in the case of phosphorylation or cleavage sensitive antibodies, 
context-specific validation has been performed in baseline and stimulated samples.255 Validation steps have 
included: 1) antibody specificity as determined by immunoblot, 2) appropriate  induction of 
phosphorylation/cleavage in response to  known inducing agents, 3) correlation of RPPA signal with 
immunoblot expression (R>0.5), 4) acceptable sigmoidal curve fit of signal with sample dilution (analyzed 
using SuperCurve),255 5) variable slope normalization258 and, in cases of high background, 6) topographical 
normalization. Slides with unacceptable variances are redone.   RPPA has acceptable intra-assay and interassay 
variability, with intra-assay coefficients of variation (COV) of 6-15% and established interassay 
reproducibility. We have established standard operating procedures (SOPs) for sample processing, cell sorting 
and RPPA, and laboratory staff in both the Horton and Kornblau labs are experienced with the procedure. 
3) Clinical trial feasibility test set: Our preliminary data shows that we can reliably assess post-
chemotherapy protein activation by analyzing samples collected during Day 1 of therapy. Seventeen patients 
from the AAML1031 clinical trial were tested by RPPA (Fig 7) using both heparin and CS tubes.  Using a test 
set of 32 validated RPPA antibodies, we assessed protein activation following ADE therapy.  We have 
determined that 1) CellSave tubes preserve protein expression profiles post-treatment, as shown by the relative 
stability of actin expression, but a decrease in p-AKT (Fig 7A); and 2) that we can detect the heterogeneous 
patterns of changes in protein expression over time, with some patients having minimal changes over time 
(Figure 7B, top panel), whereas other patients have induction of several key regulatory proteins, including 
AKT, m-TOR, MAPkinase and the FOXO3 pathway (Figure 7B, bottom panel) following treatment. 
 
 
RPPA analysis for this patient cohort will consist of 260 validated antibodies for proteins involved in 
25 -protein functional groups including PI3K-AKT, JAK-STAT, Wnt-β-catenin, apoptosis, autophagy, cell 

 
 
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cycle regulation, DNA damage response,  integrins and adhesion proteins.259 The Kornblau lab and K Coombes 
(MDACC) along with the Qutub lab (Rice University) have recently developed statistical methodology to 
generate interaction networks from RPPA datasets in combination with known networks from the literature 
and can map differences in expression onto interactome maps, thereby revealing the variations in expression 
that are present between different leukemia response groups, subtypes, or treatment regimens. 260 
 
c. Experimental design 
1) Assessment of dynamic changes in lymphoblast protein activation following chemotherapy: Peripheral 
blood will be collected in CellSave tubes at three time points on the first day of therapy (0h, 6h, and 24h) and 
lysates prepared from 200,000 cells for RPPA analysis. Samples will be divided into a training set and test set 
of roughly equal size. For training set evaluation 171 patient samples (85/treatment group) will undergo serial 
dilutions and will be spotted onto a single array in duplicate with appropriate controls (cell lines, cell lines 
treated with chemotherapy, normal PBMC).  Replicate slides will be probed with 260 validated antibodies (1 
antibody/slide) and normalized protein concentrations determined using SuperCurve.255 
 
Our statistical analysis will involve three complementary approaches to examine the dynamic changes that 
occur in the T-ALL blasts in response to therapy over time. The first will use unsupervised hierarchical 
clustering (“class discovery”) methods to look for protein expression clustering in the training set. We will 
determine what signatures, or signature components, are static and which are dynamic in response to therapy, 
and the time course of these changes.  Next we will apply the thresher method to limit the dataset to those 
proteins that are changing dynamically and to define the dynamic principal components from the relevant 
functionally related protein groups.260 Finally we will map the observed dynamic changes onto interaction 
networks, derived from the static data and the known literature, to graphically visualize how each functionally 
related protein group, and it’s direct and indirectly connected members, are being modulated. 
 
     By comparing the analysis seen between the different therapies we can discriminate what pathways are 
differentially modulated by bortezomib, compared to the standard therapy arm, and what are the critical 
components of each of dynamically modulated protein functional group. Correlation of these protein 
expression patterns with therapy outcome can reveal which are defensive responses being engaged by the 
leukemic blasts to evade therapy. Identification of these resistance associated defensive adaptations will 
suggest further therapies to employ to block bortezomib resistance and improve efficacy.  Both static changes 
(pre-treatment) and dynamic changes over time will be assessed for each protein as well as for each protein 
functional group.  Baseline protein activation, as well as changes over time, will be compared based on 4 year 
EFS as the primary response endpoint. We expect that chemotherapy responsiveness will differ between 
protein expression clusters.  We will also determine if protein expression varies within T-ALL subgroups. As 
in adults, we expect that pediatric RPPA profiles will correctly identify T-ALL subgroups234 as well as identify 
defensive resistance mechanisms not only for bortezomib-containing therapy, but for VXAD therapy as well, 
showing that this body of work will lead to integral studies whether or not bortezomib is an effective 
agent. . The training set will be used to develop a protein expression classifier to predict VXAD +/- bortezomib 
response in the test set. 
 
d. Statistical methods 
1) Sample size adjustment for drop-outs 
We are requesting sample (BM (n=476) and PB (n=342)) for RPPA (BM) and SCPFC analysis (BM and PB). 
Additional samples will account for two potential sources of sample drop-out. First, we anticipate that 
approximately 20% of samples identified will have insufficient or unusable sample for RPPA and SCPFC 
analysis (non-viable samples, collected in wrong tubes, only partially collected sample set, damaged material, 
etc) Second, during RPPA and SCPFC construction, there will be additional samples that are inevaluable, 
either due to loss of tissue spots on the RPPA array, inadequate T-ALL cells for  UPR analysis, or inadequate 
sample using quality control criteria (5%). The drop-out rate in our prior RPPA studies using local samples for 
the same analyses was approximately 5% (Horton lab, unpublished data). An historical drop-out rate of 

 
 
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approximately 5% is also supported by the leukemia RPPA literature.261 UPR qRT-PCR dropout rate will 
depend on the quality of the RNA. 
 
