Conditions: Acute Leukemia of Ambiguous Lineage B Acute Lymphoblastic Leukemia Mixed Phenotype Acute Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 78
Healthy volunteers: no

Brief summary:
This pilot phase II trial studies the side effects of azacitidine and combination chemotherapy in infants with acute lymphoblastic leukemia and KMT2A gene rearrangement. Drugs used in chemotherapy, such as methotrexate, prednisolone, daunorubicin hydrochloride, cytarabine, dexamethasone, vincristine sulfate, pegaspargase, hydrocortisone sodium succinate, azacitidine, cyclophosphamide, mercaptopurine, leucovorin calcium, and thioguanine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the tolerability of azacitidine in addition to Interfant-06 standard chemotherapy in infants with newly diagnosed acute lymphoblastic leukemia (ALL) with KMT2A gene rearrangement (KMT2A-R).

SECONDARY OBJECTIVE:

I. To evaluate the biologic activity of azacitidine by pharmacodynamic assessment of global deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of infants treated with azacitidine.

EXPLORATORY OBJECTIVES:

I. To determine the 5 year event-free survival (EFS) of infants with KMT2A-R treated with azacitidine in addition to Interfant-06 standard chemotherapy.

II. To correlate minimal residual disease (MRD) with outcome in the context of the protocol therapy.

III. To perform pharmacokinetic (PK) testing of azacitidine in infants. IV. To test the expansion of infant T lymphocytes by stimulation with artificial antigen presenting cells identical to those used in chimeric antigen receptor T-cell (CART)-19 production.

V. To collect pharmacodynamic (PD) data for asparaginase activity following pegaspargase administration in infants.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive methotrexate intrathecally (IT) on days 1 and 29, prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) on days 1-7, daunorubicin hydrochloride intravenously (IV) over 1-15 minutes on days 8-9, cytarabine IV over 30 minutes on days 8-21 and IT on day 15, dexamethasone PO, NG, or IV TID on days 8-28, vincristine sulfate IV over 1 minute on days 8, 15, 22, and 29, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 12, and hydrocortisone sodium succinate IT on days 15 and 29 in the absence of disease progression or unacceptable toxicity. Only patients with KMT2A-R continue to post-induction chemotherapy.

POST-INDUCTION CHEMOTHERAPY:

AZACITIDINE BLOCK I: Prior to CONSOLIDATION, patients receive azacitidine IV over 10-40 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Following completion of AZACITIDINE BLOCK I, patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, mercaptopurine PO or NG daily on days 1-28, cytarabine IV or subcutaneously (SC) daily on days 3-6, 10-13, 17-20, and 24-27 and IT on day 10, methotrexate IT on day 24, and hydrocortisone sodium succinate IT on days 10 and 24 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK II: Prior to INTERIM MAINTENANCE, patients receive azacitidine as in AZACITIDINE BLOCK I

INTERIM MAINTENANCE: Following completion of AZACITIDINE BLOCK II, patients receive mercaptopurine PO or NG daily on days 1-14, methotrexate IV over 24 hours on days 1 and 8 and IT on days 2 and 9, leucovorin calcium PO or IV on days 3-4 and 10-11, hydrocortisone sodium succinate IT on days 2 and 9, cytarabine IV over 3 hours every 12 hours on days 15-16 and 22-23 for a total of 8 doses, and pegaspargase IV over 1-2 hours or IM on day 23 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK III: Prior to DELAYED INTENSIFICATION PART I, patients receive azacitidine as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART I: Following completion of AZACITIDINE BLOCK III, patients receive pegaspargase IV over 1-2 hours or IM on day 1, dexamethasone PO, NG, or IV TID on days 1-14 and 15-21 with a taper on days 15-21, thioguanine PO or NG daily on days 1-28, vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine IV or SC on days 2-5, 9-12, 16-19, and 23-26 and IT on days 1 and 15, and hydrocortisone sodium succinate IT on days 1 and 15 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK IV: Prior to DELAYED INTENSIFICATION PART II, patients receive azacitidine as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART II: Following completion of AZACITIDINE BLOCK IV, patients receive thioguanine PO or NG daily on days 1-14, cyclophosphamide IV over 15-30 minutes on days 1 and 15, cytarabine IV or SC on days 2-5 and 9-12 in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Following DELAYED INTENSIFICATION PART II, patients receive mercaptopurine PO or NG on days 1-168, methotrexate IT on day 1 and 92 and PO once weekly on days 8-91 and 98-168, hydrocortisone sodium succinate IT on day 1, 57, and 99, and cytarabine IT on day 57. Starting on day 169, patients receive mercaptopurine PO or NG on days 1-84 and methotrexate PO once weekly. Cycles repeat every 84 days for 2 years from the start of INDUCTION CHEMOTHERAPY in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo collection of blood sample and an echocardiogram (ECHO) or multigated acquisition (MUGA) scan on study. Patients may also undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: See Detailed Description

Interventions: intervention 1: Azacitidine intervention 2: Biospecimen Collection intervention 3: Computed Tomography intervention 4: Cyclophosphamide intervention 5: Cytarabine intervention 6: Daunorubicin intervention 7: Daunorubicin Hydrochloride intervention 8: Dexamethasone intervention 9: Echocardiography intervention 10: Hydrocortisone Sodium Succinate intervention 11: Leucovorin intervention 12: Leucovorin Calcium intervention 13: Magnetic Resonance Imaging intervention 14: Mercaptopurine intervention 15: Methotrexate intervention 16: Multigated Acquisition Scan intervention 17: Pegaspargase intervention 18: Prednisolone intervention 19: Thioguanine intervention 20: Vincristine intervention 21: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo blood sample collection intervention 3: Undergo CT scan intervention 4: Given IV intervention 5: Given IV, SC, IT intervention 6: Given IV intervention 7: Given IV intervention 8: Given PO, NG, IV intervention 9: Undergo ECHO intervention 10: Given IT intervention 11: Given PO, IV intervention 12: Given PO, IV intervention 13: Undergo MRI intervention 14: Given PO, NG intervention 15: Given IT, IV, PO intervention 16: Undergo MUGA scan intervention 17: Given IV intervention 18: Given PO, NG intervention 19: Given PO, NG intervention 20: Given IV intervention 21: Given IV

Protocol document:
Prot_SAP_000.pdf: 
  
 
i 
 
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 
 
 
 
 
 
September 25, 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 
 
Re.: AALL15P1, A Groupwide Pilot Study to Test the Tolerability and Biologic Activity of the Addition 
of Azacitidine (IND# 133688, NSC# 102816) to Chemotherapy in Infants with Acute Lymphoblastic 
Leukemia (ALL) and MLL Gene Rearrangement –Amendment #4 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #4 to the protocol and informed consent document for the study 
AALL15P1. This amendment is being submitted in response to a Request for Rapid Amendment 
(RRA) from Dr. Richard Piekarz, Dr. Jeffrey Moscow, and Dr. Meg Mooney dated September 6, 2019. 
In this amendment, the revised CAEPR for azacitidine (Version 2.7, July 30, 2019) has been inserted 
into the protocol, and the associated risk information in the informed consent document has been 
revised.  
 
Sincerely, 
 
Rachel Vasquez, Protocol Coordinator 
 
 
(on behalf of) 
 
 
Erin M. Guest, M.D., AALL15P1 Study Chair 
Patrick Brown, M.D., AALL15P1 Study vice Chair  
John Kairalla, Ph.D., AALL15P1 Study Statistician 
Meenakashi Devidas, Ph.D., ALL Senior Statistician 
Mignon Loh, M.D., ALL Chair 
Elizabeth Raetz, M.D., ALL vice-Chair 
Peter Adamson, M.D., COG Group Chair
 
 


ii 
 
AALL15P1 SUMMARY OF CHANGES 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the Protocol.  
Section 
Page 
Comments 
Throughout 
Throughout 
Updated the version date. 
Table of Contents 
3-7 
Updated page numbers. 
Study Committee 
9 
Rachel Vasquez has replaced Arshi Reyaz as the Protocol Coordinator. 
Section 6.0 
95-100 
• 
Updated date of monograph for azacitidine 
• 
Updated date of CAEPR for azacitidine 
• 
Added New Risk:  
o 
Also Reported on Azacitidine Trials But With Insufficient Evidence for 
Attribution: Ascites; Cardiac arrest; Chronic kidney disease; Delirium; 
Edema face; Fracture; Gastrointestinal disorders - Other (enteritis); 
Gastrointestinal pain; Hallucinations; Hemolysis; Hyperphosphatemia; 
Immune system disorders - Other (GVHD); Investigations - Other 
(thrombocytosis); Laryngeal hemorrhage; Metabolism and nutrition 
disorders - Other (gout exacerbation); Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (metastases to central nervous 
system); Stroke 
o 
 
• 
Increase in Risk Attribution:  
o 
Changed to Rare but Serious from Also Reported on Azacitidine Trials But 
With Insufficient Evidence for Attribution: Tumor lysis syndrome 
• 
Decrease in Risk Attribution:  
o 
Changed to Less Likely from Likely: Anorexia; White blood cell decreased 
o 
Changed to Also Reported on Azacitidine Trials But With Insufficient 
Evidence for Attribution from Less Likely: Depression; Dyspepsia; 
Hyperhidrosis; Malaise; Non-cardiac chest pain; Pain; Skin and 
subcutaneous tissue disorders - Other (skin lesion); Vascular disorders - 
Other (pallor) 
• 
Provided Further Clarification: 
o 
Conjunctivitis, Gastrointestinal disorders - Other (diverticulitis), 
Respiratory, thoracic and mediastinal disorders - Other (pneumonia 
legionella), and Skin and subcutaneous tissue disorders - Other (ecthyma 
gangrenosum) are now reported as parts of Infection. 
o 
Postnasal drip is now reported as Postnasal drip and Rhinorrhea. 
o 
Acute coronary syndrome (CTCAE 4.0 language) is now reported as part 
of Chest-pain cardiac. 
o 
Wolff-Parkinson-White syndrome (CTCAE 4.0 language) is now reported 
as Cardiac disorders - Other (Wolff-Parkinson-White syndrome). 
o 
General disorders and administration site conditions - Other (Sweet's 
Syndrome) is now reported as Skin and subcutaneous tissue disorders - 
Other (Sweet's Syndrome). 
o 
Investigations - Other (blood LDH increased) (CTCAE 4.0 language) is 
now reported as Blood lactate dehydrogenase increased. 
o 
Metabolism and nutrition disorders - Other (fluid overload) is now reported 
as generalized edema. 
o 
Musculoskeletal and connective tissue disorder - Other (muscle cramps) 
and Musculoskeletal and connective tissue disorder - Other (muscle 
spasms) are now reported as Muscle cramp. 
o 
Sinus pain, previously listed under the NERVOUS SYSTEM DISORDERS 
SOC (CTCAE 4.0 language), is now reported under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
o 
Urinary tract pain is now reported as Dysuria. 
o 
Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal 
pain) is now reported as Oropharyngeal pain.  


iii 
 
o 
Visceral arterial ischemia, previously listed under the VASCULAR 
DISORDERS SOC (CTCAE 4.0 language), is now reported under the 
GASTROINTESTINAL DISORDERS SOC. 
o 
General disorders and administration site conditions - Other (general 
weakness) is now reported as part of Fatigue. 
 
AALL15P1 SUMMARY OF CHANGES 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the Consent.  
Section 
Page 
Comments 
Throughout 
Throughout 
Updated the version date. 
 
What side effects or risks can I 
expect from being in the study? 
7 
Made the following changes to the risk profile: 
• 
Decrease in Risk Attribution: 
o 
Changed to Occasional from Common: Loss of appetite 
o 
Changed to Also Reported on Azacitidine Trials But With 
Insufficient Evidence for Attribution from Occasional (i.e., 
removed from the Risk Profile): Heartburn; Depression; 
Increased sweating; Sores on the skin; Pale skin 
• 
Provided Further Clarification: 
o 
Swelling and redness of the eye (Occasional) is now reported 
under Infection, especially when white blood cell count is low 
(Common) 
 
 
 
 


 
 
 
AALL15P1 
Page 1 
Version date: 9/25/19 
 
Activated: 
03/27/17 
Version Date: 
09/25/2019 
Closed: 
      
Amendment 
#4 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
AALL15P1 
 
A Groupwide Pilot Study to Test the Tolerability and Biologic Activity of the Addition of 
Azacitidine (IND# 133688, NSC# 102816) to Chemotherapy in Infants with Acute 
Lymphoblastic Leukemia (ALL) and KMT2A (MLL) Gene Rearrangement 
 
 
 
A COG Groupwide Pilot Study 
 
NCI Supplied Agent: Azacitidine (IND# 133688, NSC# 102816) 
IND Sponsor for Azacitidine: DCTD, NCI 
 
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 
 
Erin Guest, M.D. 
2401 Gillham Rd. 
Kansas City, MO 64108 
Phone: (816) 302-6808 
Fax: 
(816) 302-9894 
E-mail: eguest@cmh.edu 
 
 
 
 


 
 
 
AALL15P1 
Page 2 
Version date: 9/25/19 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact  the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 


 
 
 
AALL15P1 
Page 3 
Version date: 9/25/19 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
8 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA 
11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
12 
1.1 
Primary Aims 
12 
1.2 
Secondary Aims 
12 
1.3 
Exploratory Aims 
12 
2.0 
BACKGROUND 
13 
2.1 
Introduction/Rationale for Development 
13 
2.1.1 
Rationale for Interfant Backbone Chemotherapy 
13 
2.1.2 
Rationale for Azacitidine 
14 
2.1.3 
Interfant-06 and Azacitidine 
14 
2.2 
Preclinical Studies 
14 
2.3 
Adult Studies 
15 
2.4 
Pediatric Studies 
15 
2.4.1 
Azacitidine: Cytotoxic Drug 
15 
2.4.2 
Azacitidine: DNA Methyltransferase Inhibitor 
16 
2.5 
Dosing Rationale 
17 
2.6 
Recovery Weeks 
17 
2.6.1 
Extension in the length of Induction therapy recovery time. 
18 
2.7 
Pharmacodynamic Assessment of DNA Methylation 
18 
2.8 
Molecular Profiling of Diagnostic, Remission and Refractory/Relapse Leukemic 
Cells (Banking for Future Research) 
18 
2.9 
Minimal Residual Disease (MRD) 
18 
2.10 
Pharmacokinetics (PK) of azacitidine 
19 
2.11 
Feasibility of CAR T-cell production for infants with ALL 
19 
2.12 
Pharmacodynamics of Pegaspargase 
19 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
19 
3.1 
Study Enrollment 
19 
3.1.1 
Patient Registration 
19 
3.1.2 
IRB Approval 
20 
3.1.3 
Reservation Requirements 
21 
3.1.4 
Study Enrollment 
21 
3.1.5 
Timing 
22 
3.2 
Patient Eligibility Criteria 
22 
3.2.1 
Age 23 
3.2.2 
Diagnosis 
23 
3.2.3 
Exclusion Criteria 
23 
3.2.4 
Regulatory Requirements 
24 
3.3 
KMT2A Rearrangement (KMT2A-R) Status 
24 
3.4 
Definitions 
24 
4.0 
TREATMENT PROGRAM 
27 
4.1 
Overview of Treatment Plan 
27 


 
 
 
AALL15P1 
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4.1.1 
Concomitant Therapy Restrictions 
27 
4.2 
Induction 
29 
4.2.1 
Therapy Delivery Map - INDUCTION 
29 
4.2.2 
Therapy Delivery Map – INDUCTION Continued 
30 
4.2.3 
Required Observations in Induction 
31 
4.2.4 
Induction Treatment Details 
32 
4.3 
Azacitidine EPI BLOCK #1 
36 
4.3.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #1 
36 
4.3.2 
Required Observations in Azacitidine EPI BLOCK #1 
37 
4.3.3 
Treatment Details for EPI BLOCK #1 
38 
4.4 
Consolidation 
39 
4.4.1 
Therapy Delivery Map - CONSOLIDATION 
39 
4.4.2 
Required Observations in CONSOLIDATION 
40 
4.4.3 
Treatment Details for CONSOLIDATION 
41 
4.5 
Azacitidine EPI BLOCK #2 
44 
4.5.1 
Therapy Delivery Map – EPI BLOCK #2 
44 
4.5.2 
Required Observations in Azacitidine EPI BLOCK #2 
45 
4.5.3 
Treatment Details for Azacitidine EPI BLOCK #2 
46 
4.6 
Interim Maintenance 
47 
4.6.1 
Therapy Delivery Map – INTERIM MAINTENANCE (IM) Phase 1 
47 
4.6.2 
Therapy Delivery Map – INTERIM MAINTENANCE (IM) Phase 2 
Continued 
48 
4.6.3 
Required Observations in INTERIM MAINTENANCE (IM) 
49 
4.6.4 
Treatment Details for INTERIM MAINTENANCE (IM) 
50 
4.7 
Azacitidine EPI BLOCK #3 
53 
4.7.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #3 
53 
4.7.2 
Required Observations in Azacitidine EPI BLOCK #3 
54 
4.7.3 
Treatment Details for Azacitidine EPI BLOCK #3 
55 
4.8 
Delayed Intensification Part 1 
56 
4.8.1 
Therapy Delivery Map – DELAYED INTENSIFICATION PART 1 
56 
4.8.2 
Therapy Delivery Map – DELAYED INTENSIFICATION PART 1 
Continued 
57 
4.8.3 
Required Observations in DELAYED INTENSIFICATION PART 1 
58 
4.8.4 
Treatment Details for DELAYED INTENSIFICATION PART 1 
59 
4.9 
Azacitidine EPI BLOCK #4 
62 
4.9.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #4 
62 
4.9.2 
Required Observations in Azacitidine EPI BLOCK #4 
63 
4.9.3 
Treatment Details for Azacitidine EPI BLOCK #4 
64 
4.10 
Delayed Intensification PART 2 
65 
4.10.1 Therapy Delivery Map – DELAYED INTENSIFICATION PART 2 
65 
4.10.2 Required Observations in DELAYED INTENSIFICATION PART. 2 
66 
4.10.3 Treatment Details for DELAYED INTENSIFICATION PART 2 
67 
4.11 
Maintenance Cycle 1 
68 
4.11.1 Therapy Delivery Map –MAINTENANCE Cycle 1 
68 
4.11.2 Required Observations in MAINTENANCE Cycle 1 
69 
4.11.3 Treatment Details for MAINTENANCE Cycle 1 
70 
4.12 
Maintenance Cycle 2 
72 
4.12.1 Therapy Delivery Map –MAINTENANCE Cycle 2 
72 
4.12.2 Required Observations in MAINTENANCE Cycle 2 
73 
4.12.3 Treatment Details for MAINTENANCE Cycle 2 
74 
4.13 
Maintenance Cycle 3 and Subsequent Cycles 
76 


 
 
 
AALL15P1 
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4.13.1 Therapy Delivery Map –MAINTENANCE Cycle 3 and Subsequent Cycles
 
76 
4.13.2 Required Observations in MAINTENANCE Cycle 3 and Subsequent Cycles
 
77 
4.13.3 Treatment Details for MAINTENANCE Cycle 3 and Subsequent Cycles. 78 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
79 
5.1 
Azacitidine 
79 
5.1.1 
Definition of Dose-Limiting Toxicity (DLT) 
79 
5.1.2 
Hematological Toxicity 
79 
5.1.3 
Non-Hematological Toxicity 
80 
5.2 
Cyclophosphamide 
80 
5.3 
Cytarabine (ARAC) 
81 
5.4 
Daunorubicin (Anthracycline) 
81 
5.5 
Intrathecal Methotrexate 
82 
5.6 
High Dose Methotrexate (HD MTX) and Leucovorin Rescue 
84 
5.6.1 
HD Methotrexate Infusion Guidelines 
84 
5.7 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
87 
5.8 
Pegaspargase [Asparaginase (Peg-Asparaginase) or Erwinia] 
89 
5.9 
Steroids (Dexamethasone and Prednisone) 
91 
5.10 
PO-6-Thioguanine (TG) 
92 
5.11 
VinCRIStine 
92 
5.12 
Drug Interactions 
94 
6.0 
DRUG INFORMATION 
95 
6.1 
AZACITIDINE – INJECTION 
95 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
101 
6.3 
CYTARABINE – ALL ROUTES 
102 
6.4 
DAUNORUBICIN 
105 
6.5 
DEXAMETHASONE 
107 
6.6 
HYDROCORTISONE - INTRATHECAL 
108 
6.7 
LEUCOVORIN CALCIUM 
110 
6.8 
MERCAPTOPURINE 
112 
6.9 
METHOTREXATE – ALL ROUTES 
114 
6.10 
PEGASPARGASE 
118 
6.11 
PREDNISO(LO)NE 
119 
6.12 
THIOGUANINE 
121 
6.13 
VINCRISTINE SULFATE 
122 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
124 
7.1 
End of Therapy & Follow-up 
124 
7.3 
Shipping Information for MRD Flow Cytometry Laboratories 
125 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
126 
8.1 
Criteria for Removal from Protocol Therapy 
126 
8.2 
Off Study Criteria 
126 
9.0 
STATISTICAL CONSIDERATIONS 
126 
9.1 
Sample Size and Study Duration 
126 
9.2 
Study Design 
127 
9.2.1 
Primary Endpoint 
127 


 
 
 
AALL15P1 
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9.2.2 
Secondary Endpoint 
127 
9.2.3 
Exploratory Endpoints 
127 
9.2.4 
Analysis for Primary Endpoint 
127 
9.2.5 
Analysis for Secondary Endpoint 
129 
9.2.6 
Analysis for Exploratory Endpoints 
129 
9.3 
Methods of Analysis 
129 
9.4 
Evaluability for Response 
130 
9.5 
Evaluability for Toxicity 
130 
9.6 
Gender and Minority Accrual Estimates 
130 
10.0 
EVALUATION CRITERIA 
131 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
131 
10.2 
Response Criteria for Patients with Leukemia 
131 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
132 
11.1 
Purpose 
132 
11.2 
Determination of reporting requirements 
132 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
132 
11.4 
Special Situations for Expedited Reporting 
133 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
133 
11.4.2 Persistent or Significant Disabilities/Incapacities 
133 
11.4.3 Death 
133 
11.4.4 Secondary Malignancy 
134 
11.4.5 Second Malignancy 
134 
11.5 
Reporting Requirements for Specialized AEs 
134 
11.5.1 Baseline AEs 
134 
11.5.2 Persistent AEs 
135 
11.5.3 Recurrent AEs 
135 
11.6 
Exceptions to Expedited Reporting 
135 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
135 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
135 
11.7 
Reporting Requirements – Investigator Responsibility 
135 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
136 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
137 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
138 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERs abbreviated 
pathway 
138 
11.12 Routine Adverse Event Reporting 
138 
11.13 Syndrome Reporting 
139 
12.0 
STUDY REPORTING AND MONITORING 
139 
12.1 
CDUS 
139 
12.2 
Data and Safety Monitoring Committee 
139 
12.3 
CRADA/CTA 
140 
13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
141 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
142 
14.1 
Pharmacodynamic Assessment of DNA Methylation (Required) 
142 
14.1.1 Timing of Pharmacodynamic Sampling 
142 
14.1.2 Sample Collection and Processing 
142 
14.1.3 Sample Labeling and Shipping 
142 