The sample size will be drawn from the same samples set for both RPPA and SCPFC.  As concluded 
by Simon et al.,243 “genes that have low variation across the entire set of samples would be difficult to use for 
prognostic prediction in clinical situations”. Therefore, we will demonstrate statistical power in cell signaling 
node identification using the median and 90% percentile. We will adjust for multiple comparisons (total 6 
signal transduction nodes) using the Holm’s method.262 
2) RPPA analysis  
As discussed in SA 1a, there are multiple comparisons of interest.  We predict that there will be sufficient  
power to detect at significant differences between groups as shown below (Table 6). Methods for RPPA and 
SCPFC analysis have been previously described,255 Both unsupervised and supervised clustering analyses of 
the data sets will be completed as outlined below. 
 
a) Unsupervised hierarchical clustering analysis 
Unsupervised clustering of all RPPA and SCPFC data will be performed to identify biologically-defined 
subgroups that will be correlated with clinical outcomes (MRD and EFS). Independent of potential outcome 
correlations of clusters, this approach will also identify biologically-defined T-ALL subgroups, aiding in a 
development of biologically-based (i.e. targeted) therapies for these patient populations. Unsupervised 
clustering analysis will be performed as previously described.234,263 
 
b) Stratification of RPPA protein expression profiles by treatment group 
 A similar clustering analysis as delineated above will be applied to training sets stratified by treatment group. 
The training set will 
include 171 patients. 
With 
a 
1:1 
randomization 
between 
treatment 
groups, it is expected 
that 85 patients will 
have received each 
treatment. 
compare 
protein 
expression 
patterns 
in 
VXAD 
responders (4yr EFS-
no event) to responders 
in the VXAD-B group 
(4yr EFS-no event). 
We will specifically 
look 
for 
protein 
patterns 
in 
VXAD 
non-responders that are also found in VXAD-B responders, suggesting proteins that predict patients likely to 
respond to bortezomib-containing chemotherapy. Analysis of protein expression clusters by treatment group 
will also determine if there are protein classifiers that can differentiate response between treatments. 
 
One of the advantages of this study is the ability to analyze protein expression patterns over time during 
the first day of treatment.  By comparison of patients that receive VXAD to VXAD-B, we expect be able to 1) 
determine if there are proteins induced in VXAD responders that are not present in VXAD responders; these 
proteins might be putative predictors of bortezomib response. The expression of baseline UPR proteins has 
been linked to bortezomib response in similar tumor types242,254 however, this study is unique in its ability to 
assess UPR activation over time in patients randomly assigned to VXAD+/-B therapy. We will also look for 
Table 6: Effect-size (detectable differences) based on sample size for each 
experiment (two-sample 2-sided t-test, alpha=5%, power=80%) 
1. RPPA studies 
Samples size (max) 
Effect-Size 
Baseline RPPA by tx group 
342 (171/ tx group) 
0.304 
Changes in RPPA at D1 by tx group  
280 (140/ tx group) 
0.336 
Baseline RPPA by response groups (4-yr 
EFS) 
342 
(291 
non-
event/51event) 
0.426 
Changes in RPPA at D1 by response 
groups (4 yr EFS) 
280 (238 non-event/42  
event) 
0.471 
Baseline RPPA by response groups (Day 
29 MRD) 
342 (171  >=0.01%/ 
171  <0.01%) 
0.304 
Changes in RPPA at D1 by response 
groups (Day 29 MRD) 
280 (140 >=0.01%/ 
140 <0.01%) 
0.336 
Baseline RPPA by ETP vs. non-ETP 
342 (42 ETP/300 not) 
0.463 
Changes in RPPA by ETP vs. non-ETP 
280 (35 ETP/245 not) 
0.508 
Tx = treatment, D1 = Day 1, Day 29 MRD: < or >0.01% at end of induction.  

 
 
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changes in the protein expression patterns of VXAD non-responders that are no longer present in VXAD-B 
non-responders, indicating another set of proteins that could potentially identify markers of response to 
bortezomib. Based on accrual in the AAML1031 study, we estimate that we will have Day 1 samples on 82% 
of patients (approximately 280 samples, 140 samples/tx group), allowing for sufficient samples to make 
comparisons of protein expression over time between treatment groups. 
      c) Supervised gene expression analysis by response (1y-EFS) 
We will analyze pediatric T-ALL patients as a group to determine if RPPA provides prognostic/predictive 
information independent of known prognostic variables and information that is complementary to existing 
prognostic markers. To determine the effect of current disease risk group stratification on the prognostic value 
of the RPPA and SCPFC protein profiles, EFS data will be analyzed adjusted for treatment arm and ETP status. 
 
       d) Building an outcome predictor 
 Prior data from the Kornblau lab234,264 and others suggest that protein expression profiles between VXAD 
responders and VXAD-B responders will differ; RPPA and SCPFC (see aim 2) will likely identify specific 
biochemical pathways that predict response to bortezomib-containing chemotherapy, such as the UPR265 and 
other cell stress pathways, including autophagy,265,266 and DNA damage response.267 Based on preliminary data 
from the Hermiston lab and others we also will likely identify changes in specific signal transduction pathways 
(NF-κB, JAK/STAT and NOTCH) that will track with clinical outcome.  We will build candidate classifiers 
in a stepwise fashion: 
    i. We will first look at dynamic changes in protein activations following chemotherapy in sorted 
lymphoblasts. The purpose is to discover natural groupings based on proteomic data only, without any 
information about outcome, to compare those groups with other known classifications and then to perform 
bioinformatics analysis to identify pathways active in each of the newly identified clusters 
   ii. Once clinical outcomes become available, we will analyze the difference in protein profiles between 
VXAD and VXAD-B treatment groups as they relate to clinical outcome. This part will include different 
unsupervised methods, group comparisons and will search for differentially expressed proteins and pathways. 
   iii. Finally, we will create a classifier(s) to predict clinical outcome. We will use outcome variables 
MRD status (Day 29, 0.01% cutoff) and  4-year EFS) We may have different classifiers for different outcome 
variables as well as for different risk groups and T-ALL subtypes. 
 