 
 
 
AALL15P1 
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14.2 
Minimal Residual Disease (MRD) Results Reporting (Optional) 
142 
14.2.1 Reporting of MRD Results 
142 
14.3 
Banking for Future Research (Optional) 
143 
14.3.1 Timing of Molecular profiling sampling 
143 
14.3.2 Sample Collection and Processing 
143 
14.3.3 Sample Labeling and Shipping 
143 
14.4 
Pharmacokinetics of azacitidine (Optional) 
144 
14.4.1 Timing of pharmacokinetic sampling 
144 
14.4.2 Sample Collection and Processing 
144 
14.4.3 Sample Labeling and Shipping 
144 
14.5 
Assessment of Infant T cell Proliferative Capacity (Optional) 
145 
14.5.1 Timing of (CAR) T-cell sampling 
145 
14.5.2 Sample Collection and Processing 
145 
14.5.3 Sample Labeling and Shipping 
145 
14.6 
Pharmacodynamics of Pegaspargase (Optional) 
146 
14.6.1 Timing of pharmacodynamic sampling 
146 
14.7 
Bone Marrow: Central review of Cytogenetics/FISH (Required) 
146 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
147 
16.0 
RADIATION THERAPY GUIDELINES 
147 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES CTEP INVESTIGATOR 
REGISTRATION PROCEDURES 
148 
APPENDIX II:  CYP3A4/5 SUBSTRATES, INHIBITORS AND INDUCERS 
151 
APPENDIX III:  HIGH-DOSE METHOTREXATE FLOWCHART 
154 
APPENDIX IV: SUPPORTIVE CARE GUIDELINES 
155 
APPENDIX V: POSSIBLE DRUG INTERACTIONS 
159 
APPENDIX 
VI: 
ADDITIONAL 
INFORMATION 
FOR 
PHARMACODYNAMIC 
ASSESSMENT OF DNA METHYLATION 
164 
APPENDIX VII: ADDITIONAL INFORMATION FOR T CELL PROLIFERATION CAPACITY 
CORELATIVE BIOLOGY STUDY 
167 
APPENDIX VIII: PHARMACOKINETIC OF AZACITIDINE 
169 
APPENDIX IX: PROCEDURES FOR SARSTEDT MONOVETTE DRAWING SYSTEM 
173 
APPENDIX 
X: 
FISH 
TESTING: 
INFORMATION 
REGARDING 
SPECIMENS, 
RECOMMENDED ASSAYS AND ENTRY OF DATA INTO RAVE SYSTEM 
174 
REFERENCES 
178 
 


  
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Erin Guest, MD 
Lia Gore, MD 
Hematology/Oncology  
Hematology/Oncology  
Children’s Mercy Hospital 
Children’s Hospital Colorado 
2401 Gillham Rd 
Pediatrics, Mail Stop 8302 
Kansas City, MO 64108 
Aurora, CO 80045 
Phone: (816) 302-6808  
Phone: (720) 777-4159  
Fax: 
(816) 302-9894 
Fax: 
(720) 777- 7279 
E-mail: eguest@cmh.edu 
E-mail: lia.gore@ucdenver.edu 
STUDY VICE CHAIR 
Melinda Gordon Pauly, MD 
Patrick Brown, MD 
Hematology/Oncology  
Hematology/Oncology 
Children’s Healthcare of Atlanta 
John Hopkins University 
2015 Uppergate Drive. 4th Floor 
1650 Orleans St. CRB 2M49 
Atlanta, GA 30338 
Baltimore, MD 21231 
Phone: (404) 785- 1200  
Phone: (410) 614-4915  
Fax: 
(404) 785-3610 
Fax: 
(410) 955-8897 
E-mail: melinda.pauly@choa.org 
E-mail: pbrown2@jhmi.edu 
 
 
Daniel Steven Gary Wechsler, MD 
STUDY STATISTICIAN 
Hematology/Oncology 
John Kairalla, PhD 
Children’s Healthcare of Atlanta - Egleston 
Biostatistics 
1760 Haygood Drive NE 
Children’s Oncology Group- Data Center 
HSRB-W344 
6011 NW 1st Place 
Atlanta, GA 30322 
Gainesville, FL 32607 
Phone: (404) 727- 3620  
Phone: (352) 273-0574     
Fax: 
(404) 727- 4455 
Fax: 
(352) 392-8162     
E-mail: dan.wechsler@emory.edu 
E-mail: jkairalla@cog.ufl.edu      
 
 
Meenakshi Devidas, PhD 
STUDY COMMITTEE MEMBERS 
Biostatistics 
Mignon Lee-Cheu, Loh, MD 
Children’s Oncology Group -- Data Center 
Hematology/Oncology 
6011 NW 1st Place 
Helen Diller Family Comprehensive Cancer Center- 
Gainesville, FL 32607 
Box 3112 
Phone: (352) 392-0551  
1450 3rd St., Room 284 
Fax: 
(352) 392-8162 
San Francisco CA 94158 
E-mail: medvidas@cog.ufl.edu 
Phone: (415) 476-3831 
 
Fax: 
(415) 353-2657 
Rodney R. Miles, MD, PhD 
E-mail: lohm@peds.ucsf.edu  
Pathology 
 
Primary Children’s Hospital 
Elizabeth Ann Raetz, MD 
15 N. Medical Dr. East 
Hematology/Oncology 
JMRB Rm 2100 
Laura and Isaac Perlmutter Cancer 
Salt Lake City, UT 84112-0565 
Center at NYU Langone 
Phone: (801) 584-5240 
160 East 32nd St 
E-mail: Rodney.Miles@path.utah.edu  
New York, NY 10016 
 
Phone: (212) 263-9908 
 
E-mail: elizabeth.raetz@nyumc.org.edu  
Joel M. Reid, PhD 
 
Pharmacology 
 
Mayo Clinic 
 
17-42C Guggenheim Building 
 
200 First Street SW 
 
Rochester, MN 55905 
 
Phone: (507) 284-0822 
 
Email: reid.joel@mayo.edu 
 


  
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STUDY COMMITTEE MEMBERS 
Margaret Amanda August, PharmD 
Andrew Carroll, Ph.D  
Pharmacy 
Cytogenetics 
Children’s Mercy Hospitals and Clinics 
Department of Genetics 
2401 Gillham Road 
University of Alabama at Birmingham 
Kansas City, MO 64108 
1720 20th St. South 
Phone: (816) 234-6786  
Kaul Bldg., Room 314B 
E-mail: maaugust@cmh.edu 
Birmingham, AL 35294-2050 
 
Phone: (205) 934-0665  
Nyla A. Heerema, Ph.D. 
Fax: 
(205) 934-1078 
Cytogenetics 
E-mail: acarroll@uab.edu 
Nationwide Children’s Hospital 
 
The Ohio State University 
 
167 Hamilton Hall; 1645 Neil Ave. 
Todd E. Druley, MD, PhD 
Hamilton Hall Room 129 
Hematology/Oncology 
Columbus, OH 43210 
Washington University School of Medicine 
Phone: (614) 292-7815 
4515 McKinley Ave. Rm 4302 
Fax: 
(614) 292-7072 
Campus Box 8510 
E-mail: Nyla.Heerema@osumc.edu 
St. Louis, MO 63110 
 
Phone: (314) 454-2124 
RESEARCH COORDINATOR 
Fax: 
(314) 454-2780 
Susan Conway, BA, CCRP 
E-mail: druley_t@kids.wustl.edu 
Biostatistics 
 
University of Florida 
Holly Remington Kubaney, MSN 
6011 NW 1st Place 
Nursing 
Gainesville, FL 32607 
Dell Children’s Medical Center of Central Texas 
Phone:     (352) 273-0559 
1301 Barbara Jordan Blvd. Suite 401 
Fax:         (352) 392-8162 
Austin, TX 78723 
E-mail:    sconway@cog.ufl.edu 
Phone: (512) 628- 1900 
 
Fax: 
(512) 628- 1901 
PROTOCOL COORDINATOR 
E-mail: hrkubaney@ascension.org 
Rachel Vasquez, MS 
 
Children’s Oncology Group- Operations Center 
Cynthia Kihei, BSN, CRA 
222 E. Huntington Dr. Suite 100 
Clinical Research Associate 
Monrovia, CA 91016 
St. Mary’s Hospital 
Phone: (626) 241-1620 
901 45th Street 
Fax:     (626) 445-4334 
West Palm Beach, FL 33407 
E-mail: ravasquez@childrensoncologygroup.org  
Phone: (561) 882-4745  
 
Fax: 
(561) 840-6145 
NCI Supplied Agent: Azacitidine, NSC#102816 
E-mail: Cynthia.kihei@tenethealth.com  
Other Agents: Cytarabine NSC#63878, Commercial 
 
Cyclophosphamide NSC#26271, Commercial 
 
Daunorubicin NSC# 82151, Commercial 
 
Dexamethasone NSC#34521, Commercial 
 
Hydrocortisone NSC# 10483, Commercial 
 
Leucovorin calcium NSC# 3590, Commercial 
 
Mercaptopurine, NSC#755, Commercial 
 
Methotrexate, NSC#740, Commercial 
 
Pegaspargase, NSC#624239, Commercial 
 
Prednisone NSC # 10023, Commercial 
 
Thioguanine NSC#752, Commercial 
 
Vincristine, NSC#67574, Commercial 
 
IND#: 133688 
 
IND Sponsor for azacitidine: DCTD, NCI 
 
SEE SECTION 14.0 FOR SPECIMEN SHIPPING ADDRESSES 


  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others 
 
 
ABSTRACT 
AALL15P1, a COG group-wide pilot study for infants less than 1 year of age with newly diagnosed B 
lymphoblastic leukemia (also termed B-precursor acute lymphoblastic leukemia) or acute leukemia of 
ambiguous lineage, will assess whether it is feasible to add azacitidine (VIDAZA) to the Interfant-06 
standard chemotherapy backbone. Though the rate of remission for infants with acute lymphoblastic 
leukemia (ALL) with KMT2A gene (previously referred to as the MLL gene) rearrangement (KMT2A-R) is 
high, the event-free survival (EFS) and overall survival (OS) for infants with KMT2A-R ALL remain poor. 
Epigenetic features of ALL cells with KMT2A-R, including DNA hypermethylation, may contribute to early 
chemotherapy resistance and relapse. DNA demethylating agents have been shown to reverse the 
methylation signature and improve the cytotoxicity of chemotherapy in infant ALL cells with KMT2A-R. 
Azacitidine is a DNA demethylating agent that has been used safely in combination with chemotherapy in 
pediatric patients 0-20 years of age with leukemia. The tolerability of azacitidine in combination with 
chemotherapy in infants with KMT2A-R ALL has not been previously tested. 
 
Infants with newly diagnosed B lymphoblastic leukemia or acute leukemia of ambiguous lineage will be 
treated with standard Induction chemotherapy based on AALL0631 Induction, with pegaspargase. 
Following Induction, infants with KMT2A-R will be non-randomly assigned to receive four courses of 
azacitidine therapy, as epigenetic priming, prior to each major block of post-Induction chemotherapy. 
Infants with KMT2A germline (non-rearranged) leukemia will not receive azacitidine and will be removed 
from protocol therapy following remission assessment at the completion of Induction. 
 
The post-Induction chemotherapy backbone for infants with KMT2A-R is based upon the Interfant-06 
standard chemotherapy, which is considerably less intensive than prior COG protocols, but has been 
associated with essentially identical outcomes. This trial aims to determine whether azacitidine can be 
safely incorporated into the Interfant-06 chemotherapy backbone. If the combination is tolerable, then an 
international Phase 3 trial will test the efficacy of azacitidine in preventing relapse among infants with 
KMT2A-R ALL. 
 
Amendment #1 extends the allowable time for Induction recovery to avoid unneccessary removal of 
infants from protocol therapy. 
 
 
 


  
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EXPERIMENTAL DESIGN SCHEMA 
 
  
 
Patients without 
KMT2A-R go off 
protocol therapy 
Consolidation 
(6 weeks) 
Delayed Intensification Part. 1 
(5 weeks) 
Interim Maintenance 
(6 weeks) 
Induction (5 weeks) 
Note: Age-based dosing 
Genetic Evaluation 
KMT2A-R: KMT2A gene- Rearrangement 
EPI: Azacitidine Epigenetic Therapy 
 
Induction: Methotrexate, Predniso(lo)ne, Daunorubicin, Cytarabine, Dexamethasone, Vincristine, Pegaspargase, and Hydrocortisone 
Consolidation: Cyclophosphamide, Mesna, Mercaptopurine, Cytarabine, Methotrexate, and Hydrocortisone. 
Interim Maintenance: Mercaptopurine, High-dose Methotrexate, Leucovorin, Methotrexate/Hydrocortisone, High-dose Cytarabine, and 
Pegaspargase. 
Delayed Intensification: Dexamethasone, 6-Thioguanine, Vincristine, Daunorubicin, Pegaspargase, Cyclophosphamide, Cytarabine, and 
Hydrocortisone 
Maintenance: Mercaptopurine, Methotrexate, Hydrocortisone, and Cytarabine 
KMT2A-R 
EPI #2 (Day 1-5)  
EPI #1 (Day 1-5) 
EPI #3 (Day 1-5) 
EPI #4 (Day 1-5) 
Maintenance 
AALL15P1 (Study Entry) 
Delayed Intensification Part. 2 
(3 weeks) 


  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
1.1.1 
To evaluate the tolerability of azacitidine in addition to Interfant-06 standard 
chemotherapy in infants with newly diagnosed ALL with KMT2A gene 
rearrangement (KMT2A-R). 
 
1.2 
Secondary Aims 
 
1.2.1 
To evaluate the biologic activity of azacitidine by pharmacodynamic assessment 
of global DNA methylation in peripheral blood mononuclear cells (PBMCs) of 
infants treated with azacitidine. 
 
1.3 
Exploratory Aims 
1.3.1 
To determine the 5 year event-free survival (EFS) of infants with KMT2A-R treated 
with azacitidine in addition to Interfant-06 standard chemotherapy. 
 
1.3.2 
To correlate minimal residual disease (MRD) with outcome in the context of the 
protocol therapy.  
 
1.3.3 
To perform pharmacokinetic (PK) testing of azacitidine in infants. 
 
1.3.4 
To test the expansion of infant T lymphocytes by stimulation with artificial antigen 
presenting cells identical to those used in CART-19 production. 
 
1.3.5 
To collect pharmacodynamic (PD) data for asparaginase activity following 
pegaspargase administration in infants. 
 
 
 
 


  
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2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Approximately 75-80% of infant ALL cases contain KMT2A (previously “MLL”)-R. These 
are driver mutations and there are very few, if any, other somatic mutations that accompany 
KMT2A-R in infant ALL. Survival for infants diagnosed with KMT2A-R ALL remains poor 
despite intensive chemotherapy with/without stem cell transplantation. The two largest 
completed infant ALL trials to date are COG P9407 and Interfant-99, and results in these 
two studies were quite similar for KMT2A-R patients: P9407 5-year event-free survival 
(EFS) 36% vs. Interfant 4-year EFS 37%.1,2 The results of AALL0631, which incorporated 
FLT3 inhibition with lestaurtinib into therapy for infants with ALL, demonstrate similar 
EFS to prior trials for infants with KMT2A-R ALL and no significant improvement with 
lestaurtinib [3-year EFS 37% (n=54) with chemotherapy alone vs. 3-year EFS 37% (n=67) 
for chemotherapy with lestaurtinib; p=0.90] (P. Brown, SIOP Abstract, 2016). Relapse 
frequently occurs early, and often during therapy, for infants with KMT2A-R ALL, and 
second remission is very difficult to achieve. Thus, novel treatments are necessary to 
improve the rates of sustained first remission and overall survival (OS). MLL fusion 
proteins contribute to transformation by altering the epigenetic landscape of multiple target 
genes. Epigenetic modifiers, including DNA methyltransferase inhibitors (DNMTi), have 
shown preclinical efficacy against KMT2A-R ALL blasts. This study will test the 
tolerability and biologic activity of the addition of the DNMTi azacitidine to chemotherapy 
in infants with KMT2A-R ALL in preparation for a randomized international trial of 
chemotherapy +/- this agent. One dose level will be evaluated using a design that allows 
safe and efficient monitoring of the combination. 
 
2.1.1 
Rationale for Interfant Backbone Chemotherapy 
This protocol will adopt the Interfant-06 standard as the chemotherapy backbone, 
based upon comparable outcomes (see above) of COG P9407 and the predecessor 
Interfant-99 regimen, and the lower cumulative chemotherapy exposure of the 
Interfant backbone compared with prior COG regimens. Complete remission (CR) 
rate was 94% and 4-year EFS was 47% for all patients enrolled on Interfant-99.2 
The toxicities reported were similar to previous protocols, with toxic death rate of 
5.2% in remission.2 The standard arm of Interfant-06 is based upon the standard 
risk arm of Interfant-99, with the addition of BFM Protocol IB therapy 
(cyclophosphamide, mercaptopurine, cytarabine, IT methotrexate/prednisone and 
IT cytarabine/prednisone) as the first post-Induction block. Interfant-06 was 
designed to randomize this standard treatment against additional post-Induction 
chemotherapy intensification. At the time of AALL15P1 development, 414 
patients with KMT2A-R ALL have been enrolled on Interfant-06, and 215 are being 
treated on the standard arm. The death rate for patients on the standard arm is 3% 
overall. Infections are the most common serious adverse event with suspected 
relationship to treatment, and occur most frequently during the MARMA phase. 
Interfant-06 is an active study and outcomes data for the randomized treatment are 
not yet available for review. 
 
Induction therapy for this pilot study will be based upon the amended Interfant-
based AALL0631 induction (cohort 2), but with a change to pegaspargase. Though 
infectious complications and toxic mortality have been problematic in trials of 
infants with ALL, the modification of AALL0631 to Interfant-based induction in 
cohort 2 led to reduced toxicity.3,4 Cohort 1 of AALL0631 had received P9407-


  
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based Induction with reduced anthracycline dosing and a change to pegaspargase 
(2500 IU/m2) from native L-asparaginase. Interfant-06 continues to use native L-
asparaginase during Induction, with a total cumulative dose that is 2 times higher 
than the cumulative dose provided in the amended AALL0631 Induction, but the 
native L-asparaginase formulation is no longer available in the United States. 
Pegaspargase has the advantage of sustained asparagine depletion and it is well 
tolerated in infants on Interfant and COG trials during post-Induction phases. 
Therefore, one dose of pegaspargase will be substituted for the six doses of native 
L-asparaginase. During Induction, the dose of pegaspargase will be reduced by 
20% from the standard dose to 2000 units per m2 body surface area (BSA) for 
infants ages 6 months and older at diagnosis, with additional age-based dose 
reductions for younger infants. Standard dose pegaspargase was associated with 
excessive toxicities in AALL0631 cohort 1 and standard dose pegaspargase has 
not been previously administered to infants receiving Interfant-based Induction. 
Therefore, this trial will provide the reduced dose pegaspargase to all infants in an 
effort to reduce the risk of associated toxicities.  
 
2.1.2 
Rationale for Azacitidine 
KMT2A-R ALL blasts demonstrate unique biological features, including 
characteristic gene expression profiles and epigenetic alterations. DNA promoter 
hypermethylation, which results in silencing of genes, including tumor suppressor 
genes, is a feature of infant KMT2A-R ALL.5-4 Clonal methylation changes have a 
critical role in chemoresistance and relapse in infant ALL.6 In vitro exposure of 
infant KMT2A-R ALL samples to the DNMTis decitabine and zebularine has been 
shown to reverse the methylation pattern of silenced genes and induce selective 
cytotoxicity for KMT2A-R cells.7,8 There is growing clinical experience with 
DNMTis in combination with chemotherapy in acute leukemia in children, but no 
specific treatment experience in infants. Thus, a pilot study in infants to determine 
the safety of this combination with chemotherapy is warranted. For this trial in a 
highly vulnerable infant population, azacitidine has been chosen for study, based 
upon its availability and preferred profile of safety and tolerability in prior 
pediatric studies. 
 
2.1.3 
Interfant-06 and Azacitidine 
The experimental combination of a DNMTi with chemotherapy shows preclinical 
efficacy in KMT2A-R infant blasts and this trial is designed to address the poor 
outcomes and high relapse rate of infants with KMT2A-R ALL. Many infants with 
KMT2A-R ALL present with features of mixed lineage or biphenotypic leukemia, 
and infants with mixed lineage leukemia will also be eligible, as long as the 
predominant features are lymphoblastic. Azacitidine will be given to infants with 
KMT2A-R ALL as 4 courses of epigenetic priming therapy prior to blocks of post-
Induction chemotherapy. Infants who enroll and are later found to have KMT2A 
germline ALL will continue on protocol therapy for Induction and remission 
assessment, but will be removed from protocol prior to the first course of 
azacitidine. 
 
2.2 
Preclinical Studies 
Preclinical studies of methylation patterns in infant ALL cell lines and patient samples have 
identified DNA hypermethylation as an important pathway driving leukemogenesis and is 
a potential target for testing in infant ALL models.7,9,10 Kostadinov et al., reported the 


  
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critical role of subclonal methylation changes in chemoresistance and relapse of infant 
ALL.6 Azacitidine has established efficacy as a demethylating agent in myelodysplastic 
syndrome and demonstrated a direct cytotoxic effect in vitro against pre-B ALL cells.11 
Decitabine and zebularine are similar DNA demethylation inhibitors that have 
demonstrated preclinical efficacy in the treatment of KMT2A-R ALL cells. Bhatla et al., 
described reversal of the gene methylation signature and cytotoxicity of the combination 
of decitabine with vorinostat in B-ALL patient samples and KMT2A-R cell lines.12 Stumpel 
et al., further demonstrated that infant ALL cells with KMT2A-R are susceptible to 
demethylating agents.5 In a study of the methylation patterns of infant ALL, Shaefer et al. 
identified significantly more promoter hypermethylation in KMT2A-R patient-derived 
cells, compared with KMT2A-wild type infant ALL cells.7 Genes with promoter 
hypermethylation correlated with down-regulated or silenced expression. Treatment with 
decitabine preferentially led to cytotoxicity of KMT2A-R cell lines, compared with 
KMT2A-wild type cell lines, supporting the role for demethylating agents in inducing 
cytotoxicity and chemosensitivity in the treatment of infant KMT2A-R ALL. 
 