As with other high-dimensional data, RPPA data analysis will include low-level and high-level analysis: 
iv. Low-level analysis, relative protein levels will be determined by interpolation of dilution curves from 
the global "standard curve" using the R package “SuperCurve”.268 (http://bioinformatics. md 
anderon.org/Software/OOMPA/ Current/SuperCurve-manual.pdf). After normalization for protein loading and 
appropriate transformation, assessments of quality will be performed.234,255 To the maximum extent possible, 
samples that will be directly compared to each other will be printed on the same slide to avoid possible batch 
effects. 
v.  High-level analysis: To determine clusters (classes) with potentially different outcome or treatment 
targets based on protein expression and activation, we will use Hierarchical Clustering, Principal Component 
Analysis (PCA), Self Organizing Maps (SOM) and other class discovery methods.269 Cluster stability will be 
accessed using reproducibility measures, including a modified GAP,270 known as stability GAP (prototype 
clustering) (Qutub et al, manuscript in review), 271 as well as robustness and discrepancy indices.272 
Differentially expressed proteins will be found using paired t-test as well as repeated measures, mixed 
effect ANOVA and ANOVA with contrasts. We will use the Bonferroni correction to account for multiple 
comparisons in the RPPA analysis.273 
To determine if dynamic changes in specific protein pathways predict chemoresistance, we will use 
different regression and classification methods: SOM (when no outcome is used), class prediction methods 
such as logistic regression, Support Vector Machine,274 Random Forest,275 Binary Tree Prediction, Bayesian 
Compound Covariate Predictor, Discriminant analysis (http://linus.nci.nih.gov/techreport/Manual32.pdf), and 

 
 
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finally, Cox proportional hazard models for survival analysis. We will use different boosting methods276 to 
combine different models for the purpose of producing more accurate classification and regression models. 
 
All patients with evaluable sample data will be randomized 1:1 into training and testing sets.  We 
will use cross-validation and permutation methods to estimate the model accuracy and to select a preferable 
model using the training dataset. To provide an unbiased estimate of the model accuracy on the training set, 
the model construction, including selection of proteins, will be repeated from scratch for each iteration. The 
selected classifier or regression model will be validated using the test dataset. 
To perform high level statistical analysis, as well as for visualization and integration of the results, we 
will use different software packages. The software will include but not be limited by Bioconductor 
(http://www.bioconductor.org), 
Partek 
(http://www.partek.com), 
BRB 
Array 
Tools 
(http://linus.nci.nih.gov/BRB-ArrayTools.htm, 
dChip 
(http://biosun1.harvard.edu/complab/dchip), 
SAS 
(http://www.sas.com), and R (http://www.r-project.org). We will follow new developments and use new 
software packages if more advanced ones are developed by the time of analysis. We will use scatter plots, 
multidimensional scaling, PCA, hierarchical clustering, volcano plots and other visualization methods for 
visualization of initial data and for results. 
e) Integration of RPPA and SCPFC results to build an integrated protein expression  classifier: 
All patients with evaluable RPPA and SCPFC (aim 2) will be included in the analysis plan for this aim. Protein 
expression levels as continuous variables (determined by RPPA) will be correlated with each SCPFC nodal 
output using ANOVA statistics for each protein. P-values will be adjusted for multiple comparisons using the 
Bonferroni method. We will also analyze GEP and protein datasets using other methods previously developed 
for the integration of genomic and proteomic data, including linear correlation analysis277 and cluster 
analyses278 as reviewed in Cox et al.279 These methods will enable us to determine the utility of transcript 
profiling for prediction of protein expression levels.280 Data will also be integrated at the level of protein 
interaction networks as previously described.263,281-283 
f) Assessment of protein classifiers: 
For this aim, all T-ALL samples with usable RPPA and SCPFC (aim 2) analysis will be evaluable (n≈476) and 
will be included in the analysis plan. In addition to comparison of the ROC performance characteristics, we 
will also be identifying classifiers whose operating characteristics minimize the false positive rate (1-
specificity) while having an acceptable true positive rate (sensitivity). A cutoff point for the classifier will be 
selected that maximizes the likelihood ratio (LR) of identifying standard and intermediate risk patients that 
have a “high-risk” protein classifier (i.e. an acceptable true positive rate (> 50%) with a low false positive rate 
(< 10-20% for this study). This will identify SR and IR patients in need of additional therapy, while avoiding 
potential overtreatment of SR and IR patients that have been falsely identified as high-risk by the molecular 
profile. 
g) Determination of clinical usefulness: 
Our objective is to improve the detection of the patients with a high risk signature in the SR and IR groups that 
would ultimately relapse, with the objective of improving SR and IR EFS. In this study we will assess 476 
patients for aberrations in protein cell stress pathways. Of this number, it is estimated that 90% will be either 
LR or IR (n=428); this will be the sample set available for analysis. Depending on the change in EFS for those 
correctly identified as having the putative high risk protein expression classifier, Table 7 demonstrates the 
relative risks that can be used to identify the clinical usefulness of applying the protein expression classifier to 
the SR and IR patients (overall 4-year EFS 89%). 
 
Table 7: Range of 4-yr EFS and relative risk reduction that will be used to determine the clinical 
usefulness of the protein profile classifier (n=428; alpha=5%, one-sided log-rank test) 
Proportion of patients 
classifier negative 
(sample size in classifier 
- and + grps) 
EFS associated 
with classifier 
negative group 
EFS associated 
with classifier 
positive group 
Relative Risk 
classifier+ 
/classifier (-) 
Signature 
Power  

 
 
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0.5 (n1=214, n2=214) 
0.97 
0.95 
0.81 
0.83 
6.92 
3.63 
>0.99 
0.99 
0.6 (n1=256, n2=172) 
0.95 
0.94 
0.80 
0.81 
4.35 
3.41 
>0.99 
0.99 
0.7 (n1=299, n2=129) 
0.93 
0.92 
0.80 
0.82 
3.08 
2.38 
0.99 
0.92 
0.8 (n1=342, n2=86) 
0.92 
0.91 
0.77 
0.81 
3.13 
2.23 
0.99 
0.86 
 
The table above will be used to calculate the sample size in each scenario that would lead to a high probability 
of correctly identifying a significant difference between patients with the high-risk protein classifier in the SR 
and IR groups. Our goal would be to identify a classification signature that outperforms the current method of 
risk stratification. 
 
E. Specific Aim 2: To identify biomarkers and mechanisms of chemotherapy resistance and response in 
T-ALL, focusing on ETP ALL. 
 