2.3 
Adult Studies 
Azacitidine is indicated for the treatment of all types of myelodysplastic syndrome (MDS). 
Typical dosing of azacitidine as monotherapy for MDS is 75 mg/m2/day IV or 
subcutaneous daily for 7 days, repeated in cycles every 28 days. Common adverse reactions 
include neutropenia, thrombocytopenia, and anemia, gastrointestinal toxicity, and infusion 
site reactions with subcutaneous administration [VIDAZA ® package insert]. Azacitidine 
has moderate emetogenic potential. In adult patients, azacitidine has been administered in 
combination with chemotherapy to treat acute myeloid leukemia (AML) and prostate 
cancer. The results have been mixed with regards to efficacy, and the dose limiting 
toxicities of azacitidine in combination with chemotherapy have been related to 
myelosuppression. In a pilot study of azacitidine as epigenetic treatment prior to standard 
7 + 3 cytarabine and daunorubicin chemotherapy for adult patients with AML, the 
combination was feasible.13 The doses given were 37.5 mg/m2/day and 75 mg/m2/day IV 
for 5 days. There were no dose limiting toxicities, but there were fatal adverse events in 
this older population during Induction treatment. In a randomized study of chemotherapy 
with or without azacitidine for older patients with AML by Muller-Tidow et al., azacitidine 
was dosed at 75 mg/m2/day IV for 5 days prior to each course of chemotherapy and every 
4 weeks during Maintenance therapy.14 The median age of patients in the study was 70 
years and the study authors concluded that azacitidine added toxicity, but did not provide 
benefit for unselected older patients. Singal et al. conducted a Phase 1/2 study of 
azacitidine prior to docetaxel and prednisone in men with metastatic castration-resistant 
prostate cancer, and the treatment combination demonstrated biologic activity without dose 
limiting toxicity.15 The recommended Phase II dose was 75 mg/m2/day IV for 5 days, 
followed by docetaxel with growth factor support. Objective response was noted in 3 of 10 
evaluable patients. 
 
2.4 
Pediatric Studies 
2.4.1 
Azacitidine: Cytotoxic Drug 
Azacitidine has been studied in high doses as a cytotoxic drug for acute leukemia 
since the 1970s. Karon et al., published the use of azacitidine in 37 children with 
acute leukemia in 1973.16 The maximum tolerated dose (MTD) was estimated to 
be 150 mg/m2 to 200 mg/m2 IV when given for 5 days every 14 days. The major 
dose limiting toxicities were nausea, vomiting, and diarrhea. In 1981 Look et al., 
treated relapsed AML in pediatric patients with 200 mg/m2/day of azacitidine for 


  
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2 days following etoposide on Days 1-3.17 The doses were repeated after 1-2 days 
and until the marrow became hypoplastic. Of 22 patients treated with this schedule, 
18 developed marrow hypoplasia and 10 entered CR. The major toxicity of the 
combination was prolonged pancytopenia. Azacitidine (300 mg/m2/day) IV for 
2 days, in combination with etoposide, was incorporated into a 5-drug regimen for 
newly diagnosed AML and reported by Kalwinsky et al., in 1988.18 Sixty-
eight children were treated on the study, the CR rate was 85% after Induction, but 
the failure free survival rate showed no improvement over prior trials. The 
toxicities 
reported 
included 
fungal 
infections, 
febrile 
neutropenia, 
myelosuppression, and one patient with cardiomyopathy. These toxicities were not 
specific to the addition of azacitidine. In 1996, Steuber et al., reported the results 
of a randomized study of a 3-drug combination of azacitidine (250 mg/m2/day), 
etoposide, and amsacrine compared with the control group, etoposide and 
amsacrine alone.19 The CR rate for refractory AML was significantly higher (18% 
vs 53%, p=0.03) with the addition of azacitidine.19 There was increased infectious 
toxicity in the 3-drug combination, though reported as comparable to standard 
AML Induction therapies. 
 
2.4.2 
Azacitidine: DNA Methyltransferase Inhibitor 
More recently, azacitidine and decitabine have been administered in lower doses 
as DNA methyltransferase inhibitors rather than as cytotoxic agents. Demonstrated 
efficacy in adults with myelodysplastic syndrome has led to FDA approval of both 
drugs as single agents. A number of studies have further explored the use of 
azacitidine and decitabine as “epigenetic priming” agents in combination with 
chemotherapy for resistant cancers.15,20-22 The major adverse effect of this approach 
is dose-limiting myelosuppression and the combination has increased toxicity 
without demonstrable benefit for elderly patients with acute myeloid leukemia.13,23 
Dose-limiting myelosuppression has also been noted in children with refractory 
solid tumors who received decitabine with intensive chemotherapy.24 However, 
Benton et al., trialed decitabine in combination with the first 5 days of Hyper-
CVAD therapy for children and adults (median age 33 years, range 4-67 years) 
with relapsed or refractory ALL, and the results were encouraging.25 The most 
common Grade 3 or 4 adverse events were hepatic dysfunction and hyperglycemia, 
an MTD was not reached, and the response rate to the combination was 56%. Thus, 
younger patients with ALL may tolerate the combination reasonably well at doses 
required for demethylation. 
 
Epigenetic priming therapy with a demethylating agent has been introduced into 
two pediatric trials of relapsed or refractory leukemia. The Therapeutic Advances 
in Childhood Leukemia & Lymphoma (TACL) consortium tested azacitidine as a 
priming agent prior to fludarabine and cytarabine in relapsed or refractory AML 
and ALL pediatric patients, ages 1-21 years.26 Azacitidine 75 mg/m2/day was 
given subcutaneously on Days 1-5, prior to the chemotherapy on Days 6-10. The 
rationale for this protocol was that low dose azacitidine as an epigenetic priming 
agent could reverse aberrant DNA methylation, overcome drug resistance, and 
improve the cytotoxic effect of the chemotherapy medications. Fifteen patients 
were enrolled and none experienced DLT. Non-hematologic toxicities ≥ Grade 3 
attributed to azacitidine included febrile neutropenia, infections, AST elevation, 
oral hemorrhage, and hypokalemia. Evidence of demethylation was seen in every 
patient by G-LINE analysis. The treatment was well tolerated in this population. 


  
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The TACL consortium is also testing a combination of epigenetic therapy 
(decitabine and the histone deacetylase inhibitor vorinostat) and intensive re-
Induction chemotherapy in children, ages 1-25 years, with relapsed ALL. 
Enrollment was temporarily suspended when non-albicans Candidemia developed 
in 4 of the first 5 enrolled patients, despite anti-fungal prophylaxis.27 After an 
amendment to reduce the decitabine dose and duration and to require empiric non-
azole fungal treatment, the infectious toxicity improved, but remains a significant 
concern. 
Thus, 
AALL15P1 
incorporates 
extensive 
supportive 
care 
recommendations for infants receiving azacitidine and chemotherapy (see 
Appendix IV). 
 
2.5 
Dosing Rationale 
Azacitidine will be given as pre-treatment prior to chemotherapy in 4 courses post-
Induction to infants with KMT2A-R. The rationale for pre-treatment is based upon the 
hypothesis that DNMT inhibition will reverse the epigenetic signature of the blasts and 
enhance the cytotoxicity of the chemotherapy. Following peripheral blood cell count 
recovery from the prior block, azacitidine will be given IV daily for 5 days. Chemotherapy 
will begin on the first day immediately following each azacitidine course. 
 
The dosing of azacitidine will be weight-based, with a BSA:weight conversion factor of 
30:1. The effect of the 30:1 conversion of BSA:weight dosing is to reduce doses to 
approximately 50% of BSA-based doses for newborns, up to approximately 75% of BSA-
based doses for 1-year-olds. Considering that the safe and biologically active BSA-based 
dose of azacitidine is 75 mg/m2 in older children, the starting dose (DL1) for this study will 
be 2.5 mg/kg (Table 1). If DL1 is deemed too toxic, then the azacitidine dose will be 
reduced by 30% to DL0, 1.8 mg/kg, for all infants with remaining azacitidine doses and 
for all subsequently enrolled infants. 
 
This pilot study does not seek to define maximum tolerated dose or to escalate doses to 
evaluate for clinical efficacy. Rather, DL1 (and DL0 if necessary) will be evaluated for 
tolerability and evidence of epigenetic activity in combination with chemotherapy. If both 
DL1 and DL0 are too toxic, but show evidence of biologic activity, then consideration will 
be given to amending the study to test lower doses. If not, the strategy will not be pursued 
further. 
 
Table 1: Experimental doses for infants with KMT2A-R 
Dose Level 
Azacitidine IV daily on Days 1-5 
1 
2.5 mg/kg 
0 
1.8 mg/kg 
 
2.6 
Recovery Weeks 
Interfant-06 standard therapy includes a minimum of 2 weeks of recovery time between 
MARMA and OCTADAD and 1 week of recovery time between Parts I & II of 
OCTADAD. Patients on Interfant-06 therapy must have an ANC > 500/μL and platelets > 
50,000/μL with resolution of mucositis to begin Protocol IB, MARMA, and OCTADAD. 
They must also meet specified ANC and platelet parameters for dosing of 
cyclophosphamide in Protocol IB, high dose cytarabine on Day 15 of MARMA and for all 
doses of vincristine and daunorubicin in OCTADAD. AALL15P1 includes 1 to 2 weeks of 
minimum recovery time prior to the start of each azacitidine course. Course 1 of azacitidine 
begins on Day 36 of Induction, 1 week following the end of Induction chemotherapy on 


  
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Day 29. Recovery of ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of mucositis 
and diaper area dermatitis to ≤ Grade 2, is required prior to the start of each azacitidine 
course. 
 
2.6.1 
Extension in the length of Induction therapy recovery time. 
Prior to Amendment #1 patients were required to meet criteria to begin EPI 
Block #1 by Day 50 of Induction. Induction chemotherapy on AALL15P1 begins 
with a week of prednisone on Days 1-7 and lasts for 5 weeks. The end-Induction 
bone marrow is requested on Day 35 and patients may begin EPI Block #1 as early 
as Day 36. A review of the first 5 patients enrolled on AALL15P1 demonstrated 
delayed recovery periods without excessive or unexpected adverse events. 
Similarly, Induction recovery times on AALL0631 post-Amendment #1A, which 
utilized the same chemotherapy with the exception that AALL0631 included 
Erwinia asparaginase instead of pegaspargase, resulted in mean and median 
lengths of 47 and 46 days, respectively. Induction length was > 50 days for 33 
infants (28%) and was ≥ 55 days for 17 infants (15%). The longest recovery time 
was 59 days, for 2 infants (Unpublished results). Therefore, Amendment #1 
extends the allowable time for Induction recovery to Day 64, to avoid unnecessary 
removal of infants from protocol therapy. Subjects who do not meet recovery 
criteria by Day 64 will be removed from protocol and will not receive azacitidine. 
 
 
2.7 
Pharmacodynamic Assessment of DNA Methylation 
A secondary endpoint of this trial is to determine if there is biologic activity of azacitidine 
at a tolerable dose level in infants with KMT2A-R ALL. The starting dose level is reduced 
from the typical adult BSA-based dosing of azacitidine and the metabolism of azacitidine 
may be altered in infants, so this trial will assess for evidence of demethylation at each 
dose level tested. Global methylation assessment of peripheral blood mononuclear cells 
(PBMCs) will be performed using a commercial ELISA LINE-1 kit which measures 5-
methylcytosine (5mC) content. Samples of peripheral blood will be collected on Day 1 
prior to azacitidine and on Day 5 of the first two courses of azacitidine. The mean 5mC 
content will be calculated for all patients before and after azacitidine, and a paired t-test 
will be performed to determine if there is significant demethylation in the study population 
for each tested dose level. See Sections 14.1 and Appendix VI for additional details. 
 
2.8 
Molecular Profiling of Diagnostic, Remission and Refractory/Relapse Leukemic Cells 
(Banking for Future Research) 
Submission of bone marrow aspirate material, peripheral blood, and leukapheresis material 
for molecular profiling is optional. Samples from consenting patients will be collected from 
all time points where a bone marrow evaluation is clinically indicated (at diagnosis, at the 
end of Induction, Consolidation and Interim Maintenance, and at the time of relapse). 
Submitted samples will be banked for the purpose of performing retrospective studies to 
refine risk stratification, identify new targets for therapy, identify biomarkers to predict 
response, and to link host polymorphisms with various disease characteristics and 
toxicities. Refer to Section 14.3 for details related to sample processing and shipping. 
 
2.9 
Minimal Residual Disease (MRD) 
As a part of standard care, MRD by flow cytometry in a COG-approved laboratory is 
required with bone marrow evaluations at the end of Induction, Consolidation, and Interim 


  
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Maintenance. Results will be collected from local institutions and correlated with disease 
outcome. MRD will not be used to determine treatment allocation. 
 
2.10 
Pharmacokinetics (PK) of azacitidine 
Participation in the PK of azacitidine study is optional for sites and patients. Please review 
the details outlined in Appendix VIII. Peripheral blood samples (1 mL) will be collected 
from an in-dwelling catheter or by venipuncture at 7 time points during the first course of 
azacitidine. Azacitidine is unstable in blood, and therefore all blood samples will be 
processed and plasma harvested immediately per the instructions provided in a study 
laboratory manual. A validated high-performance liquid chromatography/tandem mass 
spectrometric method (LC-MS/MS) will be used for azacitidine plasma concentration 
analysis by the bioanalytical laboratory. Sample collection kits and supplies will be 
provided by the sponsor or sponsor-designated vendor. Sample collection, processing, 
storage, and shipment instructions will be provided to study sites in a separate laboratory 
manual. 
 
2.11 
Feasibility of CAR T-cell production for infants with ALL 
This trial includes a correlative study testing the feasibility of T-cell collection for the 
purposes of chimeric antigen receptor (CAR) T-cell production from the peripheral blood 
in infants with ALL. For those patients who consent, peripheral blood samples will be 
collected prior to therapy initiation, at the end of Induction, and at the end of Consolidation 
therapy. Lymphocyte subsets will be quantified, and functional studies will be performed 
to assess the ability of the lymphocytes to expand in response to artificial antigen 
presenting cell stimulation ex vivo. The ability to expand in response to this stimulus is a 
critical determinant of the feasibility of adoptive immunotherapy, specifically for CART-
19. See Section 14.5 and Appendix VII for details. 
 
2.12 
Pharmacodynamics of Pegaspargase 
Asparaginase activity levels are recommended on the 7th day following the administration 
of pegaspargase during Induction, Interim Maintenance, and Delayed Intensification part 
1. For patients who consent, results will be collected from local institutions and correlated 
with outcome. Asparaginase activity levels are optional, are not reimbursed by the study, 
and will not be used to determine treatment allocation. Local investigators may choose to 
substitute Erwinia asparaginase for pegaspargase based on the activity level results, per 
each institution’s standard practice. Patients who develop clinical hypersensitivity to 
pegaspargase should be given Erwinia asparaginase (see Section 5.8) 
 
 
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 Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 


  
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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 I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
NOTE: 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. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 


  
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Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally. The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office. In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study.. Other site registration 
requirements 
(e.g., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password. 
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF  
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 


  
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All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in the Oncology Patient 
Enrollment Network (OPEN). Prior to discussing protocol entry with the patient, 
all site staff must use the CTSU OPEN Slot Reservation System to ensure that a 
slot on the protocol is available to the patient. Once a slot- reservation confirmation 
is obtained, site staff may then proceed to enroll the patient to this study. 
 
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. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. Patients who are started on protocol therapy prior to study 
enrollment will be considered ineligible. The only exceptions to this are steroid 
pretreatment or the administration of intrathecal methotrexate or intrathecal 
cytarabine as described in Section 3.2.3.4. 
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 


  
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of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, if applicable, must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
See Section 4.2.3 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Infants less than 1 year of age on the date of diagnosis are eligible; infants must be 
> 36 weeks gestational age at the time of enrollment.  
 
3.2.2 
Diagnosis 
 
3.2.2.1 
Patients must have newly diagnosed B lymphoblastic leukemia (2008 
WHO classification) also termed B-precursor acute lymphoblastic 
leukemia) or acute leukemia of ambiguous lineage (ALUL), which 
includes mixed phenotype acute leukemia (MPAL). For patients with 
ALUL, the morphology and immunophenotype must be at least 50% B 
lymphoblastic. 
CNS status must be determined based on a sample obtained prior to the 
administration of any systemic or intrathecal chemotherapy, with the 
exception of steroid pretreatment. 
 
3.2.3 
Exclusion Criteria 
 
3.2.3.1 
Patients with known absence of KMT2A-Rearrangement leukemia prior 
to enrollment. 
3.2.3.2 
Patients with Down syndrome. 
3.2.3.3 
Patients with secondary B-ALL that developed after treatment of a prior 
malignancy with cytotoxic chemotherapy. 
3.2.3.4 
With the exception of steroid pretreatment (defined in Section 3.4) or the 
administration of intrathecal methotrexate or intrathecal cytarabine, 
receipt of any other prior cytotoxic chemotherapy for either the current 
diagnosis of B-ALL or any cancer diagnosed prior to the initiation of 


  
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protocol therapy on AALL15P1. 
 
3.2.4 
Regulatory Requirements 
 
3.2.4.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
3.2.4.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
3.3 
KMT2A Rearrangement (KMT2A-R) Status 
All patients must undergo cytogenetic FISH testing at a COG-approved laboratory for 
KMT2A-R determination. Results must be submitted for central review and confirmation 
of KMT2A-R status. Patients will be eligible to remain on protocol therapy post-Induction 
if KMT2A-R is determined and confirmed by central review. Please refer to Appendix X 
and Section 14.7 for sample requirements and details regarding central review. 
3.4 
Definitions 
INITIAL WBC: The first WBC at the treating COG institution, or the WBC prior to 
intravenous fluids, whichever occurred first. If prior therapy (i.e. steroids) has been 
administered and a CBC is available that was obtained within 72 hrs prior to steroid 
therapy, then this pre-steroid WBC should be used. 
 
INITIAL PLATELET COUNT: The first platelet count at the treating COG institution, or 
the count before transfusion of platelets if transfused prior to arrival. 
 
INITIAL HEMOGLOBIN: The first hemoglobin at the treating COG institution, or the 
hemoglobin prior to intravenous fluid or red cell transfusions, whichever occurred first. 
 
STEROID PRETREATMENT: Patients who have received any amount of oral or IV 
steroids prior to study entry will be eligible for enrollment, provided patients meet all other 
eligibility requirements. Inhalational steroids and topical steroids are not considered to be 
pretreatment. 
 
CNS LEUKEMIA AT DIAGNOSIS: 
 
CNS 1: 
In cerebrospinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of white blood cells (WBCs). 
 
CNS 2: 
In CSF, presence < 5/L WBCs and cytospin positive for blasts, or traumatic 
LP, > 5/L WBCs, cytospin positive for blasts, but negative by Steinherz/Bleyer 
algorithm: 
 
CNS 2a: < 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; and 
CNS 2c: ≥ 10/L RBCs; ≥ 5/L WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below). 
 
CNS3: 
In CSF, after traumatic LP presence of ≥ 5/L WBCs and cytospin positive for 
blasts and/or clinical signs of CNS leukemia: 


  
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CNS 3a: < 10/L RBCs; ≥ 5/µL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer algorithm  
(see below); 
CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome). 
 
METHOD OF EVALUATING INITIAL TRAUMATIC LUMBAR PUNCTURES: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and the CSF 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 ≥ 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  and is >  2X   46000   = 0.015 
1500                       3.0 X 106 
 
TESTICULAR LEUKEMIA AT DIAGNOSIS:  
Unilateral or bilateral testiculomegaly. Biopsy is required if clinical findings are equivocal or 
suggestive of hydrocele or a non-leukemic mass. 
 
BONE MARROW STATUS: 
M1: < 5% lymphoblasts  
M2: 5%- 25% lymphoblasts 
M3: > 25% lymphoblasts. 
 
REMISSION 
M1 marrow with complete resolution of extramedullary leukemia. Must have absence of 
blasts on cytospin preparation and no clinical signs of CNS leukemia. 
 
BONE MARROW MRD STATUS (Day 35): 
Positive:  ≥ 0.01% detectable leukemia cells 
Negative:  < 0.01% detectable leukemia cells 
 
REFRACTORY DISEASE: 
Failure to achieve remission by the end of Consolidation therapy. 
 
RELAPSE: 
Any recurrence of disease, whether in marrow or extramedullary site(s), at any point after 
achieving remission. Relapse should be histopathologically confirmed. 
 
1) ISOLATED BONE MARROW RELAPSE: 
Patients with an M3 marrow at any point after achieving remission without involvement 


  
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of the CNS and/or testicles. 
 
2) COMBINED RELAPSE: 
M2 or M3 marrow at any point after achieving remission with concomitant CNS and/or 
testicular and/or other extramedullary site relapse. 
 
3) CNS RELAPSE: 
Positive cytomorphology and WBC ≥ 5/µL OR clinical signs of CNS leukemia such as 
facial nerve palsy, brain/eye involvement, or hypothalamic syndrome. If any CSF 
evaluation shows positive cytomorphology and WBC < 5/µL, a second CSF evaluation is 
required within 2-4 weeks. While identification of a leukemic clone in CSF by flow 
cytometry (TdT, CD19, CD10, etc) or FISH for diagnostic karyotypic abnormality may 
be useful, definitive evidence of CNS involvement (i.e. WBC ≥ 5/µL OR clinical signs of 
CNS leukemia) is required for the diagnosis of a CNS relapse. 
 
4) TESTICULAR RELAPSE: 
Must be documented by testicular biopsy, if not associated with a marrow relapse. 
 
5) ISOLATED EXTRAMEDULLARY RELAPSE 
Must be documented by histopathology, if not associated with a marrow relapse. 
 
DISEASE EVALUATION DURING FOLLOW-UP: 
A disease evaluation is a procedure ordered with the intent to measure or assess the disease 
status of a patient. The most common evaluations are a bone marrow aspirate and/or biopsy 
and a lumbar puncture (LP). If a CBC has findings that raise suspicion for relapse, a bone 
marrow aspirate must be performed to confirm the relapse. 
 
 
 
 


  
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4.0 
TREATMENT PROGRAM 
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 
Any infant < 1 year of age on the day of diagnosis with ALL or acute ambiguous lineage 
leukemia (ALUL) that is predominantly B lymphoblastic, which includes mixed phenotype 
acute leukemia (MPAL), is potentially eligible for enrollment on AALL15P1. Patients will 
be treated with a common 5-week Induction course, as detailed in Section 4.2. After 
Induction, only subjects with KMT2A-rearrangement (KMT2A-R) are eligible to continue 
on protocol therapy at which point they will receive azacitidine designated “EPI” prior to 
chemotherapy during 4 cycles of post-Induction therapy. 
 
Phases of Therapy:  
Post-Induction therapy includes 4 cycles of Azacitidine epigenetic therapy, Consolidation, 
1 Interim Maintenance phase with high dose methotrexate and high dose cytarabine, 2 
Delayed Intensification phases (as based on 1 OCTADAD phase from the Interfant 
backbone) and Maintenance. 
 
Chemotherapy Dosing: 
Chemotherapy dosing for infants on AALL15P1 is based on age and BSA. Induction 
chemotherapy is similar to the amended AALL0631 Induction (cohort 2), with the 
exception of a change to pegaspargase dosing. Post-Induction chemotherapy dosing is 
based upon the Interfant-06 standard backbone. Post-Induction, infants ≥ 12 months of age 
receive the full doses of chemotherapy, infants ≥ 6 months and < 12 months of age receive 
3/4 of the full doses, and infants <6 months of age receive 2/3 of the full doses. The 
AALL15P1 age-based dose-reductions are the same as the age-based dose reductions of 
Interfant-06. The appropriate BSA-based doses for each age group are listed on the therapy 
delivery maps. 
 
4.1.1 
Concomitant Therapy Restrictions 
4.1.1.1 
Patients 
cannot 
receive 
any 
non-protocol 
chemotherapy 
or 
investigational therapy while on this study. 
 
4.1.1.2 
Patients should avoid the use of Echinacea. 
 
4.1.1.3 
Cytochrome P450 Interactions with Antileukemic Drugs 
Since concurrent use of enzyme inducing anticonvulsants (e.g., 
phenytoin, phenobarbital, and carbamazepine) with antileukemic 
therapy has recently been associated with inferior EFS, every effort 
should be made to avoid these agents, as well as rifampin, which also 
induces many drug metabolizing enzymes.28 Neither gabapentin nor 
levetiracetam induce hepatic drug metabolizing enzymes and if 
clinically indicated may be suitable alternative anticonvulsants. Azole 


  
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antifungals (listed in the table below) and the macrolide group of 
antibiotics (listed in the table below) may have potent inhibitory effects 
on drug-metabolizing enzymes. Patients receiving some antileukemic 
drugs (e.g., vincristine, anthracyclines, etoposide) may experience 
excess toxicity when these agents are given concomitantly; alternate 
antifungal and antibacterial therapy should be used whenever possible 
(see table below). 
 
 
DRUGS 
POTENTIAL 
INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug 
metabolizing enzymes 
Lowered EFS 
AVOID fosphenytoin, phenytoin, phenobarbital, 
carbamazepine 
Consider gabapentin or levetiracetam as alternative 
Rifampin 
Rifabutin 
St. Johns Wort 
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, 
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.29,30  
For a more complete list of CYP3A 4/5 Inhibitors and Inducers, see Appendix II. 
 
 
4.1.1.4 
Possible Drug Interactions with High or Intermediate Dose Methotrexate 
Avoid 
non-steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
trimethoprim/sulfamethoxazole (TMP/SMX), penicillins, probenecid, 
IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin. 
Urinary acidifiers can cause methotrexate to precipitate in the urinary 
tract. 
 
4.1.1.5 
Supportive Care Guidelines 
Study-specific supportive care guidelines are provided in Appendix IV. 
In addition, for COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines 
under Standard Sections for Protocols. 
 
 
 


 
 
 
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Induction 
 
4.2 
Induction 
4.2.1 
Therapy Delivery Map - INDUCTION 
All patients will receive the same Induction therapy with regards to agents and schedule. Non-intrathecal 
doses during Induction are based on the age on the day of diagnosis. Intrathecal doses are based 
on the age on the day of administration. Induction therapy is 5 weeks (35 days) duration. 
 
 
_________________________________          _________________________ 
Patient COG ID number                                        DOB 
Treatment details and criteria to start are in Section 4.2.4. This Therapy Delivery Map is three (3) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Intrathecal Methotrexate (IT MTX) 
IT 
Age (yr)                      Dose 
< 1                              6 mg 
≥ 1                              8 mg 
1 & 29 
See Section 4.2.4 for additional guidelines. 
PredniSO(LO)NE (PRED) 
PO or NG 
Age                             Dose 
< 7d                            10 mg/m2/dose TID 
≥7d and <6mo            13 mg/m2/dose TID 
≥ 6mo                         15 mg/m2/dose TID 
1-7 
Administer 3 doses per day. See Section 4.2.4 for additional 
guidelines 
 
May substitute with methylprednisone IV at 80% of 
predniSO(LO)NE dose. 
DAUNOrubicin (DAUN) 
IV infusion over  
1-15 min 
Age                              Dose 
< 7d                             15 mg/m2/dose 
≥7d and <6mo            20 mg/m2/dose 
≥ 6mo                         23 mg/m2/dose 
8 & 9 
 
Cytarabine (ARAC) 
IV infusion over 
30 min 
Age                              Dose 
< 7d                             35 mg/m2/dose 
≥7d and <6mo             50 mg/m2/dose 
≥ 6mo                          60 mg/m2/dose 
8-21 
 
Dexamethasone (DEX) 
PO or NG or IV 
Age                             Dose 
< 7d                            1 mg/m2/dose TID 
≥7d and <6mo            1.3 mg/m2/dose TID 
≥ 6mo                         1.5 mg/m2/dose TID 
8-28 
Administer 3 doses per day. 
VinCRIStine (VCR) 
IV push over 
1 min+ 
Age                              Dose 
< 7d                             0.8 mg/m2/dose 
≥7d and <6mo            1 mg/m2/dose 
≥ 6mo                         1.2 mg/m2/dose 
8, 15,  
22 & 29 
Round final dose to the nearest 0.01 mg 
 
+Or infusion via minibag as per institutional policy 
 
Max dose 2mg 
Pegaspargase (PEG-ASP) 
IV over  
1-2 hours or IM 
Age                              Dose 
< 7d                             1250 IU/m2/dose 
≥7d and <6mo             1750 IU/m2/dose 
≥ 6mo                          2000 IU/m2/dose 
12 
 
Intrathecal Cytarabine (IT ARAC) 
IT 
Age (yr)                      Dose 
< 1                              15 mg 
≥ 1                              20 mg 
15 
 
Intrathecal Hydrocortisone (IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
15 & 29 
 
Continue to the next page for the therapy log. 
 
Page 1 of 3 
Page 2 of 3 


 
 
 
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Induction 
 
4.2.2 
Therapy Delivery Map – INDUCTION Continued 
All patients will receive the same Induction therapy with regards to agents and schedule. 
Non-intrathecal doses during Induction will be based on the age on the day of 
diagnosis. Intrathecal doses are based on the age on the day of administration. 
Induction therapy is 5 weeks (35 days) duration. 
 
 
 
_________________________________          _________________________ 
Patient COG ID number                                        DOB 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
IT MTX 
_____mg 
PRED 
___mg   ____mg 
___mg 
DAUN 
____mg 
ARAC 
____mg 
DEX 
____mg ____mg 
____mg 
VCR 
_____mg 
PEG-ASP 
_____IU 
IT ARAC 
____mg 
IT HC 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
_____mg 
 
____mg   ____mg 
                ____mg 
 
 
 
 
 
 
 
a-h, j, l, m 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
_____mg 
_____mg 
 
____mg   ____mg 
____mg 
_____mg 
 
 
 
b 
 
 
9 
 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
10 
 
 
 
_____mg 
 
 
 
 
 
 
 
11 
 
 
 
_____mg 
 
 
 
 
 
 
 
12 
 
 
 
_____mg 
 
_____IU 
 
 
 
 
 
13 
 
 
 
_____mg 
 
 
 
 
 
 
 
14 
 
 
 
_____mg 
 
 
 
 
 
 
 
15 
 
 
 
_____mg 
_____mg 
 
___mg 
_____mg 
b, c, f 
 
 
16 
 
 
 
_____mg 
 
 
 
 
 
 
 
17 
 
 
 
_____mg 
 
 
 
 
 
 
 
18 
 
 
 
_____mg 
 
 
 
 
 
 
 
19 
 
 
 
_____mg 
 
 
 
 
k 
 
 
20 
 
 
 
_____mg 
 
 
 
 
 
 
 
21 
 
 
 
_____mg 
 
 
 
 
 
 
 
22 
 
 
 
 
_____mg 
 
 
 
b 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
29 
_____mg 
 
 
 
 
_____mg 
 
 
_____mg 
f 
 
 
35 
 
 
 
 
 
 
 
 
 
b, c, h, i, j, 
l
 
 
56 
 
 
 
 
 
 
 
 
 
h* 
 
 
36 
 
Patients who do not have KMT2A-R ALL go off protocol therapy. 
 
For KMT2A -R ALL patients who have M1 or M2 marrow, following the completion of Induction therapy, begin EPI#1 (Section 4.3), when ANC ≥ 500/μL 
and platelets ≥ 50,000/ μL, and resolution of mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). Patients who do not meet criteria to 
start by Day 64 go off-protocol therapy. 
 
For KMT2A -R ALL patients with M3 marrow at the end of Induction, proceed to EPI #1 (Section 4.3), as soon as marrow results are known, irrespective 
of hematologic values, mucositis, and/or diaper dermatitis, and provided there is no active infection or life threatening organ malfunction. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 


  
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Induction 
 
 
 
4.2.3 
Required Observations in Induction 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below. 
*If count requirements are not met by Day 56 to begin EPI course #1, complete 
observation h. 
 
a) History & physical exam (including weight, height, BSA) 
b) CBC/diff/platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) Echo or MUGA 
e) CrCl or GFR (may be estimated using Schwartz formula) 
f) CSF cell count/diff/cytospin 
g) TPMT and NUDT15 genotype (TPMT highly recommended for all subjects; 
NUDT15 is highly recommended for subjects of Hispanic/Native American 
or East Asian ancestry, and optional for all other subjects (See Section 5.7)) 
h) Local bone marrow evaluation (pre-treatment must include KMT2A FISH and 
standard cytogenetic studies performed at COG-approved cytogenetics 
laboratory). Peripheral blood may be substituted pre-treatment if the bone 
marrow cannot be performed for medical reasons or inadequate marrow 
material is obtained, refer to Appendix X for sample requirements. SUBMIT 
RESULTS BY INDUCTION DAY 10 FOR CENTRAL REVIEW, see 
Section 14.7 and Appendix X 
i) MRD by flow cytometry in a COG-approved laboratory, please refer to the 
Section 7.3 for laboratory details. Note: For patients who consent, enter MRD 
results into RAVE (Section 14.2). 
j) Peripheral blood for the optional (CAR) T-cell study (Section 14.5). 
k) Report 
Asparaginase 
activity 
levels 
for 
optional 
pegaspargase 
pharmacodynamic study (Section 14.6). 
l) 
Bone marrow aspirate for the optional molecular profiling study (peripheral 
blood may be substituted in some cases, see Section 14.3). 
m) If apheresis is performed for clinical purposes, submit an apheresis sample for 
the optional molecular profiling study (Section 14.3). 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
Page 3 of 3 


  
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Induction 
 
4.2.4 
Induction Treatment Details 
Patients must be enrolled on study prior to the start of treatment with the 
exception of steroid pretreatment, IT methotrexate or IT cytarabine as 
defined in Section 3.2.3.4. 
 
All patients will receive the same Induction chemotherapy with regards to 
agents and schedule. Non-intrathecal drug doses during Induction are based 
on age on the day of diagnosis. Intrathecal drug doses are based on age on the 
day of administration. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Methotrexate: Intrathecal (IT) 
Days: 1 and 29 
Dose: Age-based dosing. 
Note: If a dose was received within 7 days prior to the start of protocol therapy 
and is per protocol dosing, Day 1 administration does not need to be repeated. 
Count this dose of IT therapy as the initial intrathecal dose. 
 
Age: 
Dose: 
< 1 year  
6 mg 
≥ 1 year  
8 mg 
 
PredniSO(LO)NE: Oral (PO) or Nasogastric (NG)  
Days: 1-7 
Dose: Age-based dosing. Administer 3 doses per day. 
Notes: If equivalent or higher doses are received within 7 days prior to the start of 
protocol therapy and are per protocol dosing, doses do not need to be repeated. 
Count protocol therapy beginning with the first dose of prednisone and adjust 
Day 8 therapy accordingly. 
 
Age: 
Dose: 
< 7 days 
10 mg/m2/dose TID 
≥7 d and <6 mo 
13 mg/m2/dose TID 
≥6 months 
15 mg/m2/dose TID 
 
Note: If a patient is unable to take predniSO(LO)NE by mouth or nasogastrically, 
IV methylprednisolone may be given at 80% of predniSO(LO)NE dose. 


  
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Induction 
 
DAUNOrubicin: Intravenous (IV) over 1-15 minutes 
Days: 8 & 9 
Dose: Age-based dosing. 
 
Age: 
Dose: 
< 7 days 
15 mg/m2/dose 
≥ 7 d and <6 mo 
20 mg/m2/dose 
≥6 months 
23 mg/m2/dose 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DAUNOrubicin is available in a liposomal 
formulation (DAUNOrubicin citrate, DaunXome®). The conventional and 
liposomal formulations are NOT interchangeable; use of the liposomal formulation 
is not permitted in this trial. 
 
Cytarabine: Intravenous (IV) over 30 minutes 
Days: 8-21 
Dose: Age-based dosing. 
 
Age: 
Dose: 
< 7 days 
35 mg/m2/dose 
≥ 7 d and <6 mo 
50 mg/m2/dose 
≥6 months 
60 mg/m2/dose 
 
 
Dexamethasone: Oral (PO), Nasogastric (NG) or Intravenous (IV) 
Days: 8-28 
Dose: Age-based dosing. Administer 3 doses per day. 
 
Age: 
Dose: 
< 7 days 
1 mg/m2/dose TID 
≥7 d and <6 mo 
1.3 mg/m2/dose TID 
≥ 6 months 
1.5 mg/m2/dose TID 
 
VinCRIStine: Intravenous (IV) over 1 minute or infusion via minibag as per 
institutional policy 
Days: 8, 15, 22, 29 
Dose: Age-based dosing. Max dose 2 mg. 


  
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Induction 
 
Age: 
Dose: 
< 7 days 
0.8 mg/m2/dose 
≥7 d and <6 mo 
1 mg/m2/dose 
≥ 6 months 
1.2 mg/m2/dose 
 
Note: round vinCRIStine dose to the nearest 0.01 mg 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine should be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only- Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). The conventional and liposomal 
formulations are NOT interchangeable; use of the liposomal formulation is not 
permitted in this trial. 
 
Pegaspargase: Intravenous (IV) over 1-2 hours or Intramuscular (IM) 
Day: 12 
Dose: Age-based dosing. 
 
Age: 
Dose: 
< 7 days 
1250 International Units (IU)/m2/dose 
≥ 7 d and <6 
mo 
1750 International Units/m2/dose 
≥ 6 months 
2000 International Units/m2/dose 
 
Cytarabine: Intrathecal (IT) 
Days: 15 
Dose: Age-based dosing. 
 
Age: 
Dose: 
< 1 year  
15 mg 
≥ 1 year  
20 mg 
 
Hydrocortisone: Intrathecal (IT) 
Days: 15 & 29 
Dose: Age-based dosing. 
 
Age: 
Dose: 
< 1 year 
12 mg 
≥ 1 year 
16 mg 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Patients who do not have KMT2A-R ALL go off protocol therapy. 
 


  
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Induction 
Patients with KMT2A-R ALL who have M1 or M2 marrow following the 
completion of Induction therapy should begin Azacitidine Epigenetic Therapy 1 
(EPI#1, Section 4.3), when ANC ≥ 500/μL and platelets ≥ 50,000/ μL, and 
resolution of mucositis and/or diaper area dermatitis to ≤ Grade 2 (whichever 
occurs later). Patients with KMT2A-R ALL who do not meet criteria to start by 
Day 64 go off protocol therapy (See Section 8.1). 
 
For KMT2A-R ALL patients with M3 marrow at the end of Induction, proceed to 
EPI #1 (Section 4.3), as soon as marrow results are known, irrespective of 
hematologic values mucositis, and/or diaper dermatitis, and provided there is no 
active infection or life threatening organ malfunction. 
 
 
 


  
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Azacitidine EPI Block 1 
4.3 
Azacitidine EPI BLOCK #1 
4.3.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #1 
Following Induction therapy and the recovery of peripheral blood 
cell counts, azacitidine will be administered as a pre-treatment prior 
to Consolidation therapy, for 5 days. Azacitidine therapy is 5 days. 
 
 
______________________     ______________________ 
      Patient COG ID number                            DOB 
 
Patients with KMT2A-R M3 marrow, start EPI Block #1 immediately following the completion of Induction therapy. Patients with KMT2A-R M1 or 
M2 marrow, start EPI Block # 1 when ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of mucositis and/or diaper area dermatitis to ≤ Grade 
2 (whichever occurs later).Treatment details and criteria to start are in Section 4.3.3. This Therapy Delivery Map is two (2) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Azacitidine (AZA) 
IND# 133688 
Do not use 
commercial supply 
IV over 10-40 mins 
2.5 mg/kg/dose 
1-5 
Note: Infusion must be completed within 
45 minutes of vial reconstitution. 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Azacitidine _______mg 
Studies 
 
Enter actual dose administered below 
 
 
 
1 
_______mg 
a-d 
 
 
2 
_______mg 
 
 
 
3 
_______mg 
e 
 
 
4 
_______mg 
e 
 
 
5 
_______mg 
d-e 
 
 
6 
Continue to Consolidation (Section 4.4) on Day 6 irrespective of ANC and platelet counts.  
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
 
 
Page 1 of 2 


  
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Azacitidine EPI Block 1 
 
4.3.2 
Required Observations in Azacitidine EPI BLOCK #1 
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) Peripheral blood for the required pharmacodynamic assessment of DNA 
methylation (Section 14.1). 
e) Peripheral blood for the optional azacitidine pharmacokinetic study (Section 
14.4). 
 
This listing only includes evaluations necessary to answer the primary 
and secondary aims. OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


  
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Azacitidine EPI Block 1 
4.3.3 
Treatment Details for EPI BLOCK #1 
Azacitidine will be given as pre-treatment prior to Consolidation 
therapy. 
 
Criteria to Start Azacitidine EPI Block #1 
Begin Azacitidine EPI Block #1 on Day 36 or when peripheral counts 
recover with ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of 
mucositis and/or diaper area dermatitis to ≤ Grade 2 (whichever occurs 
later). 
 
Azacitidine: Intravenous (IV) over 10-40 mins 
Days: 1-5 
Dose: 2.5 mg/kg/dose 
Note:  infusion must be completed within 45 minutes of vial reconstitution 
Do not use commercial supply. 
 
See Section 5.0 for Dose Modifications on Toxicities. 
 
Following completion of Azacitidine Epigenetic Therapy Block 
1 (EPI#1), begin Consolidation therapy (Section 4.4) on Day 6 
irrespective of ANC and platelet counts. 
 
 
 


 
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Consolidation 
 
4.4 
Consolidation 
4.4.1 
Therapy Delivery Map - CONSOLIDATION 
All patients will receive the same Consolidation therapy with regards to agents and 
schedule. Non-IT drugs are dosed based on age on Day 1 of Consolidation and BSA, as 
outlined below. IT doses are based on age on the day of administration. Consolidation 
therapy is 6 weeks (42 days) duration. 
 
 
_____________________  _____________ 
   Patient COG ID Number          DOB 
Following completion of Azacitidine Block 1 (EPI#1), begin Consolidation therapy on Day 6 irrespective of peripheral blood cell counts. Details and criteria 
to start are in Section 4.4.3. This Therapy Delivery Map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Cyclophosphamide 
(CPM) 
IV over 
30-60 min 
Age 
 
Dose 
< 6 mo 
 
670 mg/m2/dose 
≥ 6 mo & < 12 mo 
750 mg/m2/dose 
 ≥ 12 mo  
1000 mg/m2/dose 
1 & 29 
Patients should have ANC ≥ 500/μL and platelets 
≥ 30,000/μL to begin Day 29 therapy.  
 
Refer to Section 4.4.3 for admin guidelines.  
Mesna 
IV over 
15min 
Age 
 
Dose 
< 6 mo 
 
134 mg/m2/dose 
≥ 6 mo & < 12 mo 
150 mg/m2/dose 
≥ 12 mo 
 
200 mg/m2/dose 
1 & 29 
Administer at 0, 4 and 8 hours from the start of CPM 
infusion. 
 
Refer to Section 4.4.3 for admin guidelines.  
Mercaptopurine (MP) 
PO or NG 
Age 
 
Dose 
< 6 mo 
 
40 mg/m2/dose 
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose 
1-28 
 
Refer to Section 4.4.3 and Section 5.7 for admin 
guidelines.  
Cytarabine (ARAC) 
IV push 
or SubQ 
Age 
 
Dose 
< 6 mo 
 
50 mg/m2/dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose 
3-6, 10-
13, 17-20, 
& 24-27 
Patients should have ANC ≥ 300/μL and platelets 
≥ 30,000/μL to start each 4-day cytarabine block 
beginning on Days 10, 17, and 24. 
 
Refer to Section 4.4.3 for admin guidelines. 
Cytarabine (IT ARAC) 
IT 
Age (yr)                  Dose 
< 1                          15 mg 
≥ 1                          20 mg 
10 
 
Intrathecal 
Hydrocortisone (IT HC) 
IT 
Age (yr)                  Dose 
< 1                          12 mg 
≥ 1                          16 mg 
10 & 24 
 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yr)                  Dose 
< 1                          6 mg 
≥ 1                          8 mg 
24 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
MESNA 
____mg  ___mg  ___mg 
MP 
____mg 
ARAC 
____mg 
IT ARAC 
____mg 
IT HC 
_____mg 
IT MTX 
____mg 
Studies 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
____mg 
____mg  ____mg  ____mg 
 
____mg 
 
 
 
 
 
b-c 
 
 
3 
 
 
____mg 
 
 
 
 
 
 
4 
 
 
____mg 
 
 
 
 
 
 
5 
 
 
____mg 
 
 
 
 
 
 
6 
 
 
____mg 
 
 
 
 
 
 
10 
 
 
____mg 
____mg 
____mg 
 
b, d 
 
 
11 
 
 
____mg 
 
 
 
 
 
 
12 
 
 
____mg 
 
 
 
 
 
 
13 
 
 
____mg 
 
 
 
 
 
 
17 
   
 
____mg 
 
 
 
b 
 
 
18 
 
 
____mg 
 
 
 
 
 
 
19 
 
 
____mg 
 
 
 
 
 
 
20 
 
 
____mg 
 
 
 
 
 
 
24 
 
 
____mg 
 
____mg 
____mg 
b, d 
 
 
25 
 
 
____mg 
 
 
 
 
 
 
26 
 
 
____mg 
 
 
 
 
 
 
27 
 
 
____mg 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
____mg 
____mg  ____mg  ____mg 
 
 
 
 
 
a-c 
 
 
42 
 
 
 
 
 
 
 
b, e-g 
 
 
43 
If M1 marrow is achieved, continue to azacitidine EPI Block #2 (Section 4.5) on Day 43 or when ANC ≥ 500/μL and platelets 
≥ 50,000/μL, and resolution of mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later).  
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Consolidation 
4.4.2 
Required Observations in CONSOLIDATION  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) CSF cell count/diff/cytospin 
e) Local bone marrow evaluation. Obtain on Day 42 or when ANC is rising for 
2 consecutive days post-nadir (whichever occurs later). MRD by flow 
cytometry in a COG-approved laboratory please refer to the Section 7.3 for 
laboratory details. Note: For patients who consent, enter MRD results into 
RAVE (Section 14.2). 
f) Peripheral blood for the optional (CAR) T-cell study (Section 14.5). 
g) For patients that consent, collect additional bone marrow sample for the 
optional molecular profiling study (Section 14.3). 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
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Consolidation 
4.4.3 
Treatment Details for CONSOLIDATION  
Administer Non-Intrathecal drug dosages based on the age on Day 1 of 
Consolidation. Administer Intrathecal drug dosages based on the age on the 
day of administration. 
 