Overview: The objective of this aim is to systematically evaluate the biochemical signature of T-ALL 
leukemic blasts at diagnosis and in response to chemotherapy in order to identify a biomarker for patients at 
high risk of relapse. T ALL is a genetically heterogeneous disease with variable responses to therapy. The 
behavior of a given patient’s leukemia and its response to therapy are determined by the accumulation of 
genetic mutations and epigenetic alterations. To date, the genetic heterogeneity of T-ALL has precluded risk-
adapted therapy based on genetic abnormalities. (Epi)genetic aberrations are manifest biochemically as 
changes in signal transduction and cellular responses. However, recent data suggests that genetic abnormalities 
in T-ALL may converge on a more limited set of biochemical abnormalities.  We predict that these biochemical 
signatures may serve as biomarkers predictive of chemotherapy response or resistance.  We will focus on the 
ETP, a newly identified phenotype of T ALL with a particularly poor prognosis in some reports284 in order to 
identify new biomarkers for enhanced risk stratification and better treatment strategies for high-risk T-ALL 
patients. 
 
We will test two hypotheses: 1) that the signaling network profile of patients with ETP ALL will be distinct 
from non-ETP ALL and 2) that these differences in signal network wiring will predict whether the leukemia 
responds to chemotherapy (with or without bortezomib). 

 
 
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The rationale for this work is two-fold. First, ETP ALL blasts frequently have mutations more commonly 
associated with myeloid leukemia, including mutations in histone-modifying proteins and in genes that regulate 
RAS and cytokine receptor signaling. Our approach will be to delineate signaling in 1) the basal state, 2) in 
response to in vitro stimulation, or 3) in response to exposure to chemotherapy using SCPFC. In light of the 
observed biologic and clinical heterogeneity of T-ALL and the recent trend towards the development of 
“targeted” therapeutics, identification of patients likely to benefit from biologic therapies such as bortezomib 
would allow consideration at diagnosis for including these alternative therapeutic strategies. Second, successful 
completion of this aim will also allow us to identify a high-risk classifier of chemotherapy resistance in a large 
clinical trial and to directly compare 
the 
predictive 
power 
of 
this 
technology with RPPA (SA1).  Our 
expectation is that understanding the 
biochemical aberrations that reflect 
the genetic and epigenetic alterations 
in the leukemic blasts will enable 
identification of biomarkers that 
predict risk of relapse and inform the 
use of targeted agents in future 
clinical trials. Given that intracellular 
staining of protein epitopes is a 
mainstay of the diagnostic evaluation 
of T-ALL (e.g., TDT and cytoplasmic 
CD3 staining), addition of a protein 
biomarker to future clinical trials 
should be technically feasible as an 
integral study. 
 
1. 
Subaim 2a. To determine if 
differences in activation of the NF-
κB, 
MAPK, 
PI3K/AKT/mTOR, 
and/or JAK/Stat pathways between 
ETP and non-ETP T cell subtypes 
will 
serve 
as 
indicator 
of 
chemotherapy resistance. 
 
a. Rationale and preliminary data.  
Multi-parameter 
phosphoflow 
cytometry represents a powerful and 
highly 
sensitive 
approach 
for 
analyzing and interpreting post-
translational protein modifications 
(e.g. phosphorylation, acetylation, 
cleavage etc.) at the single cell level in minimal sample size (0.5x106 cells/assay). Measurements are made on 
endogenous proteins before and after exposure to extracellular modulators such as growth factors, cytokines 
and drugs. This enables a comprehensive, dynamic, and functional assessment of signaling pathways within 
heterogeneous populations of primary cells.285 SCPFC has been used to demonstrate that hyperactivation of 
STAT5 and PI3K/mTOR pathway signaling is a common feature of human CRLF2-rearranged pre B-ALL.227 
This approach has also been successfully applied to pediatric AML bone marrow samples to identify and 
validate a classifier for prediction of response and to build a single cell network profiling (SCNP) classifier in 
adult AML and pediatric AML studies have confirmed the importance of the JAK/STAT pathway.230 These 
classifiers are now being validated in a phase three prospective clinical trial (AML1031).  While these studies 
 
Figure 9. A. Basal levels of pSTAT5 are elevated in ETP-ALL. Plot 
of mean fluorescence intensity (MFI) for basal pSTAT5 in ETP and 
non ETP lymphoblasts. B.  Representative histograms of pSTAT5 
levels in the basal state (grey, filled) and after stimulation with Il7 for 
20 min (Black, open). Graph depicts change in MFI between 
stimulated and basal for several independent samples. p-values 
calculated using the non-parametric Mann-Whitney test. C. The 
JAK1/2 inhibitor ruxolitinib blocks hyperactive pSTAT5 in the basal 
state (left panel) and in response to IL7 stimulation (right panel). 
Filled line, vehicle treatment, open line, ruxolitnib treatment.  
 

 
 
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demonstrate the feasibility and clinical utility of SCPFC, this approach has yet to be systematically applied to 
pediatric T-ALL. 
 
Hyperactivation of signaling networks in ETP ALL. The Mullighan laboratory performed a comprehensive 
genetic analysis of ETP ALL.284,286,287 Activating mutations in signaling proteins and inactivating mutations in 
proteins regulating hematopoietic development were common. The Hermiston laboratory performed a 
biochemical analysis of a subset of these leukemias using SCPFC. Relative to normal human thymocytes, the 
MAPK, PI3K/AKT/mTOR pathway and the JAK/STAT pathways were hyper-responsive to 
stimulation.284,286,287 There was excellent correlation between genetic mutations and the occurring phenotype. 
For example, IL7 receptor mutations were associated with constitutive pSTAT5 activation while T-ALL 
samples with Ras pathway mutations were not.284,286,287  
 
Evidence of common signaling changes despite heterogeneous genetic alterations in ETP T-ALL. Interestingly, 
gene expression profiling suggested hyperactivation of the JAK/STAT pathway in ETP ALL whether or not 
there was an underlying cytokine signaling pathway mutation. This was tested using SCPFC. Regardless of 
their mutation status, ETP lymphoblasts were hyper-responsive to IL-7 stimulation relative to normal 
thymocytes or non-ETP T-ALL (FIG 9A). Activation of pSTAT5 in the basal state or in response to IL7 could 
be completely inhibited by the JAK1/2 inhibitor ruxolitinib in vitro and correlated (FIG 9B) (Maude et al., 
manuscript submitted). These data suggest that hyperactivation of the IL7/JAK/STAT pathway may be a 
common feature of ETP-ALL and support the notion that multiple genetic (or epigenetic) mutations may 
converge on a more limited 
set 
of 
deregulated 
cell 
signaling pathways. 
 