Criteria to start Consolidation 
Begin Consolidation on Day 6 following Azacitidine Epigenetic Block #1 (EPI #1 
Section 4.3) irrespective of peripheral blood cell counts  
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
Cyclophosphamide: Intravenous (IV) over 30-60 minutes  
Days: 1 and 29 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 months (mo)  
670 mg/m2/dose 
≥ 6 mo & < 12 mo 
750 mg/m2/dose 
≥ 12 mo  
 
1000 mg/m2/dose 
 
Note: Infants should have an ANC ≥ 500/μL and platelets ≥ 30,000/μL to begin 
Day 29 therapy. 
 
Mesna: Intravenous (IV) over 15 min at hours 0, 4 and 8 hours from the start 
of cyclophosphamide infusion 
Days: 1 and 29 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
134 mg/m2/dose 
≥ 6 mo & < 12 mo 
150 mg/m2/dose 
≥ 12 mo  
 
200 mg/m2/dose 
 
Note: Total of 3 doses per day. 
 
Mercaptopurine: Oral (PO) or Nasogastric (NG) daily 
Days: 1-28 
Dose: Aged based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
40 mg/m2/dose 
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo  
 
60 mg/m2/dose 
 
See Section 5.7 for suggested starting dose based on TPMT and NUDT15 status (if 


 
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Consolidation 
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. 
 
Note: Mercaptopurine should be interrupted if cytarabine blocks are delayed or 
interrupted. Omitted mercaptopurine doses should be made up until the planned 
cumulative dose 1680 mg/m2 (60 mg/m2 x28 doses) for infants ≥ 12 months, 
1260 mg/m2 (45 mg/m2 x28 doses) for infants 6 to < 12 months, 1120 mg/m2 (40 
mg/m2 x28 doses) for infants < 6 months has been administered. 
 
Cytarabine: Intravenous (IV) push or Subcutaneous (SubQ) daily 
Days: 3-6, 10-13, 17-20, and 24-27 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
50 mg/m2/dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo  
 
75 mg/m2/dose 
 
Note: Patients should have ANC ≥ 300/μL and platelets ≥ 30,000/μL to start each 
4-day cytarabine block beginning on Days 10, 17, and 24. Once a 4-day block has 
started, do not interrupt for uncomplicated myelosuppression. 
 
Cytarabine: Intrathecal (IT) 
Day: 10 
Dose: Age based dosing 
 
Age: 
 
Dose: 
< 1 year  
15 mg 
≥ 1 year  
20 mg 
 
Hydrocortisone: Intrathecal (IT) 
Days: 10 & 24 
Dose: Age based dosing 
 
Age: 
 
Dose: 
< 1 year  
12 mg 
≥ 1 year  
16 mg 
 


 
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Consolidation 
Methotrexate: Intrathecal (IT) 
Day: 24 
Dose: Age based dosing 
 
Age: 
 
Dose: 
< 1 year  
6 mg 
≥ 1 year  
8 mg 
 
Note: If a 4-day cytarabine block is delayed due to myelosuppression, then 
intrathecal therapy should be delayed until the 4-day cytarabine block and 
mercaptopurine resume. 
 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following the completion of Consolidation, infants must have an M1 marrow to 
remain on protocol therapy. Infants with M2 or M3 marrow are removed from 
protocol (see Section 8.1). Begin Azacitidine Epigenetic Block #2 (EPI #2, Section 
4.5) on Day 43 after determination of M1 marrow status or when ANC ≥ 500/μL 
and platelets ≥ 50,000/ μL, and resolution of mucositis and diaper area dermatitis to 
≤ Grade 2 (whichever occurs later). 
 


  
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Azacitidine EPI Block 2 
4.5 
Azacitidine EPI BLOCK #2 
4.5.1 
Therapy Delivery Map – EPI BLOCK #2 
Following Consolidation and peripheral blood count recovery, 
azacitidine will be administered as a pre-treatment prior to Interim 
Maintenance for 5 days. Azacitidine therapy is 5 days. 
 
 
__________________________     __________________ 
        Patient COG ID number                     DOB 
 
Following the completion of Consolidation, begin Azacitidine Block #2 on Day 43 or when ANC ≥ 500/μL and platelets ≥ 50,000/ μL, 
and resolution of mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). Extensive details and criteria to start are in 
Section 4.5.3 (treatment overview). This Therapy Delivery Map is two (2) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Azacitidine (AZA) 
IND# 133688 
Do not use 
commercial supply 
IV over 10-40 mins 
2.5 mg/kg/dose 
1-5 
Note: infusion must be completed 
within 45 minutes of vial 
reconstitution.  
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Azacitidine _______mg 
Studies 
 
Enter actual dose administered below 
 
 
 
1 
_______mg 
a-d 
 
 
2 
_______mg 
 
 
 
3 
_______mg 
 
 
 
4 
_______mg 
 
 
 
5 
_______mg 
d 
 
 
6 
Continue to Interim Maintenance (Section 4.6) on Day 6 irrespective of ANC and platelet counts. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines.
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Azacitidine EPI Block 2 
 
4.5.2 
Required Observations in Azacitidine EPI BLOCK #2  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) Peripheral blood for the required pharmacodynamic assessment of DNA 
methylation (Section 14.1). 
  
This listing only includes evaluations necessary to answer the primary 
and secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


  
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Azacitidine EPI Block 2 
4.5.3 
Treatment Details for Azacitidine EPI BLOCK #2 
Azacitidine will be given as pre-treatment prior to Interim Maintenance (IM) 
therapy.  
 
Criteria to Start Azacitidine EPI Block #2 
Begin Azacitidine EPI Block #2 on Day 43 following Consolidation and 
determination of M1 marrow or when peripheral counts recover with ANC ≥ 
500/μL and platelets ≥ 50,000/μL, and resolution of mucositis and diaper area 
dermatitis to ≤ Grade 2 (whichever occurs later). 
 
Azacitidine: Intravenous (IV) over 10-40 mins 
Days: 1-5 
Dose: 2.5 mg/kg/dose 
Note: Infusion must be completed within 45 minutes of vial reconstitution 
Do not use commercial supply. 
 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following completion of Azacitidine Epigenetic Therapy Block #2 
(EPI#2), begin Interim Maintenance therapy (Section 4.6) on Day 6 
irrespective of ANC and platelet counts. 
 
 


  
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Interim Maintenance 
4.6 
Interim Maintenance 
4.6.1 
Therapy Delivery Map – INTERIM MAINTENANCE (IM) Phase 1 
All patients will receive the same Interim Maintenance Phase 1 therapy with regards to agents 
and schedule. Non-IT drugs are dosed based on age on Day 1 of IM and BSA, as outlined 
below. IT doses are based on age on the day of administration. Interim Maintenance therapy 
is 6 weeks (42 days) duration. 
 
_________________________ 
       Patient COG ID number 
 
______________ 
         DOB 
Following completion of Azacitidine Block #2, begin Interim Maintenance therapy on Day 6 irrespective of ANC and platelet counts.  Treatment 
details and criteria to start are in Section 4.6.4. This Therapy Delivery Map is three (3) pages in length.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Mercaptopurine (MP) 
PO/NG 
Age 
 
Dose 
< 6 mo 
 
17 mg/m2/dose  
≥ 6 mo & < 12 mo 
19 mg/m2/dose 
≥ 12 mo 
 
25 mg/m2/dose  
1-14 
Refer to Section 4.6.4 for admin guidelines. 
 
If Day 8 HD MTX is delayed due to toxicity, then 
interrupt MP. Resume MP when Day 8 HD MTX is 
given and complete the planned 14 days of MP 
(Section 5.7 ) 
High Dose Methotrexate 
(HD MTX) 
IV over 24 
hours 
Age 
 
Dose 
< 6 mo 
 
3300 mg/m2/dose  
≥ 6 mo & < 12 mo 
3750 mg/m2/dose 
≥ 12 mo 
 
5000 mg/m2/dose  
1 & 8 
Refer to Section 4.6.4 and Section 5.6.1 for admin 
guidelines. 
 
The Day 8 dose of MTX may be given regardless of 
blood counts, but should be held until mucositis is ≤ 
Grade 2. 
 
Administer 10% of the dose over 30 minutes, followed 
by the remainder of the dose (90%) over 23.5 hours. 
Leucovorin (LCV) 
PO/IV 
Age 
 
Dose 
All ages 
 
15 mg/m2/dose  
3-4 & 
10-11 
Refer to Section 4.6.4 for admin guidelines. 
 
Leucovorin should be given at 42, 48, and 54 hours 
after the start of methotrexate infusion and continued 
every 6 hours until plasma methotrexate  level is < 0.1 
µM. 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yr)                      Dose 
< 1                              6 mg 
≥ 1                              8 mg 
1 & 8 
Deliver the IT therapy within 6 hours of the beginning 
of the IV MTX infusion (hour -6 to +6, with 0 being 
the start of the MTX bolus). 
Intrathecal 
Hydrocortisone  
(IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
1 & 8 
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). 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
HD MTX 
____mg 
LCV 
____mg ____mg ___mg 
IT MTX 
____mg 
IT HC 
____mg 
Studies 
Enter calculated dose above and actual dose administered below 
 
 
1 
 
____mg 
 
____mg 
 
____mg 
____mg 
b-d 
 
 
2 
 
 
 
 
 
 
 
3 
 
____mg____mg____mg 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
____mg 
 
____mg 
____mg 
b-d 
 
 
9 
 
 
 
 
 
 
 
10 
 
____mg____mg____mg 
 
 
 
 
 
11 
 
 
 
 
 
 
14 
Continue to Day 15 of Interim Maintenance Phase 2 when there is no mucositis and ANC ≥ 500 μL and 
platelets ≥ 50,000/µL 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
Page 1 of 3 


  
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Interim Maintenance 
 
4.6.2 
Therapy Delivery Map – INTERIM MAINTENANCE (IM) Phase 2 Continued 
All patients will receive the same Interim Maintenance Phase 2 therapy with regards to agents and 
schedule. Non-IT drugs are dosed based on age on day 1 of IM and BSA, as outlined below. Begin 
Day 15 of IM when there is no mucositis and when the absolute neutrophil count (ANC) is ≥ 500/μL 
and platelets ≥ 50,000/μL. Interim Maintenance therapy is 6 weeks (42 days) duration. 
 
_______________________ 
    Patient COG ID number 
___________________ 
            DOB 
 
Treatment details and criteria to start are in Section 4.6.4. This Therapy Delivery Map is three (3) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
High Dose Cytarabine 
(HD ARAC) 
IV over 3hrs 
Age 
 
Dose 
< 6 mo 
 
2000 mg/m2/dose  
≥ 6 mo & < 12 mo 
2250 mg/m2/dose 
≥ 12 mo 
 
3000 mg/m2/dose  
15-16 & 
22-23 
Refer to Section 4.6.4 for admin guidelines.  
 
Administer every 12 hours (for a total of 8 
doses over the 2 courses) 
Pegaspargase (PEG-ASP) 
IV over 1-2 hours 
or IM 
Age 
 
Dose 
< 6 mo 
 
1650 IU/m2/dose  
≥ 6 mo & < 12 mo 
1875 IU/m2/dose 
≥ 12 mo 
 
2500 IU/m2/dose  
23 
Administer 3 hours after the completion of the 
last cytarabine infusion on Day 23 
 
Refer to Section 4.6.4 for admin guidelines. 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
HD ARAC 
___mg  __mg 
PEG-ASP 
_____IU 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
15 
____mg       ____mg 
 
a-c 
 
 
16 
____mg       ____mg 
 
 
 
 
22 
____mg       ____mg 
 
 
 
 
23 
____mg       ____mg 
____IU 
 
 
 
30 
 
 
f 
 
 
36 
 
 
 
 
 
42 
 
 
e, g 
 
 
43 
Begin Azacitidine EPI Block #3 (Section 4.7) on Day 43 or when ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of 
mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
 
Page 2 of 3 


   
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Interim Maintenance 
 
4.6.3 
Required Observations in INTERIM MAINTENANCE (IM)  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) CSF cell count/diff/cytospin 
e) Local bone marrow evaluation. Obtain on Day 42 or when ANC is rising for 
2 consecutive days post-nadir (whichever occurs later). MRD by flow 
cytometry in a COG-approved laboratory, please refer to the Section 7.3 for 
laboratory details. Note: For patients that consent, enter MRD results into 
RAVE (Section 14.2). 
f) Report 
asparaginase 
activity 
levels 
for 
optional 
pegaspargase 
pharmacodynamic study (Section 14.6). 
g) For patients that consent, collect additional bone marrow aspirate for the 
optional molecular profiling study (Section 14.3). 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 


   
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Interim Maintenance 
4.6.4 
Treatment Details for INTERIM MAINTENANCE (IM) 
Interim Maintenance is 2 phases. 
 
Administer IM Phase 1 and 2 non-Intrathecal drug dosages based on the age 
on Day 1 of IM. 
 
Intrathecal drug doses are based on age on the day of administration. 
 
Criteria to start Interim Maintenance 
Begin Interim Maintenance on Day 6 following Azacitidine Epigenetic Block #2 
irrespective of peripheral blood cell counts. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at:  
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Interim Maintenance Phase 1: 
 
Mercaptopurine: Oral (PO) or Nasogastric (NG) daily 
Days: 1-14 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
17 mg/m2/dose 
≥ 6 mo & < 12 mo 
19 mg/m2/dose 
≥ 12 mo 
 
25 mg/m2/dose 
 
See Section 5.8 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. 
 
High Dose Methotrexate: Intravenous (IV) over 24 hours 
Days: 1 and 8 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
3300 mg/m2/dose 
≥ 6 mo & < 12 mo 
3750 mg/m2/dose 
≥ 12 mo 
 
5000 mg/m2/dose 
 
Note: The Day 8 dose of MTX should be given regardless of blood counts, but 
should be held until mucositis is ≤ Grade 2. 
 
Administer over 24 hours on Days 1 and 8 (10% of the dose in 30 minutes followed 
by 90% of the dose in 23.5 hours). 


   
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Interim Maintenance 
 
See Section 5.6.1 for hydration, leucovorin rescue and high dose methotrexate 
infusion guidelines. 
 
Leucovorin: Oral (PO) or Intravenous (IV) 
Days 3-4 and 10-11 
Dose: 15 mg/m2/dose. Administer at 42, 48, and 54 hrs after the start of the MTX 
infusion and every 6 hours until the plasma MTX level is < 0.1 µM. 
 
See Section 5.6.1 for hydration, leucovorin rescue and high dose methotrexate 
infusion guidelines. 
 
Methotrexate: Intrathecal (IT) 
Days: 1 & 8 
 
Age: 
Dose: 
< 1 year 
6 mg 
≥ 1 year 
8 mg 
 
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). 
 
Hydrocortisone: Intrathecal (IT) 
Days: 1 & 8 
 
Age: 
Dose: 
< 1 year 
12 mg 
≥ 1 year 
16 mg 
 
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). 
 
Interim Maintenance Phase 2: 
Day 15 may start only when there is no mucositis and when the absolute neutrophil 
count (ANC) is ≥ 500/μL and platelets ≥ 50,000/μL. The HD Cytarabine and 
Pegaspargase on Days 22 and 23 should be given irrespective of blood counts. 
 
High Dose Cytarabine: Intravenous (IV) over 3 hours 
Days: 15-16 and 22-23. Administer every 12 hours x 4 doses on Days 15-16 and 
on Days 22-23 (for a total of 8 doses). 
Dose: Age based dosing. 
 
Age 
 
 
Dose 
< 6 months (mo) 
2000 mg/m2/dose 
≥ 6 mo & < 12 mo 
2250 mg/m2/dose 
≥ 12 mo 
 
3000 mg/m2/dose 
 
Note: Days 22-23 should be given irrespective of blood counts. 
 


   
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Interim Maintenance 
Suggested premedications and supportive care: Administer steroid eye drops 
(0.1% dexamethasone or 1% predniso(lo)ne 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: Intravenous (IV) over 1-2 hours or Intramuscular (IM) 
Day: 23 
Dose: Age based dosing. Administer 3 hours after the completion of the last 
cytarabine infusion on Day 23. 
 
Age 
 
 
Dose 
< 6 mo  
 
1650 International Units/m2/dose 
≥ 6 mo & < 12 mo 
1875 International Units/m2/dose 
≥ 12 mo 
 
2500 International Units/m2/dose 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following completion of Interim Maintenance, begin Azacitidine Epigenetic 
Block #3 (EPI #3, Section 4.7) on Day 43 or when ANC ≥ 500/μL and 
platelets ≥ 50,000/μL, and resolution of mucositis and/or diaper area dermatitis to 
≤ Grade 2 (whichever occurs later) 
 
.


  
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Azacitidine EPI Block 3 
 
4.7 
Azacitidine EPI BLOCK #3 
4.7.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #3 
Following IM and peripheral blood cell count recovery, azacitidine 
will be administered as a pre-treatment prior to Delayed 
Intensification Pt. 1 for 5 days. Azacitidine therapy is 5 days. 
 
_______________________      _________________ 
  Patient COG ID number                          DOB 
 
Begin Azacitidine Block #3 on Day 43 or when ANC ≥ 500/µl and platelets ≥ 50,000/µl and resolution of mucositis and diaper 
area dermatitis to ≤ Grade 2 (whichever occurs later). Treatment details and criteria to start are in Section 4.7.3. This Therapy 
Delivery Map is two (2) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Azacitidine (AZA) 
IND# 133688 
Do not use 
commercial supply 
IV over 10-
40 mins 
2.5 mg/kg/dose 
1-5 
Note: infusion must be completed within 45 
minutes of vial reconstitution 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Azacitidine _______mg 
Studies 
 
Enter actual dose administered below 
 
 
 
1 
_______mg 
a-c 
 
 
2 
_______mg 
 
 
 
3 
_______mg 
 
 
 
4 
_______mg 
 
 
 
5 
_______mg 
 
 
 
6 
Continue to Delayed Intensification Pt.1 (Section 4.8) on Day 6 irrespective of ANC and platelet 
counts. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive 
Care Guidelines. 
 
 
Page 1 of 2 


   
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AALL15P1 
Page 54 
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Azacitidine EPI Block 3 
4.7.2 
Required Observations in Azacitidine EPI BLOCK #3  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
Page 2 of 2 


   
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Page 55 
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Azacitidine EPI Block 3 
 
4.7.3 
Treatment Details for Azacitidine EPI BLOCK #3 
Azacitidine will be given as pre-treatment prior to Delayed Intensification Part. 1 
therapy. 
 
Criteria to Start Azacitidine EPI Block #3 
Begin Azacitidine EPI Block #3 on Day 43 of Interim Maintenance or when peripheral 
counts recover with ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of 
mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
 
Azacitidine: Intravenous (IV) over 10-40 mins 
Days: 1-5 
Dose: 2.5 mg/kg/dose 
Note: infusion must be completed within 45 minutes of vial reconstitution 
Do not use commercial supply. 
 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following completion of Azacitidine Epigenetic Therapy Block #3 (EPI#3), begin 
Delayed Intensification Part 1 therapy (Section 4.8) on Day 6 irrespective of ANC and 
platelet counts. 
 
 
 
 


`   
THIS  
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AALL15P1 
Page 56 
Version date: 9/25/19 
Delayed Intensification Pt. 1 
4.8 
Delayed Intensification Part 1 
4.8.1 
Therapy Delivery Map – DELAYED INTENSIFICATION PART 1 
All patients will receive the same Delayed Intensification therapy with regards to agents 
and schedule. Non-IT drugs are dosed based on age on Day 1 of DI Pt. 1 and BSA, 
as outlined below. IT drugs are dosed based on age on the day of administration. 
Delayed Intensification Pt. 1 therapy is 5 weeks (35 days) duration. 
 
________________   ________________ 
        Patient COG ID                   DOB 
               number 
Following completion of Azacitidine Block #3, begin DI Pt. 1 therapy on Day 6 irrespective of peripheral blood cell counts. Treatment details and 
criteria to start are in Section 4.8.4 This Therapy Delivery Map is three (3) pages in length.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Pegaspargase (PEG-ASP) 
IV over 1-2 
hours or IM 
Age 
 
Dose 
< 6 mo 
 
1650 IU/m2/dose   
≥ 6 mo & < 12 mo 
1875 IU/m2/dose 
≥ 12 mo 
 
2500 IU/m2/dose  
1 
Refer to Section 4.8.4 for admin guidelines. 
Dexamethasone (DEX) 
PO or NG or 
IV 
Age 
 
Dose 
< 6 mo 
 
1.3 mg/m2/dose TID  
≥ 6 mo & < 12 mo 
1.5 mg/m2/dose TID 
≥ 12 mo 
 
2 mg/m2/dose TID  
1-14 & 
15-21 
Administer 3 doses per day. 
 
Taper to 0mg over Days 15-21 
6-Thioguanine (TG) 
PO or NG 
Age 
 
Dose 
< 6 mo 
 
40 mg/m2/dose  
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose  
1-28 
Refer to Section 4.8.4 for admin guidelines. 
VinCRIStine (VCR) 
IV over 
1 min+ 
Age 
 
Dose 
< 6 mo 
 
1 mg/m2/dose  
≥ 6 mo & < 12 mo 
1.1 mg/m2/dose 
≥ 12 mo 
 
1.5 mg/m2/dose  
1, 8, 15 
& 22 
Round dose to the nearest 0.01 mg. 
 
+Or infusion via minibag as per institutional policy. 
 