Correlation of MRD status 
with in vitro response to 
dexamethasone. To test the 
hypothesis that analysis of 
signaling profiles in response 
to 
conventional 
and/or 
targeted therapeutics in vitro 
could facilitate identification 
of resistant T-ALL/LL at 
diagnosis or relapse and 
facilitate choice of optimal 
therapy in high-risk patients, 
we successfully developed a 
Caspase-3 
(a 
marker 
of 
commitment to apoptosis) 
based 
assay 
to 
monitor 
response to drug therapy in 
vitro 
(Figure 
10B). 
An 
advantage of this approach is the ability to gate on the viable, chemotherapy resistant, Caspase-3 negative cells 
to further interrogate mechanisms of chemotherapy resistance. Because the upfront prednisone response can 
be predictive of outcome, especially in T-ALL,288 we tested the hypothesis that in vitro sensitivity to 
dexamethasone would correlate with prognosis as defined by end of induction MRD status. As anticipated 
based upon clinical response, MRD negative samples were quite sensitive to drug while the majority of ETP 
and MRD positive samples were resistant (FIG 10 A, B). Interestingly, dexamethasone resistance did not 
correlate with expression of the glucocorticoid receptor (data not shown), suggesting that other mechanisms 
are mediating drug resistance. 
 
Figure 10. Interrogating chemotherapy resistance and response with 
SCPFC. A. Representative MRD negative and MRD positive diagnostic 
samples from AALL0434 were incubated with vehicle or 10 uM 
dexamethasone for 48 hours in vitro and analyzed by phosphoflow 
cytometry. Histograms depict Caspase-3 induction. B. Drug sensitivity 
index was calculated for each diagnosic sample. Statistical significance 
was determined using the Student T test.  

 
 
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4.) T-ALL cells rewire their signaling networks in response to genotoxic stress. The mechanisms mediating 
chemotherapy resistance in T-ALL are unclear It is clear in normal biologic systems that cells upregulate 
multiple signaling pathways in response to stress. We hypothesized that chemotherapy resistant cells might 
similarly rewire their signaling networks in response to genotoxic stress. In addition to the obvious advantage 
of requiring many fewer cells, an advantage of SCPFC relative to traditional biochemistry using western blots 
is the opportunity to gate on drug-resistant, Caspase-3 negative cells and to interrogate signaling networks that 
are activated or inhibited in response to drug. We find that chemotherapy resistant cells upregulate the MAPK 
and PI3K/AKT/S6 pathways as well as pro-survival proteins such as survivin in T-ALL samples when exposed 
to 
genotoxic 
chemotherapy 
(FIG 11 A, B). Similar signal 
network rewiring has been 
reported as a mechanism of 
chemotherapy 
resistance 
in 
breast cancer289 
5. Targeted inhibitors prevent 
network rewiring and restore 
chemosensitivity. 
Network 
rewiring can be prevented with 
the addition of the appropriate 
targeted inhibitor. Interestingly, 
our 
preliminary 
data 
of 
chemotherapy resistant T-ALL 
(as defined by end-induction 
MRD) suggests that despite 
adequate inhibition of the target 
and downregulation of the pro-
survival 
protein 
Survivin, 
targeted agents generally are not 
cytotoxic 
as 
monotherapy. 
However, when combined with 
standard 
genotoxic 
chemotherapy, a synergistic 
effect is often seen. SCPFC 
enables 
analysis 
of 
the 
mechanistic 
basis 
for 
this 
observation. In the presence of 
targeted inhibitor, cells are no longer able to rewire their signaling networks, leading to downregulation of 
survivin and other pro-survival proteins and increased chemosensitivity when cytotoxic agents are added (FIG 
11C). These data argue that identifying the signaling pathways that are hyperactivated in the basal state or after 
exposure to chemotherapy could be of clinical benefit in determining which targeted therapy would be most 
beneficial for a given patient. Thus, a goal of this aim will be to determine the relative frequencies that common 
signaling pathways are deregulated in ETP-TALL. 
Experimental design.  
1.) Compare signal network wiring in the basal state and in response to IL7 or targeted inhibitors in ETP and 
non-ETP T-ALL. The goal of this experiment is to determine whether alterations in single network profiles can 
be identified and whether these correlate with MRD status and/or EFS. Diagnostic samples (either fresh bone 
marrow or peripheral blood, provided the blast count is greater than 1000 cells/HPF, collected and shipped in 
heparinized tubes) will be subject to SCPFC using established methods287. Briefly, cells will processed on a 
ficol gradient to remove red blood cells and cellular debris, rested 30 minutes in serum free media, treated with 
Figure 11. A. T-ALL cells were incubated with vehicle of 4-HC (the 
active metabolite of cyclophosphamide) for 24 hours and processed for 
SCPFC.An advantage of SCOFC is the ability to gate on the Caspase-3 
negative cells and interrogate mechanism of chemotherapy resistance. B. 
Caspase-3 negative rewire their signaling networks and upregulate pS6 
in response to genotoxic stress .C. Top, ALL cells were treated with 
vehicle, 4HC (the active metabolite of cyclophosphamide), and/or a dual 
mTOR/PI3K inhibitor. Combination therapy shows enhanced cell death 
relative to either agent alone. Gating on Caspase-3 negative cells (middle 
and lower panels) shows inhibition of pS6 with inhibitor and correlation 
with downregulationof the pro-apoptotic mediator Survivin.  

 
 
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vehicle, signal pathway inhibitors, or IL7 for 20 minutes, then rapidly fixed, permeablized, and stained with 
fluorescently conjugated monoclonal antibodies. 
 
Based on a conservative estimate of the number of pretreatment lymphooblasts obtained from 2 mL PBMC (2-
5x106 cells), we estimate that we will have sufficient sample to test a minimum of 10 biological conditions 
(modulators, kinetic time points), with 2 to 3 proteins measured in each condition, resulting in 
approximately 25 nodes representing relevant leukemia biology. The proteins assessed by SCNP will 
include the same proteins analyzed by RPPA. We will focus on the MAPK (pERK1/2, pMEK), JAK/STAT 
(pSTAT5), and PI3K/Akt/mTOR (pAKT, pS6) pathways and treat cells with a inhibitors specific to each of 
these key signaling nodes (i.e., a MEK inhibitor, ruxolitinib (JAK1 inhibitor), or rapamycin (mTOR inhibitor). 
The phosphatase inhibitor pervanadate will be used as a positive control. These pathways were chosen based 
on the high frequency of dysregulation in T-ALL and ETP ALL. Over 20% of T-ALL have aberrant 
PI3K/Akt/mTOR signaling.290 Early data suggest over 40% of ETP ALL samples have mutations in genes that 
regulate MAPK and that JAK/STAT pathway activation may be a universal feature of this T-ALL subset.287 
To identify leukemic blasts, cells will be stained with monoclonal antibodies (previously validated for 
SCPFC287) that recognize cell surface proteins (e.g., CD3, CD5, CD7) and signaling proteins (pS6, p-Akt, p-
MEK1/2, p-ERK1/2, active NF-κB). Activated Caspase-3 will be used to identify cells committed to apoptosis. 
The well characterized T-LBL cell line Jurkat and normal human thymocytes (obtained under an IRB approved 
protocol) at the same developmental stage as defined by cell surface staining will be used as positive controls. 
Cells will be processed on a FACSverse 2 housed in the Hermiston laboratory. An advantage of the FACSverse 
is that it contains an algorithm for controlling for day-to-day machine variability. Inclusion of the well-
characterized Jurkat cell line with each sample analysis will be used to control for any potential technical 
variability. 
 
B. Evaluate in vitro responsivness to dexamethasone. The goal of this experiment is to validate whether in 
vitro resistance to dexamethasone correlates with MRD responsiveness. We will also test whether 
chemotherapy resistant cells upregulate specific signaling pathways in response to dexamethasone exposure. 
After ficol, 0.5x106 cells/ml will be incubated in vehicle or 5µM dexamethasone in complete media for 48 
hours and then processed as outlined above for flow cytometry. Dexamethasone sensitive and resistant CEM 
T-ALL cells with well defined signal network rewiring responses to steroid will be used as positive and 
negative controls. 
 
Data analysis We will analyze the data by gating on the leukemia population (as defined by forward and side 
scatter characteristics and cell surface marker expression), eliminating doublets, and then identifying the 
Caspase-3 negative, viable cell population using FlowJo v.9.3.1 and Cytobank software. The mean 
fluorescence intensity (MFI) will then be calculated for each phosphoepitope. Samples will be comparing to 
each other and among subsets (e.g., ETP to non-ETP, end consolidation MRD+ to MRD-). The arcsinh ratio 
for each plot and the fold-change in intensity relative to the basal state will be calculated in Cytobank and used 
to generate heat maps for subsequent unsupervised and supervised clustering with the goal of identifying a 
single cell network profiling (SCPFC) classifier (see statistics section below). For the dexamethasone 
experiment, induction of Caspase-3 will be monitored in vehicle and drug treated cells by phosphoflow 
cytometry. A drug sensitivity index will be calculated as the ratio of non-apoptotic (Caspase 3 negative) cells 
in control vehicle treated vs. drug-treated samples. Additive, synergistic, or antagonistic effects will be 
calculated using the universal response surface approach.291 Multivariate analyses will be used to define the 
parameters that best discriminate patient populations. We expect that signal network wiring will be distinct in 
ETP-ALL relative to non-ETP ALL. Given that chemotherapy resistance reflects, at least in part the phenotypic 
consequences of genetic and epigenetic alterations in the leukemic blasts, we also anticipate that patients with 
persistent MRD at the end of induction and consolidation will have distinct network wiring relative to MRD 
negative patients, and that these phospho-signatures will correlate with EFS. 
 

 
 
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Statistical methods and justification: The objective of the statistical analysis In Aim 2a is to provide an 
assessment of baseline signal network wiring prior to chemotherapy in ETP versus non-ETP T-ALL and to 
determine whether it correlates with MRD status at the end of induction at 0.01% cutoff and/or or clinical 
outcome (4-year EFS). 
a) SCNP sample size: Based on analysis described in Aim 1, we expect approximately 50% of 
patients to provide BM and 36% to provide PBMC samples. Therefore, we estimate that we will have 
evaluable BM samples from 476 patients and PBMC samples from 342 patients  (171/treatment group) for 
power estimations. Given an incidence of 12.4% ETP, we estimate that we will have evaluable BM samples 
from 59 ETP ALL patients and evaluable PBMC samples from 42 patients. 
b) Definition of test and training sets: The statistics team, led by M. Devidas will randomize 
patients in approximately equal numbers to either the training or test (validation) set. The training set will 
be used to develop the SCNP-derived diagnostic classifier that will produce a score for each patient 
indicating the predicted likelihood of response or relapse. The training data will also be used to determine 
the decision rule (cutpoint) that will be applied to the classifier score to assign patients to one of two 
groups: e.g. MRD >0.01% vs. MRD <0.01%, or event vs. non-event based on 4 year EFS. The final 
diagnostic classifier and final decision rule will be referred to as the SCPFC classifier (DXSCNP). The ability 
of DXSCNP to predict patient’s response (or relapse) will be evaluated by applying DXSCNP to predict 
outcomes for patients in the test set. Estimates of accuracy of these classifiers will be made in the training 
set using out of bag (OOB) sample data for multiple bootstrapped samples. This will provide an updated 
estimate of the power calculation at the end of training set analysis. 
c) Determine if SCNP can predict response or relapse risk in each treatment group: Differences in 
the classifiers among patients treated with VXAD vs. VXAD+B will be explored. Based on the estimated 
performance of these classifiers in the training set, a decision will be made if independent classifiers are 
needed for response prediction within each treatment group. Logistic regression will be used to model 
treatment response within each treatment group.  
Specific Aim 2b. To determine if augmented NFkB signaling predicts response to induction 
chemotherapy +/- bortezomib.  
 