Max dose 2 mg 
 
Refer to Section 4.8.4 for admin guidelines. 
DAUNOrubicin (DAUN) 
IV over 1-15 
min 
Age 
 
Dose 
< 6 mo 
 
20 mg/m2/dose 
≥ 6 mo & < 12 mo 
23 mg/m2/dose 
≥ 12 mo 
 
30 mg/m2/dose 
1, 8, 15 
& 22 
Refer to Section 4.8.4 for admin guidelines. 
Cytarabine (ARAC) 
IV push or 
SubQ 
Age 
 
Dose 
< 6 mo 
 
50 mg/m2/dose  
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose  
2-5, 9-
12, 16-
19 & 23-
26 
Patients should have ANC ≥ 300/μL and platelets 
≥ 30,000/μL to start each 4-day cytarabine block 
beginning on Days 9, 16, and 23. 
 
Refer to Section 4.8.4 for admin guidelines. 
Intrathecal Hydrocortisone  
(IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
1 & 15 
Refer to Section 4.8.4 for admin guidelines. 
Intrathecal Cytarabine 
(IT ARAC) 
IT 
Age (yr)                      Dose 
< 1                              15 mg 
≥ 1                              20 mg 
1 & 15 
Refer to Section 4.8.4 for admin guidelines. 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
PEG-ASP 
___IU 
DEX 
____mg  ____mg____mg 
TG 
____mg 
VCR 
____mg 
DAUN 
____mg 
ARAC 
____mg 
IT HC 
____mg 
IT ARAC 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
___IU 
 
____mg  ____mg  ____mg 
 
____mg 
____mg 
____mg 
 
____mg 
____mg 
b-d 
 
 
2 
 
 
 
____mg 
 
 
 
 
 
3 
 
 
 
____mg 
 
 
 
 
 
4 
 
 
 
____mg 
 
 
 
 
 
5 
 
 
 
___mg 
 
 
 
 
 
8 
 
____mg 
____mg 
 
 
 
b, f 
 
 
9 
 
 
 
___mg 
 
 
 
 
 
10 
 
 
 
___mg 
 
 
 
 
 
11 
 
 
 
___mg 
 
 
 
 
 
12 
 
 
 
___mg 
 
 
 
 
 
14 
 
Continue DI Pt. 1 (Days 15-36) on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
 
 
Page 1 of 3 


`   
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PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL15P1 
Page 57 
Version date: 9/25/19 
Delayed Intensification Pt. 1 
 
4.8.2 
Therapy Delivery Map – DELAYED INTENSIFICATION PART 1 Continued 
All patients will receive the same Delayed Intensification therapy with regards to agents and schedule. 
Non-IT drugs are dosed based on age on Day 1 of DI Pt. 1 and BSA, as outlined below. IT drugs are 
based on age on the day of administration. Delayed Intensification Pt. 1 therapy is 5 weeks (35 days). 
_________________ 
 Patient COG ID number 
 
____________________ 
           DOB 
Treatment details and criteria to start are in Section 4.8.4 This Therapy Delivery Map is three (3) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Dexamethasone (DEX) 
PO or NG or 
IV 
Taper dexamethasone stepwise to zero mg 
over 7 days 
15-21 
Taper to 0 mg over 7 days (Days 15-21). 
 
Suggested taper: reduce dexamethasone dose by 
20-30% of the administered dose every 1-2 days, 
then discontinue. Consider tapering to BID or 
once daily schedule as clinically appropriate. 
6-Thioguanine (TG) 
PO or NG 
Age 
 
Dose 
< 6 mo 
 
40 mg/m2/dose  
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose  
15-28 
Refer to Section 4.8.4 for admin guidelines. 
VinCRIStine (VCR) 
IV over 
1 min+ 
Age 
 
Dose 
< 6 mo 
 
1 mg/m2/dose  
≥ 6 mo & < 12 mo 
1.1 mg/m2/dose 
≥ 12 mo 
 
1.5 mg/m2/dose  
15 & 22 
Round dose to the nearest 0.01 mg.  
 
+Or infusion via minibag as per institutional 
protocol 
 
Max dose 2 mg. 
 
Refer to Section 4.8.4 for admin guidelines. 
DAUNOrubicin (DAUN) 
IV over 
1-15 min 
Age 
 
Dose 
< 6 mo 
 
20 mg/m2/dose  
≥ 6 mo & < 12 mo 
23 mg/m2/dose 
≥ 12 mo 
 
30 mg/m2/dose  
15 & 22 
Refer to Section 4.8.4 for admin guidelines. 
Cytarabine (ARAC) 
IV push or 
SubQ 
Age 
 
Dose 
< 6 mo 
 
50 mg/m2/dose  
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose  
16-19 & 
23-26 
Patients should have ANC ≥ 300/μL and platelets 
≥ 30,000/μL to start each 4-day cytarabine block 
beginning on Days 9, 16, and 23. 
 
Refer to Section 4.8.4 for admin guidelines. 
Intrathecal Hydrocortisone  
(IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
15 
Refer to Section 4.8.4 for admin guidelines. 
Intrathecal Cytarabine 
(IT ARAC) 
IT 
Age (yr)                      Dose 
< 1                              15 mg 
≥ 1                              20 mg 
15 
Refer to Section 4.8.4 for admin guidelines. 
Enter Cycle #: _____ 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
DEX 
____mg  ____mg____mg 
TG 
____mg 
VCR 
____mg 
DAUNO 
____mg 
ARAC 
____mg 
IT HC 
____mg 
IT ARAC 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
15 
____mg  ____mg  ____mg 
    
   ___mg  
____mg 
____mg 
 
____mg 
____mg 
a-c, e 
 
 
16 
____mg  ____mg  ____mg 
 
 
___mg 
 
 
 
 
 
17 
____mg  ____mg  ____mg 
 
 
___mg 
 
 
 
 
 
18 
____mg  ____mg  ____mg 
 
 
___mg 
 
 
 
 
 
19 
____mg  ____mg  ____mg 
 
 
___mg 
 
 
 
 
 
20 
____mg  ____mg  ____mg 
 
 
 
 
 
 
 
 
21 
____mg  ____mg  ____mg 
 
 
 
 
 
 
 
 
22 
 
____mg 
____mg 
 
 
 
b 
 
 
23 
 
 
 
___mg 
 
 
 
 
 
24 
 
 
 
___mg 
 
 
 
 
 
25 
 
 
 
____mg 
 
 
 
 
 
26 
 
 
 
____mg 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
 
 
 
36 
Begin Azacitidine EPI Block #4 (Section 4.9) on Day 36 or when all ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of 
mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
Page 2 of 3 


  
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AALL15P1 
Page 58 
Version date: 9/25/19 
Delayed Intensification Pt. 1 
 
4.8.3 
Required Observations in DELAYED INTENSIFICATION PART 1  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) Echo or MUGA 
e) CSF cell count/diff/cytospin 
f) Report asparaginase activity levels for optional pegaspargase 
pharmacodynamic study (Section 14.6). 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 


  
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AALL15P1 
Page 59 
Version date: 9/25/19 
Delayed Intensification Pt. 1 
4.8.4 
Treatment Details for DELAYED INTENSIFICATION PART 1 
Administer non-intrathecal drug doses based on the age on Day 1 of DI Part 
1. Administer intrathecal drug doses based on the age on the day of 
administration. 
 
Criteria to Start Delayed Intensification Part 1 
Begin Delayed Intensification Part 1 on Day 6 following Azacitidine Epigenetic 
Therapy #3 irrespective of peripheral blood cell counts. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Pegaspargase: Intravenous (IV) over 1-2 hours or Intramuscular (IM)  
Day: 1 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 months (mo) 
1650 International Units/m2/dose 
≥ 6 mo & < 12 mo 
1875 International Units/m2/dose 
≥ 12 mo 
 
2500 International Units/m2/dose 
 
Dexamethasone: Oral (PO), Nasogastric (NG) or Intravenous (IV) 
Days: 1-14 and 15-21 
Dose: Age based dosing. Administer full dose during Days 1-14 (3 doses per 
day) and taper to zero (0) over Days 15-21. 
 
Age 
 
 
Dose 
 
< 6 mo  
 
1.3 mg/m2/dose TID 
≥ 6 mo & < 12 mo 
1.5 mg/m2/dose TID 
≥ 12 mo  
 
2 mg/m2/dose TID 
 
Note: Suggested taper: reduce dexamethasone dose by 20-30% of the administered 
dose every 1-2 days, then discontinue. Consider tapering to BID or once daily 
schedule as clinically appropriate. 
 
 
6-Thioguanine: Oral (PO) or Nasogastric (NG) daily 
Days: 1-28 
Dose: Age based dosing. 
 
Age 
 
 
Dose 
< 6 mo  
 
40 mg/m2/dose 
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose 
 
Note: VinCRIStine, DAUNOrubicin, and the start of a 4-day cytarabine block on 
Days 9, 16, and 23 should be delayed and thioguanine interrupted if the ANC falls 


  
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Page 60 
Version date: 9/25/19 
Delayed Intensification Pt. 1 
to <300/μL or platelets < 30,000/μL. If a 4-day cytarabine block has been started, 
then cytarabine and thioguanine should not be interrupted. 
 
 
VinCRIStine: Intravenous (IV) over 1 minute or infusion via minibag as per 
institutional policy 
Days: 1, 8, 15, and 22 
Dose: Age based dosing. Max dose 2 mg. 
 
Age 
 
 
Dose 
< 6 mo  
 
1 mg/m2/dose 
≥ 6 mo & < 12 mo 
1.1 mg/m2/dose 
≥ 12 mo 
 
1.5 mg/m2/dose 
 
Note: Round vinCRIStine dose to the nearest 0.01 mg. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vincristine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only- Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine 
sulfate liposomal injection, VSLI, Marqibo®). The conventional and liposomal 
formulations are NOT interchangeable; use of the liposomal formulation is not 
permitted in this trial. 
 
DAUNOrubicin: Intravenous (IV) over 1-15 minutes 
Days: 1, 8, 15, and 22 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
20 mg/m2/dose  
≥ 6 mo & < 12 mo 
23 mg/m2/dose 
≥ 12 mo 
 
30 mg/m2/dose  
 
Cytarabine: Intravenous (IV) push or Subcutaneous (SubQ) 
Days: 2-5, 9-12, 16-19, 23-26 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
50 mg/m2/dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose 
 
Note: Patients should have ANC ≥ 300/μL and platelets ≥ 30,000/μL to start each 
4-day cytarabine block beginning on Days 9, 16, and 23. 
 


  
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Page 61 
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Delayed Intensification Pt. 1 
Hydrocortisone: Intrathecal (IT) 
Days: 1 and 15 
 
Age: 
Dose: 
< 1 year 
12 mg 
≥ 1 year 
16 mg 
 
Cytarabine: Intrathecal (IT) 
Days: 1 and 15 
 
Age: 
Dose: 
< 1 year 
15 mg 
≥ 1 year 
20 mg 
 
See Section 5.0 for Dose Modifications on Toxicities. 
 
Following completion of Delayed Intensification Part. 1, begin 
Azacitidine Epigenetic Block #4 (EPI#4, Section 4.9) on Day 36 or when 
ANC ≥ 500/μL and platelets ≥ 50,000/ μL, and resolution of mucositis and 
diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
 
 
 


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AALL15P1 
 
Page 62 
Version date: 9/25/19 
Azacitidine EPI Block 4 
 
4.9 
Azacitidine EPI BLOCK #4 
4.9.1 
Therapy Delivery Map – Azacitidine EPI BLOCK #4 
Following DI Pt. 1 and peripheral blood count recovery, azacitidine 
will be given as a pre-treatment prior to Delayed Intensification 
Part 2. Azacitidine therapy is 5 days. 
 
______________________  __________________ 
  Patient COG ID number               DOB 
 
Begin Azacitidine Block# 4 on Day 36 or when ANC ≥ 500/µL and Platelets ≥ 50,000/µL, and resolution of mucositis and diaper area 
dermatitis to ≤ Grade 2 (whichever occurs later).Treatment details and criteria to start are in Section 4.9.3. This Therapy Delivery Map is two 
(2) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Azacitidine (AZA) 
IND # 133688 
Do not use 
commercial supply 
IV over 10-40 
mins 
2.5 mg/kg/dose 
1-5 
Infusion must be completed within 45 
minutes of vial reconstitution 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Azacitidine _______mg 
Studies 
 
Enter actual dose administered below 
 
 
 
1 
_______mg 
a-c 
 
 
2 
_______mg 
 
 
 
3 
_______mg 
 
 
 
4 
_______mg 
 
 
 
5 
_______mg 
 
 
 
6 
Continue to Delayed Intensification Part 2 (Section 4.10) on Day 6 irrespective of ANC and platelet 
counts. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines.
Page 1 of 2 


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Page 63 
Version date: 9/25/19 
Azacitidine EPI Block 4 
4.9.2 
Required Observations in Azacitidine EPI BLOCK #4  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


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AALL15P1 
Page 64 
Version date: 9/25/19 
Azacitidine EPI Block 4 
4.9.3 
Treatment Details for Azacitidine EPI BLOCK #4 
Azacitidine will be given as pre-treatment prior to Delayed Intensification 
Part 2 therapy. 
 
Criteria to Start Azacitidine EPI Block #4 
Begin Azacitidine EPI Block #4 on Day 36 of DI Part. 1 or when peripheral counts 
recover with ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of mucositis 
and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
 
Azacitidine: Intravenous (IV) over 10-40 mins 
Days: 1-5 
Dose: 2.5 mg/kg/dose 
Note: infusion must be completed within 45 minutes of vial reconstitution 
Do not use commercial supply. 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following completion of Azacitidine Epigenetic Therapy Block #4, begin Delayed 
Intensification Part 2 therapy (Section 4.10) on Day 6, irrespective of ANC and 
platelet counts. 
 
 


  
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AALL15P1 
Page 65 
Version date: 9/25/19 
Delayed Intensification Pt. 2 
4.10 
Delayed Intensification PART 2 
4.10.1 Therapy Delivery Map – DELAYED INTENSIFICATION PART 2 
All patients will receive the same Delayed Intensification therapy with regards to agents and schedule. 
All drugs are dosed based on age on Day 1 of DI Part. 2 and BSA, as outlined below. Delayed 
Intensification Pt. 2 therapy is 3 weeks (21 days) duration. 
 
 
___________________________            ______________________ 
           Patient COG ID number                                                   DOB 
 
Following completion of EPI Block #4, begin on Day 6 irrespective of peripheral blood cell counts. Treatment details and criteria to start are in Section 4.10.3. This Therapy Delivery Map is two (2) 
pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
6-Thioguanine (TG) 
PO or NG 
Age 
 
Dose 
< 6 mo 
 
40 mg/m2/dose  
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose  
1-14 
 
Cyclophosphamide (CPM) 
IV over 15-30 min 
Age 
 
Dose 
< 6 mo 
 
330 mg/m2/dose  
≥ 6 mo & < 12 mo 
375 mg/m2/dose 
≥ 12 mo 
 
500 mg/m2/dose  
1 & 15 
Refer to Section 4.10.3 for admin guidelines. 
Cytarabine (ARAC) 
IV push or SubQ 
Age 
 
Dose 
< 6 mo 
 
50 mg/m2/dose  
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose  
2-5 & 9-12 
Patients should have ANC ≥ 300/μL and platelets ≥ 30,000/μL to start 
the 4-day cytarabine block beginning on Day 9. 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date Due 
Date Given 
Day 
TG 
____mg 
CPM 
____mg 
ARAC 
_____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
 
____mg 
____mg 
 
a-c 
 
 
2 
 
____mg 
 
 
 
3 
 
____mg 
 
 
 
4 
 
____mg 
 
 
 
5 
 
____mg 
 
 
 
8 
 
 
 
 
 
9 
 
____mg 
 
 
 
10 
 
____mg 
 
 
 
11 
 
____mg 
 
 
 
12 
 
____mg 
 
 
 
14 
 
 
 
 
 
15 
 
____mg 
 
a-c 
 
 
22 
Continue to Maintenance (Section 4.11) on Day 22 or when ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of mucositis and diaper area dermatitis 
to ≤ Grade 2 (whichever occurs later). 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines.
Page 1 of 2 


  
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AALL15P1 
Page 66 
Version date: 9/25/19 
Delayed Intensification Pt. 2 
4.10.2 Required Observations in DELAYED INTENSIFICATION PART. 2  
 
a) History & physical (including length, weight, BSA, and performance status 
(if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


  
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AALL15P1 
Page 67 
Version date: 9/25/19 
Delayed Intensification Pt. 2 
4.10.3 Treatment Details for DELAYED INTENSIFICATION PART 2 
Administer drug doses based on the age on Day 1 of DI Part 2. 
 
Criteria to Start Delayed Intensification Part 2 
Begin Delayed Intensification Part 2 on Day 6 following Azacitidine Epigenetic 
Block #4 irrespective of peripheral blood cell counts. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
6-Thioguanine: Oral (PO) or Nasogastric (NG) daily 
Days: 1-14 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
40 mg/m2/dose 
≥ 6 mo & < 12 mo 
45 mg/m2/dose 
≥ 12 mo 
 
60 mg/m2/dose 
 
Note: The 4-day cytarabine block beginning on Day 9 should be delayed and 
thioguanine interrupted if the ANC falls to <300/μL or platelets < 30,000/μL. If a 
4-day cytarabine block has been started, then cytarabine and thioguanine should 
not be interrupted. 
 
Cyclophosphamide: Intravenous (IV) over 15-30 minutes 
Days: 1 and 15 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
330 mg/m2/dose 
≥ 6 mo & < 12 mo 
375 mg/m2/dose 
≥ 12 mo 
 
500 mg/m2/dose 
 
Cytarabine: Intravenous (IV) push or Subcutaneous (SubQ) 
Days: 2-5 and 9-12 
Dose: Age based dosing 
 
Age 
 
 
Dose 
< 6 mo  
 
50 mg/m2/dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose 
 
Patients should have ANC ≥ 300/μL and platelets ≥ 30,000/μL to start the 4-day 
cytarabine block beginning on Day 9. 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following completion of Delayed Intensification Part 2, begin Maintenance 
therapy (Section 4.11) on Day 22 or when ANC > 500/μL and platelets > 50,000/ 
μL, and resolution of mucositis and diaper area dermatitis to ≤ Grade 2 (whichever 
occurs later). 


  
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AALL15P1 
Page 68 
Version date: 9/25/19 
Maintenance Cycle 1 
4.11 
Maintenance Cycle 1 
4.11.1 Therapy Delivery Map –MAINTENANCE Cycle 1 
All patients will receive the same Maintenance therapy with regards to agents and schedule. Non-IT drugs are dosed based on 
age on Day 1 of Maintenance Cycle 1 and BSA, as outlined below. IT drugs are dosed based on age on day of 
administration. Cycle 1 lasts 12 weeks (84 days). 
 
 
________________________           _____________ 
         Patient COG ID number                     DOB 
Begin Maintenance on Day 22 of DI Pt. 2 or when ANC ≥ 500/µL and platelets ≥ 50,000/ µL and resolution of mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later) Details and 
criteria to start are in Section 4.11.3. This Therapy Delivery Map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES≥ 
Mercaptopurine (MP) 
PO or NG 
Age 
 
Dose 
≥ 6 mo & < 12 mo 
38 mg/m2/dose 
≥ 12 mo 
 
50 mg/m2/dose  
1-84 
Refer to Section 4.11.3 for admin guidelines. 
Methotrexate (MTX) 
PO 
Age 
 
Dose 
≥ 6 mo & < 12 mo 
15 mg/m2/dose 
≥ 12 mo 
 
20 mg/m2/dose  
Once weekly 
Omit during weeks when IT MTX is administered. 
 
Refer to Section 4.11.3 for admin guidelines. 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yr)                      Dose 
< 1                              6 mg 
≥ 1                              8 mg 
1 
 
.Intrathecal Hydrocortisone  
(IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
1 & 57 
 
Intrathecal Cytarabine  
(IT ARAC) 
IT 
Age (yr)                      Dose 
< 1                              15 mg 
≥ 1                              20 mg 
57 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
MTX 
____mg 
IT MTX 
____mg 
IT HC 
____mg 
IT ARAC 
_____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg   
 
mg 
mg 
 
a-d 
 
 
8 
 
 ____mg 
 
 
 
 
 
 
15 
____mg 
 
 
 
 
 
 
22 
____mg 
 
 
 
 
 
 
29 
____mg 
 
 
 
b 
 
 
36 
____mg 
 
 
 
 
 
 
43 
____mg 
 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
 
57 
____mg 
 
____mg 
____mg 
b, d 
 
 
64 
____mg 
 
 
 
 
 
 
71 
____mg 
 
 
 
 
 
 
78 
____mg 
 
 
 
 
 
 
84 
 
 
 
 
 
 
 
85 
Following completion of Maintenance therapy Cycle 1, continue onto Maintenance therapy Cycle 2 on Day 85 per Section 4.12. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV and the COG Member website for Supportive Care Guidelines. 
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Maintenance Cycle 1 
 
4.11.2 Required Observations in MAINTENANCE Cycle 1 
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) CSF cell count/diff/cytospin 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE. 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


   
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Maintenance Cycle 1 
4.11.3 Treatment Details for MAINTENANCE Cycle 1  
Administer drug dosages based on the age on Day 1 of Maintenance Cycle 1. 
 
Criteria to start Maintenance 
Begin Maintenance on Day 22 of Delayed Intensification Part 2 or when peripheral 
counts recover with ANC ≥ 500/μL and platelets ≥ 50,000/μL, and resolution of 
mucositis and diaper area dermatitis to ≤ Grade 2 (whichever occurs later). 
 
The administration schedule below describes the 12-week cycle of Maintenance 
therapy Cycle 1.  
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Mercaptopurine: Oral (PO) or Nasogastric (NG) 
Days: Days 1-84  
Dose: Age based dosing 
 
Age 
 
 
Dose 
≥ 6 mo & < 12 mo 
38 mg/m2/dose 
≥ 12 mo 
 
50 mg/m2/dose 
 
See Section 5.7 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. 
 
Methotrexate: Oral (PO)  
Days: Once weekly, omit during week 1. 
Dose: Aged based dosing 
 
Age 
 
 
Dose 
≥ 6 mo & < 12 mo 
15 mg/m2/dose 
≥ 12 mo 
 
20 mg/m2/dose 
 
Note: Administer the tablets on an empty stomach (at least 1 hour before or 2 
hours after food or milk). Food or milk delays absorption and decreases the peak 
concentration. 
 


   
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Maintenance Cycle 1 
Methotrexate: Intrathecal (IT) 
Day: 1 
Dose: Aged based dosing 
 
Age: 
Dose: 
< 1 year  
6 mg 
≥ 1 year  
8 mg 
 
Hydrocortisone: Intrathecal (IT) 
Days: 1 & 57 
Dose: Aged based dosing 
 
Age: 
Dose: 
< 1 year  
12 mg 
≥ 1 year 
16 mg 
 
Cytarabine: Intrathecal (IT) 
Day: 57 
Dose: Aged based dosing 
 
Age: 
Dose: 
< 1 year 
15 mg 
≥ 1 year 
20 mg 
 
See Section 5.0 for Dose Modifications on Toxicities.  
 