Rationale and preliminary data: Nuclear Factor kappa B (NF-κB) is a family of transcription factors that 
plays an important role in cancer development by preventing apoptosis and facilitating tumor cell growth. 
Consistent with this, a small study of primary pediatric leukemia cases, including thirteen T-ALL cases, found 
evidence of constitutive NF-κB pathway activation in more than 90% of cases. 31,89 This is perhaps not 
surprising since NF-κB is a target of constitutively active NOTCH or PTEN/AKT/mTOR pathways, which are 
each mutated in over 50% to T-ALL cases. However, whether activation of the NF-κB pathway is a ‘driver’ 
mutation in these leukemias and/or contributes to chemotherapy resistance is not known. Interestingly, in other 
systems tumor cells in which NF-κB is constitutively active, cells are highly resistant to chemotherapy and 
radiation, but inhibition of NF-κB sensitizes these cells to apoptosis.82 It is therefore of great interest to 
understand how deregulated NF-κB signaling can drive disease progression and to explore NF-κB inhibitors 
as a potential therapeutic strategy. We will test the hypothesis that activation of the NF-κB pathway correlates 
with chemotherapy responsiveness as measured by MRD at end induction and consolidation and EFS at four 
years. 
 
Bortezomib is a proteasome inhibitor that prevents NF-κB activity by blocking proteasome-mediated 
degradation of IκB, a requirement for NF-κB nuclear translocation. However, despite its use in clinical trials 
for a variety of cancers, how bortezomib exerts its antitumor activity remains incompletely understood. 
Therefore there is an unmet need to study how bortezomib affects cell proliferation in T-ALL at a molecular 
level. Recent studies show that bortezomib can overcome or reverse chemoresistance in multiple myeloma (by 
sensitizing tumor cells to traditional chemotherapy drugs resulting in increased apoptosis.19 We have developed 
a flow based assay to evaluate NF-κB activity (FIG 12). NF-B activity was shown to be inhibited in early 
trials of bortezomib in pediatric leukemia.235 Recent data with a larger sample sample size (n=61) collected 

 
 
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from patients enrolled on both Phase II trials of bortezomib in pediatric leukemia (AAML07P1 and 
AALL07P1) have shown that, although NF-B is decreased in most patients, the decrease did not correlate 
with clinical response (CR2).246 Whether or not this is true for T-ALL has yet to be established as there were 
only six T-ALL patients on AALL07P1. 
Experimental Design. Determine whether NF-κB activation at baseline and after exposure to induction 
chemotherapy +/- bortezomib correlates with MRD status at end induction and/or consolidation.  
We will evaluate NF-κB 
activation status at baseline 
and at 6h and 24 hours after 
exposure to bortezomib using 
the methods in subaim2A. As 
notch status and activation of 
PI3K pathway shown to 
enhance activation of the NF-
κB pathway, we will include 
antisera to pAKT and pS6, 
components 
of 
the 
PI3K/mTOR 
signaling 
network, to test whether 
increased levels of these 
phosphoepitopes 
correlates 
NF-κB activation.  
Determine whether exposure 
to in vitro exposure to 
bortezomib 
increases 
sensitivity to dexamethasone. 
The goal of this experiment is 
to use SCPFC to determine if 
exposure to dexamethasone 
and/or bortezomib induces 
differences 
in 
signal 
transduction network wiring 
that predict chemotherapy 
resistance in ETP and non-ETP T-ALL cell subtypes. The Caspase-3 phosphoflow cytometry assay and the 
data analysis strategy described in Aim 2a will be used to assess apoptosis. An advantage of multiparameter 
flow is the ability to gate on Caspase-3 negative (i.e., drug resistant cells). This will allow us to interrogate 
potential mechanisms of resistance by comparing expression profiles of known target proteins (such as the cell 
survival mediators survivin, Bcl2, Noxa and PUMA) before and after treatment. The URSA method will be 
used to determine whether combinational drug treatments exhibit an additive, synergistic, or antagonistic 
effect. 291 
Statistical methods and justification. The statistical approaches described in Aim 1 and 2a will be applied 
here. We expect that bortezomib-containing chemotherapy VXAD-B will sensitize T-ALL cells to 
chemotherapy treatment and that combinational treatment will enhance apoptosis compared to treating cells 
with VXAD. 
b. Specific Aim 2c: Compare the performance characteristics of an SCNP classifier to alternative 
classifiers developed with RPPA data or other clinical/molecular data. 
1) Approach: As both RPPA and SCNP can be used a predictive models of response to therapy or risk 
of relapse, we plan to compare the performance characteristics of both methods. The SCNP training set will 
Figure 12. A. Flow-based NF-B assay. Progressive degradation of IkBa 
after 20 minutes of stimulation with increasing doses of TNFalpha. B. The 
ETP-like cell line Loucey was incubated with the drugs in the order shown 
(24 hours drug one followed by 24 hours with drug 1 and 2). Survivin 
levels were evaluated in the Caspase3 negative population. Note that 
bortezomib induces efficient  down regulation of survivin only when the 
cells have been pre-treated with dexamethasone first. C. . Induction of 
caspase 3 was used to calculate the drug sensitivity index. D. ETP 
xenograft samples are sensitive to the combination of borteomib and 
dexamethasone but not either agent alone. 

 
 
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be used to develop a predictor of response (or relapse) based on clinical variables (DXClin) that are reported 
in the literature to correlate to relapse. By developing and applying DXClin in this manner, the study will 
provide an estimate of the true predictive utility of clinical/laboratory variables compared to RPPA. This 
will facilitate a fair comparison of the relative contribution of DXSCNP, DXRPPA and DXClin to the prediction 
of response or relapse. 
 