Following the completion of Maintenance therapy Cycle 1, continue onto 
Maintenance therapy Cycle 2 on Day 85, per  Section 4.12. 
 
 
 


  
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Maintenance Cycle 2 
4.12 
Maintenance Cycle 2 
4.12.1 Therapy Delivery Map –MAINTENANCE Cycle 2 
All patients will receive the same Maintenance therapy with regards to agents and schedule. Non-IT drugs are dosed based on 
age on Day 1 of Maintenance Cycle 2 and BSA, as outlined below. IT drugs are dosed based on age on day of administration. 
Cycle 2 lasts 12 weeks (84 days). 
______________________________ 
            Patient COG ID number           
______________________________ 
                        DOB 
Treatment details and criteria to start are in Section 4.12.3. This Therapy Delivery Map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Mercaptopurine (MP) 
PO or NG 
Age 
 
Dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo  
75 mg/m2/dose  
1-84 
Refer to Section 4.12.3 for admin guidelines. 
Methotrexate (MTX) 
PO 
Age 
 
Dose 
≥ 6 mo & < 12 mo 15 mg/m2/dose 
≥ 12 mo  
20 mg/m2/dose  
Once weekly 
Omit during weeks when IT MTX is administered. 
 
Refer to Section 4.12.3 for admin guidelines. 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yr)                      Dose 
< 1                              6 mg 
≥ 1                              8 mg 
15 
 
.Intrathecal Hydrocortisone  
(IT HC) 
IT 
Age (yr)                      Dose 
< 1                              12 mg 
≥ 1                              16 mg 
15 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
MTX 
____mg 
IT MTX 
____mg 
IT HC 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
 
____mg   
____mg 
 
 
a-c 
 
 
8 
____mg 
 
 
 
 
 
15 
 
____mg 
____mg 
d 
 
 
22 
____mg 
 
 
 
 
 
29 
____mg 
 
 
b 
 
 
36 
____mg 
 
 
 
 
 
43 
____mg 
 
 
 
 
 
50 
____mg 
 
 
 
 
 
57 
____mg 
 
 
b 
 
 
64 
____mg 
 
 
 
 
 
71 
____mg 
 
 
 
 
 
78 
____mg 
 
 
 
 
 
84 
 
 
 
 
 
 
 
85 
Following the completion of Maintenance therapy Cycle 2, continue onto Maintenance Therapy Cycle 3 on Day 85 per Section 4.13. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV the COG Member website for Supportive Care Guidelines. 
Page 1 of 2 


   
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Maintenance Cycle 2 
 
4.12.2 Required Observations in MAINTENANCE Cycle 2  
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
d) CSF cell count/diff/cytospin 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


   
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Maintenance Cycle 2 
 
4.12.3 Treatment Details for MAINTENANCE Cycle 2  
Administer drug dosages based on age on Day 1 of Maintenance Cycle 2. 
 
Criteria to start Maintenance 
Begin Maintenance Cycle 2 on Day 85 of Maintenance therapy Cycle 1. 
 
The administration schedule below describes the 12-week cycle of 
Maintenance therapy Cycle 2. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Mercaptopurine: Oral (PO) or Nasogastric (NG) 
Days: 1-84 
Dose: Age based dosing 
 
Age 
 
 
Dose 
≥ 6 mo & < 12 mo 
56 mg/m2/dose 
≥ 12 mo 
 
75 mg/m2/dose 
 
See Section 5.7 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. 
 
Methotrexate: Oral (PO)  
Days: Once weekly. Omit during weeks when IT MTX is administered. 
Dose: Age based dosing 
 
Age 
 
 
Dose 
≥ 6 mo & < 12 mo 
15 mg/m2/dose 
≥ 12 mo 
 
20 mg/m2/dose 
 
Note: Administer the tablets on an empty stomach (at least 1 hour before or 2 hours 
after food or milk). Food or milk delays absorption and decreases the peak 
concentration. 
 
Methotrexate: Intrathecal (IT) 
Day: 15 
Dose: Age based dosing 
 
Age: 
Dose: 
< 1 year 
6 mg 
≥ 1 year 
8 mg 
 


   
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Maintenance Cycle 2 
Hydrocortisone: Intrathecal (IT) 
Days: 15 
 
Age: 
Dose: 
< 1 year 
12 mg 
≥ 1 year 
16 mg 
 
See Section 5.0 for Dose Modifications on Toxicities. 
 
Following the completion of Maintenance therapy Cycle 2, continue onto 
Maintenance therapy Cycle 3 on Day 85 per Section 4.13. 
 
 
 


  
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Maintenance Cycle 3 and Subsequent Cycles 
4.13 
Maintenance Cycle 3 and Subsequent Cycles 
4.13.1 Therapy Delivery Map –MAINTENANCE Cycle 3 and Subsequent Cycles 
All patients will receive the same Maintenance therapy with regards to agents and schedule. Each 
cycle of Maintenance will last 12 weeks (84 days), cycles are to be repeated until 2 years have 
passed from the start of Induction therapy. Use this TDM for the remainder of Maintenance 
Therapy. Note cycle number below. 
 
_________________________ 
     Patient COG ID number       
________________________ 
                 DOB 
 
Treatment details and criteria to start are in Section 4.13.3. This Therapy Delivery Map is two (2) pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Mercaptopurine (MP) 
PO or NG 
Age 
 
Dose 
≥ 12 mo 
 
75 mg/m2/dose  
1-84 
 
Refer to Section 4.13.3 for admin 
guidelines. 
Methotrexate (MTX) 
PO 
Age 
 
Dose 
≥ 12 mo 
 
20 mg/m2/dose  
Once weekly 
Refer to Section 4.13.3 for admin 
guidelines. 
 
Enter Cycle #: _____ 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
MP 
____mg 
MTX 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
 
____mg   
____mg 
a-c 
 
 
8 
____mg 
 
 
 
15 
____mg 
 
 
 
22 
____mg 
 
1
 
 
29 
____mg 
b 
 
 
36 
____mg 
 
 
 
43 
____mg 
 
 
 
50 
____mg 
 
 
 
57 
____mg 
b 
 
 
64 
____mg 
 
 
 
71 
____mg 
 
 
 
78 
____mg 
 
 
 
84 
 
 
 
 
85 
Continue Maintenance therapy until 2 years from the start of Induction therapy. 
See Section 5.0 for Dose Modifications for Toxicities and Appendix IV the COG Member website for Supportive Care Guidelines. 
Page 1 of 2 


   
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Maintenance Cycle 3 and Subsequent Cycles 
 
4.13.2 Required Observations in MAINTENANCE Cycle 3 and Subsequent Cycles 
 
a) History & physical exam (including length, weight, BSA, and performance 
status (if ≥ 12 months of age)) 
b) CBC/diff/ platelets 
c) Electrolytes/BUN/Cr/AST/ALT/total bili 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE. 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 


   
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4.13.3 Treatment Details for MAINTENANCE Cycle 3 and Subsequent Cycles. 
Administer drug dosages based on age on Day 1 of each Maintenance cycle. 
 
Criteria to start Maintenance 
Begin Maintenance Cycle 3 on Day 85 of Cycle 2. 
 
The administration schedule below describes one 12-week cycle of Maintenance 
therapy. Follow this schedule for Cycle 3 and all subsequent cycles. Maintenance 
is to be continued until 2 years from the start of Induction therapy.  
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at:  
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusions. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according 
to institutional guidelines. 
 
Mercaptopurine: Oral (PO) or Nasogastric (NG) 
Days: 1-84 
Dose: Administer up to 75 mg/m2/dose as tolerated. 
 
See Section 5.7 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. 
 
Methotrexate: Oral (PO)  
Days: Once weekly 
Dose: 20 mg/m2/dose 
 
Note: Administer the tablets on an empty stomach (at least 1 hour before or 2 hours 
after food or milk). Food or milk delays absorption and decreases the peak 
concentration. 
 
See Section 5.0 for Dose Modifications on Toxicities. 
 
Maintenance therapy continues until 2 years from the start of Induction therapy. 
 
 
 
 


   
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
Azacitidine 
5.1.1 
Definition of Dose-Limiting Toxicity (DLT) 
The DLT evaluation period consists of the first 3 courses of azacitidine in 
combination with chemotherapy (EPI #1 through Delayed Intensification Part 1) 
and until the patient meets counts requirements to begin the fourth course of 
azacitidine therapy (EPI #4). 
 
A DLT is defined as any of the following that occurs during the DLT evaluation 
period: 
 
• 
Any Grade 5 toxicity. 
 
• 
Any Grade 3 or 4 toxicity that occurs during the 5 days of azacitidine AND 
results in: 
o The omission of 2 or more of the 5 planned doses of azacitidine, OR 
o The delay of the start of the first day of chemotherapy for ≥ 72 hours. 
 
• 
Any Grade 3 or 4 toxicity that occurs during the 5 days of azacitidine and/or a 
chemotherapy course AND results in: 
 
o The delay of Consolidation Day 29 chemotherapy for ≥ 4 weeks from the 
expected start date. 
o The delay of the start of the subsequent course of therapy for ≥ 4 weeks 
from the expected start date (with the expected start date of EPI #2 as 2 
weeks following administration of Consolidation Day 29 chemotherapy), 
OR 
o The removal of the patient from the planned protocol therapy. 
 
5.1.2 
Hematological Toxicity 
Patients who experience hematological toxicity during any 5-day course of 
azacitidine will continue to receive full dose azacitidine. Chemotherapy will begin 
on Day 6 regardless of peripheral blood cell numbers. 
 
Patients who experience a delay in the start of any azacitidine course of at least 4 
weeks from the expected start date will be considered to have dose-limiting 
toxicity (see definition of DLT as defined above).  
 
Patients with any Grade 3 or greater hematological toxicity that is considered by 
the local investigator to be immediately life-threatening, regardless of attribution 
or duration, will have doses of azacitidine withheld. 
 
Missed doses of azacitidine will not be made up. If doses of azacitidine are 
withheld then azacitidine and/or Day 6 chemotherapy may not resume until the 
toxicity has resolved to ≤ Grade 2. 
 
If the toxicity that caused the delay or cessation is NOT a DLT (as defined in 
Section 5.1.1), then azacitidine therapy may resume without a dose reduction with 
the next scheduled dose.  
 


   
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If the patient experiences a single DLT, then azacitidine will resume with a 30% 
dose reduction when the patient meets count parameters and for all remaining 
azacitidine doses in all remaining courses. If the patient experiences a second DLT 
of any type, the patient will be removed from protocol therapy. 
 
Notify the Study Chair at the time azacitidine doses are withheld, or when a 
DLT occurs that may result in a dose reduction. 
 
5.1.3 
Non-Hematological Toxicity 
Patients who experience any Grade 3 or greater toxicity that is of at least 48 hours 
duration and occurs on days when the patient is receiving scheduled doses of 
azacitidine (Days 1-5 of any course) will have azacitidine doses omitted until the 
toxicity has resolved to ≤ Grade 2. Specific exceptions will include febrile 
neutropenia, infection, constitutional symptoms, mucositis, and diaper area skin 
ulceration. 
 
Patients with any Grade 3 or greater non-hematological toxicity that is considered 
by the local investigator to be immediately life-threatening, regardless of 
attribution or duration, will have doses of azacitidine withheld. 
 
Missed doses will not be made up. If doses of azacitidine are withheld, then 
azacitidine and/or Day chemotherapy may not resume until the toxicity has 
resolved to ≤ Grade 2. 
 
If the toxicity that caused the delay or cessation is NOT a DLT (as defined in 
Section 5.1.1), then azacitidine therapy may resume without a dose reduction with 
the next scheduled dose.  
 
If the patient experiences a single DLT, then azacitidine will resume with a 30% 
dose reduction when the patient meets count parameters and for all remaining 
azacitidine doses in all remaining courses. If the patient experiences a second DLT 
of any type, the patient will be removed from protocol therapy. 
 
Notify the Study Chair at the time azacitidine doses are withheld, or when a 
DLT occurs that may result in a dose reduction. 
 
5.2 
Cyclophosphamide 
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of previous 
significant hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010 
and hydrate at 125 mL/m2/hr for 24 hours after dose. Monitor for adequate urine output as 
per institution guidelines. Give IV mesna at a 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. 
 


   
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Renal Dysfunction: If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, 
reduce dose of cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the 
creatinine clearance should be repeated with good hydration. 
 
5.3 
Cytarabine (ARAC) 
Consolidation: 
Patients should have ANC ≥ 300/μL and platelets ≥ 30,000/μL to start each 4-day 
cytarabine block beginning on Days 10, 17, and 24. Once a 4-day block has started, do not 
interrupt for uncomplicated myelosuppression. 
 
Delayed Intensification Part 1: 
Vincristine, daunorubicin, and the start of each 4-day cytarabine block on Days 9, 16, and 
23 should be delayed and thioguanine interrupted if the ANC falls to <300/μL or platelets 
< 30,000/μL. If a 4-day cytarabine block has been started, then cytarabine and thioguanine 
should not be interrupted. 
 
Delayed Intensification Part 2: 
The start of the 4-day cytarabine block on Day 9 should be delayed and thioguanine 
interrupted if the ANC falls to <300/μL or platelets < 30,000/μL. If a 4-day cytarabine 
block has been started, then cytarabine and thioguanine should not be interrupted. 
 
Cytarabine Syndrome: Do not withhold cytarabine for fever if it is likely to have been 
caused by the cytarabine. Obtain blood cultures if a central line is present. For rash or 
conjunctivitis, withhold for Grade 3-4 toxicity until resolved. Make up missed doses and 
consider concurrent treatment with hydrocortisone or dexamethasone, and/or with 
dexamethasone ophthalmic drops for conjunctivitis. 
 
Adequate renal function (defined as creatinine within normal range) is required for the 
administration of high dose cytarabine. 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. 
 
 
5.4 
Daunorubicin (Anthracycline) 
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.  
 
Delayed Intensification Part 1: 
Vincristine, daunorubicin, and the start of each 4-day cytarabine block on Days 9, 16, and 
23 should be delayed and thioguanine interrupted if the ANC falls to <300/μL or platelets 
< 30,000/μL. 
 
Note: use the following updated term to report decreases in the EF or SF: cardiac 
disorders-others 
 
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. 
 


   
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Hyperbilirubinemia:31 
 
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. 
 
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/extravasationreference.p
df for COG extravasation management reference. 
 
5.5 
Intrathecal Methotrexate 
Do not withhold dose given on Day 1 of Induction. 
 
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. 
 
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.32-34 
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.34-39 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, cytarabine 
and hydrocortisone). Certain protocols, for example BFM 2000,40include 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 cytarabine has not been studied or described in the context of ALL 
therapy nor can one demonstrate the safety of omitting multiple doses of IT therapy without 
concomitant use of cranial irradiation or high dose methotrexate. 
 
The following guidelines are offered for consideration following an acute event, but it must 
be recognized that there are little data to support these approaches or any others. Thus the 
treating physician must evaluate the patient and, with the family, make the best possible 
decision with respect to the relative risk and benefit of continued therapy. 
 
Following an acute neurotoxic event, a history and physical exam should guide the 
differential diagnosis. A neurology consult may be of value and should be considered. 


   
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Seizures and other transient events may be linked to fever, infection, encephalitis, 
meningitis, hypertension, electrolyte disturbance, hypoglycemia, trauma, intracranial 
hemorrhage or thrombosis, narcotic withdrawal, 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.41 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.42-44 Additional studies, including MR angiography and/or venogram should be 
considered, if clinically indicated (e.g., focal deficits). 
 
Many acute events, seizures or episodes of transient hemiparesis, are temporally related to 
the administration of intrathecal therapy, commonly 9 to 11 days after the IT 
administration.45 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 
nterventions. It is reasonable to hold the next dose of IT therapy, or, substitute IT cytarabine 
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.45 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.46-49 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.50-53 At 
doses thought to be therapeutic, side effects have included nystagmus, nausea and 
vomiting, distorted vision, ataxia, and dizziness. In addition, Hollander et al 54 have raised 
concerns about the potential deleterious effects of long-term NMDA receptor blockade on 
memory because hippocampal long-term potentiation is dependent on the activation of the 
NMDA receptor. Thus in the absence of a clinical trial there are few data to support the 
addition of DM. 
 
Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal 
chemotherapy via lumbar puncture: 


   
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Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal 
therapy delivered by LP. Intraventricular chemotherapy should be given according to the 
same schedule, but at 50% of the corresponding age-based doses that would be given by 
LP. NOTE: Obstruction to CSF flow may be a contraindication to intrathecal and/or 
intraventricular therapy. 
 
Viral, bacterial, or fungal meningitis: Omit until resolved. 
 
5.6 
High Dose Methotrexate (HD MTX) and Leucovorin Rescue 
[Please note that HD methotrexate refers to IV methotrexate 5g/m2 given over 24 hrs] 
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 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. 
 
5.6.1 
HD Methotrexate Infusion Guidelines 
See Appendix III for a flowchart of the High Dose methotrexate / leucovorin 
guidelines. 
 
Hold trimethoprim-sulfamethoxazole on the days of HD methotrexate infusion and 
for at least 72 hours after the start of the HD methotrexate infusion and until the 
methotrexate 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 HD methotrexate 
infusion and for at least 72 hours after the start of the HD methotrexate infusion 
and until the methotrexate level is less than 0.1 μM.  
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld 
on the day HD methotrexate is administered and for the following 24 hours due to 
the risk of delayed methotrexate excretion, renal dysfunction and resultant toxicity. 
 
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. Recommend 
hydration for a minimum of 54 hours after the methotrexate bolus is started for 
patients who meet expected clearance parameters. In patients with delayed 
methotrexate clearance, continue hydration and leucovorin as instructed 
(Appendix III) until the plasma methotrexate concentration is below 0.1 µM. 
 
Hour 0: methotrexate 10 % of the total dose to be administered IV infused over 
30 minutes. This is followed, immediately, by the remaining 90% of the 
methotrexate dose given by continuous IV infusion over 23.5 hours. Be certain that 
the HD methotrexate infusion is completed in the 24 hour period. Unintentional 
prolongation to as long as 26 hours though not encouraged is acceptable. 
 


   
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Hours 24, (36), 42 and 48: Draw methotrexate level and serum creatinine; NOTE: 
36 hour level is only drawn if needed (see below) 
 
 
For methotrexate levels that exceed these expected values modify the rescue 
regimen as noted below and increase hydration to 200 mL/m2/hr, monitor urine 
pH to assure a value ≥ 7.0 and monitor urine output to determine if volume is ≥ 
80% of the fluid intake, measured every 4 hours. If serum creatinine rises 
significantly, at any time point, assure appropriate urine pH and urine volume as 
above and draw a 42 hour level. If urine output fails to continue at 80% of the fluid 
intake, consider furosemide. Regardless of urine output, also consider glucarpidase 
(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. 
 
If the 24 hour level is ≥ 150 M and/or creatinine > 125% baseline, repeat level 
if methotrexate 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. Continue to check methotrexate level every 12-24 hours and give Leucovorin 
15 mg/m2 IV/PO every 6 hours until the methotrexate level is <0.1µM. 
 
(36 hr MTX level) 
42 hr MTX level 
 
48 hr MTX level 
Leucovorin Rescue++ 
Only required if 24 hr 
level is ≥ 150 µM. See 
below for guidelines** 
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. 
 
** 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 methotrexate (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. 
 


   
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Nephrotoxicity: Postpone course if pre-treatment (methotrexate) serum creatinine 
is > 1.5 x baseline or GFR creatinine clearance < 65 mL/minute/1.73m2. If renal 
function does not recover, omit methotrexate. Do not give HD methotrexate to a 
patient with this degree or renal impairment, assuming that prolonged excretion 
can be managed with glucarpidase. 
 
NOTE: For patients who have markedly delayed methotrexate clearance secondary 
to renal dysfunction, consider using glucarpidase (carboxypeptidase G2, 
Voraxaze).55,56 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 protocol therapy. 
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn 
within 72 hours, PRIOR to a course of intravenous methotrexate. Blood samples 
for ALT should not be drawn following the start of methotrexate infusions as 
methotrexate causes significant short term elevation in ALT levels. 
 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 consecutive cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption. 
Do not skip doses. 
> 20 X ULN 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption.  
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy given. Notify Study 
Chair. 
* Please see Supportive care Guidelines in Appendix IV 
 
Hold IV methotrexate for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
Mucositis: For Grade 3-4 mucositis, withhold IV methotrexate 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 methotrexate by 25%, increase hydration to 200 mL/m2/hr and continue 
increased leucovorin as above. Should subsequent courses be well tolerated, use a 
stepwise approach to resuming a standard approach to drug delivery. Consider 
culturing lesions for herpes simplex if mucositis persists or recurs. 
 
Myelosuppression: All chemotherapy should be held for ANC < 750/µL and 
platelets < 75 000/µL. 
 


   
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5.7 
PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
Consolidation 
If possible, mercaptopurine therapy should not be interrupted. If a cytarabine block has to be 
postponed or interrupted, then mercaptopurine should also be interrupted. Omitted 
mercaptopurine doses should be made up until the planned cumulative total dose 1680 mg/m2 
(60 mg/m2 x 28 doses) for infants ≥ 12 months, 1260 mg/m2 (45 mg/m2 x 28 doses) for infants 
6 to < 12months, 1120 mg/m2 (40 mg/m2 x 28 doses) for infants < 6 months. 
 
Interim Maintenance: 
If Day 8 HD methotrexate is delayed due to toxicity, then interrupt mercaptopurine. 
Resume mercaptopurine when Day 8 HD methotrexate is given and complete the planned 
14 days of mercaptopurine. 
 
Maintenance:  
If neutrophil count falls below 500/L or if platelet count falls below 50 000/L during 
Maintenance, mercaptopurine and methotrexate will be held until recovery above these levels. 
For the first drop in ANC or platelets, resume chemotherapy (both mercaptopurine and 
methotrexate) 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 mercaptopurine and 
methotrexate until ANC is ≥ 750/µL and platelets are ≥ 75 000/µL. Restart both 
mercaptopurine and methotrexate 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 mercaptopurine and methotrexate simultaneously. 
Consider discontinuing TMP/SMX as per COG Supportive care Guidelines in Appendix IV. 
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. 
 
Dose escalation during Maintenance:  
This protocol includes a planned dose escalation of mercaptopurine from 50 mg/m2/day in 
Maintenance Cycle 1 to 75 mg/m2/day in Maintenance Cycle 2. Proceed with the dose 
escalation in Cycle 2 if ANC ≥ 500/µL and platelets ≥ 50 000/µL. 
 