2)  Statistical hypothesis and test of significance: Our primary hypothesis is that the empiric area under 
the receiver operating characteristic (ROC) curve (AUC) will be significantly greater than 0.5, based on 
the continuous score from the pre-specified classifier, where higher scores indicate greater probability of 
continuous complete response at 4 years. Our secondary hypothesis is that DXSCNP contributes significantly 
to the prediction of treatment response after accounting for clinical variables, T-ALL subtypes and RPPA 
data. Based on performance characteristics of SCPFC based classifiers in previous studies,228 we expect 
accuracy measured by area under the receiver operator characteristic curve (AUROC) for the prediction of 
response to be in the range of 0.75 to 0.85 and for the prediction of relapse to be in the range of 0.7 to 0.8. 
Assuming an equal split of the evaluable samples into training and validation sets, we expect 172 samples 
in the test set. Under an alternative hypothesis that the true AUC is 0.70, a 1-sided 0.05 level test of the null 
hypothesis that the AUC = 0.5 has approximately 95% power when there are 26 events (relapse (n = 23) or 
induction failure (n = 3)) and 146 controls. If separate classifiers are deemed necessary for each treatment 
group, with approximately 10-15% patients in relapse and 85-90% patients who do not for each treatment 
group (~85% expected 4 year EFS in VXAD and ~90% expected 4 year EFS in VXAD-B), approximately 
80% power is expected for the primary objective if the true area under the ROC curve for each classifier 
is greater than 0.7. 
 
Expected Results: We expect to be able to provide prospective “validation of clinical usefulness” for both the 
RPPA and the SCNP method by determining the operating characteristics of both RPPA and SCNP using this 
data set.  Using the same set of prospectively collected samples, we expect to be able to directly compare the 
predictive power of the RPPA and SCNP classifiers.  When successfully completed, the results will 
significantly advance our knowledge of the predictive capability of two methods and allow for the development 
of a simple, robust classifier that can aid with therapy risk stratification early in therapy.  It will also allow us 
to determine which SR and IR groups have a “high-risk” protein expression profile that may benefit from more 
intensive (HR) therapy.  
 
 
 

 
 
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APPENDIX XIII:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
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>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
 

 
 
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Requirements for AALL1231 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval 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. 
 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
 
 
 

 
 
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APPENDIX XIV POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Bortezomib 
 
Drugs that may interact with bortezomib 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin, tetracycline 
• Antidepressants and antipsychotics  
o Aripiprazole, citalopram, clozapine, escitalopram, fluoxetine, nefazodone, sertraline 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, telaprevir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, clopidogrel, diltiazem, nicardipine, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, bosentan, cimetidine, cyclosporine, deferasirox, esomeprazole, haloperidol, 
ivacaftor, lomitapide, mifepristone, omeprazole, pimozide 
 
Food and supplements that may interact with bortezomib* 
• Echinacea  
• Grapefruit, grapefruit juice, Star fruit, Seville oranges 
• Green tea or a major component of green tea called ECGC 
• St. John’s Wort  
• Vitamin C, ascorbic acid, or multivitamins/minerals containing vitamin C or ascorbic acid 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
Green tea, ascorbic acid (vitamin C), and other antioxidants may decrease the activity of bortezomib. 
To avoid the interaction, you should stop taking the following products/foods from 1 day before the 
start of bortezomib until 3 days after the last dose of bortezomib: 
1. Green tea and its components 
2. Vitamin products containing vitamin C and antioxidants 
3. Foods with high vitamin C content, such as fruits 
4. Herbal products and any products containing flavonoids or other antioxidant compounds 
 

 
 
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Drinking grapefruit juice or eating grapefruit may increase the concentration of bortezomib in 
the blood. Therefore, eating grapefruit or drinking its juice should be avoided for the duration 
of treatment with bortezomib. 
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” 
 
Daunorubicin 
 
Drugs that may interact with daunorubicin 
• Some antibiotics and antifungals (clarithromycin, erythromycin, itraconazole, ketoconazole) 
• Some antiepileptics (carbamazepine, phenobarbital, phenytoin, fosphenytoin) 
• Some antiretrovirals (darunavir, lopinavir; nelfinavir, ritonavir, saquinavir, telaprevir, tenofovir, 
tipranavir) 
• Some heart medications (amiodarone, carvedilol, digoxin, dronedarone, nicardipine, propranolol, 
verapamil) 
• Other agents, such as atorvastatin, clozapine, cyclosporine, dexamethasone, ivacaftor, leflunomide, 
natalizumab, nefazodone, progesterone, rifampin, tacrolimus, tofacitinib, and trazodone 
 
Food and supplements that may interact with daunorubicin* 
• Echinacea 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• St. John’s Wort 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
 

 
 
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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 
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 
 
 
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  

 
 
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• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Etoposide 
 
Drugs that may interact with etoposide 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, clozapine, nefazodone 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, 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, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide, 
mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide* 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
 
 

 
 
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Hydrocortisone 
 
Drugs that may interact with hydrocortisone 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Antiretrovirals and antivirals  
o Darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tenofovir, tipranivir 
• Anti-seizure medications  
o Carbamazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, dronedarone, 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, aripiprazole, clarithromycin, cyclosporine, deferasirox, itraconazole, ivacaftor, 
ketoconazole, mifepristone, natalizumab, nefazodone, rifampin, tacrolimus, trazodone, 
warfarin 
Food and supplements that may interact with hydrocortisone* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Ifosfamide 
 
Drugs that may interact with ifosfamide 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, nefazodone, paliperidone, 
quetiapine, thioridizine, ziprasidone 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, dronedenarone, verapamil 

 
 
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• Stomach and reflux medications 
o Esomeprazole, omeprazole 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Bosentan, sitaxentan, aprepitant, dexamethasone, lomitapide, mifepristone, natalizumab, 
pimozide  
 
Food and supplements that may interact with ifosfamide* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
Mercaptopurine 
 
Drugs that may interact with mercaptopurine 
o Artiritis medications: leflunomide, tofacitinib 
o Other medications, such as allopurinol, azathioprine, clozapine, febuxostat, natalizumab, olsalazine, 
sulfasalazine, warfarin 
 
Food and supplements that may interact with mercaptopurine* 
• Echinacea 
 
 
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 
 
 
 

 
 
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Food and supplements that may interact with methotrexate* 
• 
Alcohol 
• 
Echinacea 
• 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
 
 
Pegaspargase 
 
Drugs that may interact with pegaspargase 
o Leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with pegaspargase* 
• Echinacea 
 
 
Thioguanine 
 
Drugs that may interact with thioguanine 
o Arthritis medications: leflunomide, tofacitinib 
o Other medications, such as allopurinol, clozapine, natalizumab, olsalazine, sulfasalazine 
 
Food and supplements that may interact with thioguanine* 
• Echinacea 
 
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  

 
 
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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 
 
 

 
 
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