Beginning in Maintenance Cycle 2, for ANC ≥ 1500/L on 3 CBC(s) done over 6 weeks or 2 
successive monthly CBC(s) alternately increase doses of methotrexate or mercaptopurine by 
25%. As a general rule, do not increase doses more often than every 4 weeks. If both 
methotrexate and mercaptopurine are increased once without a fall in ANC, consider 
noncompliance as a possibility. Noncompliance can be assessed by obtaining a sample for 
RBC thioguanine nucleotides (TGNs). Consider observing the administration of an oral dose 
of methotrexate and checking plasma methotrexate concentration 2-4 hours later. This will 
document whether or not poor absorption contributes to lack of response and may facilitate 
discussions about noncompliance. 
 
Mucositis Grade 3-4: 
Methotrexate 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. 
 


   
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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 methotrexate 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 methotrexate but without mercaptopurine, 
especially if red cell mercaptopurine 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. 
 
Pharmacology Testing (TPMT and NUDT15) and Dosage Adjustments: 
mercaptopurine and 6-TG are methylated directly by thiopurine methyltransferase (TPMT) 
to an inactive metabolite. TPMT activity varies tremendously among patients, because of a 
common inherited genetic defect in TPMT. One in 300 patients is completely deficient 
(homozygous defective) and 10% of the population are moderately deficient in TPMT 
activity because they have inherited one variant (non-functional) TPMT allele (i.e., 
heterozygotes). 57-60 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 
mercaptopurine (10 to 30 mg/m2/day 3 days per week). About 35% of heterozygotes 
require a lower dose of mercaptopurine to avoid dose-limiting myelosuppression. 61 
 
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-mercaptopurine intolerance.62 There are now CLIA certified 
tests for TPMT genotype and phenotype, NUDT15 polymorphism, and for measurement 
of thiopurine metabolites (6-methyl mercaptopurine [6-MMP] and 6-TGN) measurements. 
Only 3 SNPs constitute well over 90% of the inactivating mutations in the gene, based on 
studies in numerous racial and ethnic groups worldwide. 57,63-66 Thus, the genotyping test 
has a low false negative rate, and may be preferable to TPMT phenotype testing in cases 
where a history of red cell transfusions would potentially confound assessments of RBC 
TPMT activity. When the genotyping result is coupled with a phenotyping test for TPMT 
or with thiopurine metabolite concentrations in erythrocytes, the reliability of the tests will 
be even greater. Moreover, metabolite levels can provide an index of patient compliance 
with thiopurine therapy. 
 
Recommendations for Thiopurine Monitoring and Dosage Adjustments:  
When myelosuppression has led to significant delays in therapy (> 2 weeks) or is 
disproportionate to the therapy, thiopurine testing should be performed: 


   
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-  
For 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.  Genotyping 
can be done despite recent transfusions. 
 
Suggested Dose Adjustments in Subjects 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 is has two polymorphisms in 
NUDT15 (ie heterozygous for both the R139C and the R139H), they should be treated 
as if they are 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 
mercaptopurine and methotrexate see the beginning of this section (5.7). 
 
5.8 
Pegaspargase [Asparaginase (Peg-Asparaginase) or Erwinia] 
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, which 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 


   
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severe systemic or recurrent local allergic reaction, Erwinia chrysanthemi asparaginase 
(Erwinaze®), which is FDA-approved for this indication, should be substituted. 
 
Therapeutic Drug Monitoring (TDM): TDM of asparaginase activity is available as a CLIA 
approved assay from AIBioTech®. Centers may elect to discontinue pegaspargase and 
switch to Erwinia asparaginase based upon laboratory evidence of silent inactivation of 
asparaginase activity in the absence of clinical symptoms of hypersensitivity at their 
discretion. 
 
Anaphylaxis  
Discontinue pegaspargase if the patient develops Grade 3 anaphylaxis as defined by 
CTCAE v4.0 (symptomatic bronchospasm, with or without urticaria, parenteral 
intervention indicated; allergy-related edema/angioedema; hypotension). If this occurs, 
Erwinia asparaginase 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.67,68 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.69 Current COG trials have 
adopted pegaspargase as the preparation of choice, based on the results of CCG 1962.70 
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 initially approved 
Erwinia asparaginase for use following allergy to pegaspargase, with a dose of Erwinia 
25,000 International Units/m2 x 6 doses IM on a Monday/Wednesday/Friday schedule 
substituted for a single dose of pegaspargase.  In December 2014, the FDA expanded its 
approval to include intravenous as well as intramuscular administration. 
 
The dose modification guidelines for ALL trials recommend the substitution for 
replacement of Erwinia asparaginase for either native or pegaspargase utilizing the 
following schedule. For each dose of 2500 International Units/m2 of pegaspargase, replace 
with Erwinia 25,000 International Units/m2/dose IM or IV Monday/Wednesday/Friday x6 
doses. AALL15P1 includes age based doses of pegaspargase, including doses lower than 
2500 International Units/m2. For infants on this protocol, replace pegaspargase with 6 
doses of Erwinia asparaginase M/W/F at a ratio of 1:10 International Units (e.g. the 
replacement dose for 2,000 International Units/m2 of pegaspargase is 20,000 International 
Units/m2/dose of Erwinia). 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 


   
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patients who are clinically stable. Up to 6 doses of Erwinia asparaginase may be 
administered, as tolerated, to replace the incomplete intravenous pegaspargase dose. Of 
note, Erwinia asparaginase is recommended only for pegaspargase hypersensitivity 
reactions, and not for pancreatitis, hepatitis, coagulation abnormalities, or other non-
hypersensitivity toxicities associated with pegaspargase. To best suit the needs of each 
individual patient, additional modifications to these recommendations may be made at the 
discretion of the treating physician. 
 
Coagulopathy: If symptomatic, hold asparaginase until symptoms resolve, then resume with 
the next scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do 
not withhold dose for abnormal laboratory findings without clinical symptoms.  
 
Hyperbilirubinemia: asparaginase may need to be withheld in patients with an elevated direct 
bilirubin, since asparaginase has been associated with hepatic toxicity. No specific guidelines 
are available. 
 
Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically indicated. 
 
Hyperlipidemia: Do not modify dose 
 
Ketoacidosis: Hold asparaginase until blood glucose can be regulated with insulin. 
 
Pancreatitis: 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. 
 
Thrombosis: Withhold asparaginase until resolved, and treat with appropriate antithrombotic 
therapy, as indicated. Upon resolution of symptoms consider resuming asparaginase, while 
continuing LMWH or antithrombotic therapy. Do not withhold dose for abnormal laboratory 
findings without clinical correlate. For significant thrombosis, 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. 
 
5.9 
Steroids (Dexamethasone and Prednisone) 
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. 
 
Hyperglycemia: Dose should not be reduced for hyperglycemia. Rather, insulin therapy 
should be employed to control the blood glucose level. 
 
Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase. 
Discontinue steroids, except for stress doses, in the presence of hemorrhagic pancreatitis or 
severe pancreatitis. 
 


   
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Osteonecrosis (ON): Do not modify corticosteroid therapy for osteonecrosis (also referred to 
as avascular necrosis) during Induction or Delayed Intensification. 
 
Varicella: Steroids should be held during active infection except during Induction. Do not hold 
during incubation period following exposure. 
 
Inability to use oral doses: 
For dexamethasone, substitute the IV preparation mg for mg. 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. 
 
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.” 
 
Severe psychosis: Dexamethasone dose may be reduced by 50% for severe psychosis. If 
symptoms persist, consider switching to an equivalent dose of prednisone. 
 
5.10 
PO-6-Thioguanine (TG) 
Delayed Intensification Part 1: 
Vincristine, daunorubicin, and the start of each 4-day cytarabine block on Days 9, 16, 
and 23 should be delayed and thioguanine interrupted if the ANC falls to <300/μL or 
platelets < 30,000/μL. If a 4-day cytarabine block has been started, then cytarabine and 
thioguanine should not be interrupted. 
 
Delayed Intensification Part 2: 
The start of the 4-day cytarabine block on Day 9 should be delayed and thioguanine 
interrupted if the ANC falls to <300/μL or platelets < 30,000/μL. If a 4-day cytarabine 
block has been started, then cytarabine and thioguanine should not be interrupted. 
 
For severe and/or unexpected myelosuppression, evaluate for TPMT activity as described 
in Section 5.7. 
 
5.11 
VinCRIStine 
PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See text box 
below) 
 
Severe neuropathic pain (Grade 3 or greater):  
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated. NOTE: neuropathic pain 
can be not only severe but difficult to treat. However, because vincristine is an important 
component of curative therapy and the majority of neuropathies are ultimately reversible, 
vincristine therapy may be given at full dose at investigator discretion. Severe peripheral 
neuropathies, with or without a positive family history might suggest the need for a 
molecular diagnostic evaluation to rule out Charcot Marie Tooth Disease (CMT), Type 1A 
or Hereditary neuropathy with liability to pressure palsies. Drugs such as gabapentin may 
be of value. 
 


   
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Vocal Cord paralysis:  
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated. See above for comment on 
CMT. 
 
Foot Drop, paresis:  
Should be Grade 3 to consider holding or decreasing dose. These toxicities are largely 
reversible but over months to years. Accordingly, holding doses of vincristine and/or 
lowering the dose may not result in rapid resolution of symptoms and may compromise 
cure. See above for comment on CMT. Physical therapy may be beneficial to maintain 
range of motion and provide AFO’s and other forms of support. Drugs such as gabapentin 
may be of value. 
 
Jaw pain: Treat with analgesics; do not modify vincristine dose. 
 
Hyperbilirubinemia71,72: 
 
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. 
 
Constipation or ileus (≥ Grade 3) or typhlitis: Hold dose(s); institute aggressive regimen to 
treat constipation if present. When symptoms abate resume at 50% of calculated dose 
(maximum dose: 1 mg) and escalate to full dose as tolerated. 
 
Extravasation: 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to 
institutional guidelines. Also see: 
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationreference.p
df for COG extravasation management recommendations. 
 
 


   
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5.12 
Drug Interactions 
Possible Drug Interactions with Antileukemic drugs: 
See Section 4.1.1.3 and Appendix II. 
 
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. 
 
Possible Drug Interactions with High Dose Methotrexate: 
Hold TMP/SMX on the days of high dose methotrexate infusion and for at least 72 hours after 
the start of the high dose methotrexate infusion and until the methotrexate level is less than 
0.1 M.  
 
Hold any NSAIDs, penicillins, proton pump inhibitors, or aspirin-containing medications 
on the day of high dose methotrexate infusion and for at least 72 hours after the start of 
the high dose methotrexate infusion and until the methotrexate level is less than 0.1 M.  
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the 
day HD methotrexate is administered and for the following 24 hours due to the risk of 
delayed methotrexate excretion, renal dysfunction and resultant toxicity. 
 
 
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 
AZACITIDINE – INJECTION 
(VIDAZA ®, 5-azacitidine) NSC# 102816, IND# 133688 
 
 
 
 
 
 
 
 
 
(09/09/19) 
 
Source and Pharmacology: 
Azacitidine (4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one) is an analog of the 
naturally occurring pyrimidine nucleoside, cytidine. It differs from cytidine in having 
nitrogen in the 5-position of the heterocyclic ring. This substitution renders the ring 
chemically unstable and leads to rapid decomposition of the compound in neutral or 
alkaline solution. Therefore, for SC or IV administration, the drug is supplied as a 
lyophilized powder to be reconstituted immediately prior to use. 
 
Azacitidine was developed based on its strong in vitro and in vivo antileukemic activity at 
cytotoxic concentrations, and its differentiation-inducing potential at lower concentrations 
in hematopoietic and non-hematopoietic cell lines. The cytotoxic effects of azacitidine may 
be due to inhibition of protein synthesis and activation of DNA damage pathways, through 
incorporation into ribonucleic acid (RNA) and DNA, respectively. The ability of 
azacitidine to cause differentiation is attributed to its activity as a hypomethylating agent. 
Similar to cancer cells, the disturbed maturation of morphologically dysplastic 
hematopoietic cells in MDS is thought to reflect a block in their differentiation, resulting 
in accumulation of these precursors in the bone marrow in spite of low peripheral blood 
counts. This block in maturation (differentiation), with proliferation of preleukemic 
myeloblasts, provides a rationale for clinical trials of DNA methylation inhibitors (e.g., 
azacitidine) in the treatment of MDS. 
 
Pharmacokinetic studies using 14C-radiolabeled azacitidine to evaluate drug disposition 
demonstrated that azacitidine undergoes rapid and complete absorption following SC 
administration, with SC bioavailability greater than 70% and maximum concentration 
(Cmax) achieved 0.5 to 2 hours after dosing. The volume of distribution of azacitidine is 
76 ± 26 L following IV administration. Its protein binding in human serum is low (< 10% 
bound). Azacitidine and/or its metabolites are cleared by the kidneys. The plasma 
elimination half-life (t1/2) is 3.4 to 6.2 hours and amount of radioactivity recovered in urine 
(50% to 98% of administered dose) were similar after IV and SC dosing. 
 
In vitro and in vivo studies have demonstrated that spontaneous hydrolysis of azacitidine 
is the major pathway in different species, regardless of the route of administration. 
Azacitidine is not metabolized by cytochrome P450 isozymes (CYPs) and it will not 
produce clinically relevant PK drug-drug interactions due to CYP enzyme inhibition or 
induction when coadministered with CYP substrates, inducers, or inhibitors. Azacitidine is 
not a substrate for P-glycoprotein (P-gp) and is unlikely to produce any clinically relevant 
interactions as a P-gp substrate or an inhibitor. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Azacitidine (NSC 102816) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 


   
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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 1800 patients. Below is the CAEPR for Azacitidine. 
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, July 30, 20191 
 
 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 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) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
Heart failure 
 
 Heart failure (Gr 2) 
 
Pericardial effusion 
 
 Pericardial effusion (Gr 2) 
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 2) 
 
Supraventricular tachycardia 
 
 Supraventricular tachycardia (Gr 
2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Colitis 
 
 Colitis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Esophagitis 
 
 Esophagitis (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 3) 
Injection site reaction 
 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
Infection3 
 
 
 Infection3 (Gr 4) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
 Bruising (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 4) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased 
(Gr 2) 


   
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 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)    
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 4) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 
4) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 2) 
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Hypokalemia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Generalized muscle weakness 
 
 Generalized muscle weakness (Gr 
2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Peripheral motor neuropathy 
 
 Peripheral motor neuropathy (Gr 2) 
 
Somnolence 
 
 Somnolence (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Confusion 
 
 Confusion (Gr 2) 
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Bronchopulmonary 
hemorrhage 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 4) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Pharyngolaryngeal pain 
 
  
 
Postnasal drip 
 
 Postnasal drip (Gr 2) 
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(abnormal breath sound)4 
 
 Respiratory, 
thoracic 
and 
mediastinal 
disorders 
- 
Other 
(abnormal breath sound)4 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Purpura 
 
 Purpura (Gr 2) 


   
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 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 5.0 Term) 
[n= 1800] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)    
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hematoma 
 
 Hematoma (Gr 2)  
 
Hypotension 
 
 Hypotension (Gr 3) 
 
 
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. 
 
3Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
4Abnormal breath sounds include rales and rhonchi. 
 
 
Adverse events reported on azacitidine trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that azacitidine caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(agranulocytosis); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and lymphatic 
system disorders - Other (pancytopenia); Blood and lymphatic system disorders - Other (splenomegaly); 
Blood and lymphatic system disorders - Other (transfusion: platelets); Bone marrow hypocellular; 
Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (cardiac valve vegetation); Cardiac disorders - Other (Wolff-Parkinson-White 
syndrome); Chest pain - cardiac; Myocardial infarction; Palpitations; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
EYE DISORDERS - Eye disorders - Other (eye/conjunctival hemorrhage); Eye disorders - Other (retina 
hemorrhage); Papilledema; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal ulcer; Flatulence; Gastritis; Gastrointestinal 
disorders - Other (enteritis); Gastrointestinal disorders - Other (inguinal hernia, obstructive); 
Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal disorders - Other (intussusception); 
Gastrointestinal pain; Hemorrhoids; Pancreatitis; Periodontal disease; Small intestinal obstruction; Visceral 
arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other (systemic 
inflammatory response syndrome); Generalized edema; Malaise; Multi-organ failure; Non-cardiac chest 
pain; Pain; Sudden death NOS 


   
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HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct 
stone); Hepatobiliary disorders - Other (hepatic cirrhosis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder; Immune system disorders - Other (GVHD) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Burn; Fall; Fracture; Hip fracture; Injury, 
poisoning and procedural complications - Other (excoriation); Injury, poisoning and procedural 
complications - Other (transfusion reaction); Postoperative hemorrhage; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate dehydrogenase 
increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; 
Investigations - Other (blood urea increased); Investigations - Other (cardiac murmur); Investigations - 
Other (coagulopathy); Investigations - Other (protein total decreased); Investigations - Other 
(thrombocytosis); Lipase increased; Lymphocyte count increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (gout exacerbation); Metabolism and 
nutrition disorders - Other (hypovolemia); Metabolism and nutrition disorders - Other (low carbon dioxide) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Chest wall pain; 
Flank pain; Muscle cramp; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - 
Other (chondritis); Musculoskeletal and connective tissue disorder - Other (intervertebral disc protrusion); 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(colonic polyp, vaginal polyp); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(metastases to central nervous system); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Dysgeusia; Hydrocephalus; Intracranial hemorrhage; 
Lethargy; Memory impairment; Nervous system disorders - Other (head injury); Paresthesia; Peripheral 
sensory neuropathy; Seizure; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Delirium; Depression; Hallucinations; Psychiatric disorders - Other (mental 
status changes) 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Dysuria; Hematuria; Proteinuria; Renal 
and urinary disorders - Other (bladder distention); Renal and urinary disorders - Other (calculus urinary); 
Renal calculi; Urinary frequency; Urinary retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive system and 
breast disorders - Other (benign prostatic hyperplasia); Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Hypoxia; Laryngeal 
hemorrhage; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; 
Pneumothorax; Productive cough; Pulmonary edema; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (chronic obstructive pulmonary disease); Respiratory, thoracic and 
mediastinal disorders - Other (pharyngeal erythema); Rhinorrhea; Sinus pain; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin laceration); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin and subcutaneous tissue disorders - Other (skin 
nodule); Skin and subcutaneous tissue disorders - Other (Sweet's Syndrome); Skin induration; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (poor venous access); Vasculitis 
 
Note: Azacitidine 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. 
Formulation and Stability: 
Azacitidine is supplied as a lyophilized powder in single-use vials. Each vial contains 100 
mg of azacitidine and 100 mg of mannitol as a freeze-dried cake or powder. The azacitidine 
vial does not contain any preservative and is for single use. Store unreconstituted vials at 
25° C (77° F); excursions permitted to 15°-30° C (59°-86° F). 
For IV administration: Reconstitute vial with 10 mL SWFI to form a 10 mg/mL solution; 


   
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vigorously shake or roll vial until solution is dissolved and clear. Following reconstitution, 
further dilute azacitidine in NS or lactated Ringer's injection for infusion to a final 
concentration between 0.9 mg/mL and 4 mg/mL. The reconstituted product may be stored 
at 25° C (77° F), but the administration of the intravenous solution must be completed 
within 45 minutes of reconstitution. Solutions for IV administration have very limited 
stability and must be prepared immediately prior to each dose. 
Azacitidine is a cytotoxic drug and caution should be exercised when handling and 
preparing injectable azacitidine. Procedures for proper handling and disposal of azacitidine 
(vials or reconstituted azacitidine) should be applied according to standards established at 
each facility for cytotoxic drugs. If a vial is broken or damaged, dispose of the drug product 
and do not use. 
Azacitidine is incompatible with 5% dextrose solution, Hespan, or solutions that contain 
bicarbonate. These solutions have the potential to increase the rate of degradation of 
azacitidine and should therefore be avoided. 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Supplier: 
Azacitidine is supplied by Celgene and distributed by the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI. Do not use commercial supply. 
Obtaining the Agent 
Agent Ordering 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. Sites may order initial agent supplies 
when a subject is being screened for enrollment onto the study. The CTEP assigned protocol 
number must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), NIH Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP supplied investigational agents for the study should be 
ordered under the name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, and a “current” password, 
and active person registration status. For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management. 
Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 


   
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the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” password 
and active person registration status. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
Useful Links and Contacts: 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci. 
nih.gov/OAOP/ 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci. 
nih.gov/iam/ 
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
(Cytoxan) NSC#26271  
 
 
 
 
 
(03/13/13) 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in 
the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) 
which is in equilibrium with aldophosphamide which spontaneously releases acrolein to 
produce phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional 
alkylating species, is 10 times more potent in vitro than is 4-HC and has been shown to 
produce interstrand DNA cross-link analogous to those produced by mechlorethamine. 
Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges from 4.1 to 
16 hours after IV administration. 
 
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 


   
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Immediate: 
Within 1-2 
days of 
receiving 
drug 
Anorexia, nausea & 
vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal stuffiness with 
rapid administration, arrhythmias (rapid 
infusion), skin rash, anaphylaxis, SIADH 
Prompt: 
Within 2-3 
weeks, prior 
to the next 
course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose (acute – CHF 
hemorrhagic myocarditis, myocardial necrosis) 
(L), hyperpigmentation, nail changes, impaired 
wound healing, infection secondary to immune 
suppression 
Delayed: 
Any time 
later during 
therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or 
permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian failure1 (L), 
interstitial pneumonitis, pulmonary fibrosis2 (L)  
Late: 
Any time 
after 
completion 
of treatment 
 
 
Secondary malignancy (ALL, ANLL, AML), 
bladder carcinoma (long term use > 2 years), 
bladder fibrosis  
Unknown 
Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other 
antineoplastic agents) have been noted in humans. Toxicities include: chromosomal abnormalities, 
multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is excreted into breast milk. 
Cyclophosphamide is contraindicated during 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 (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  
(Cytosine arabinoside, Ara-C, Cytosar ®) NSC #63878   
 
(07/13/15) 
 


   
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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. 
 
 
Toxicity:  (Intrathecal) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
 
Arachnoiditis 
Rash, somnolence, 
meningismus, convulsions, 
paresis 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia 


   
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Delayed: 
Any time later during 
therapy, excluding the above 
condition 
 
 
Necrotizing 
leukoencephalopathy, 
paraplegia, blindness (in 
combination with XRT & 
systemic therapy) 
 
Formulation:  
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a 
sterile powder for reconstitution. It is also available at a 20 mg/mL concentration with 
benzyl alcohol (25 mL per vial) or as a preservative free solution (5 mL, 50 mL per vial), 
and at a 100 mg/mL concentration with benzyl alcohol (20 mL vial) or as preservative free 
solution (20 mL vial). Hydrochloric acid and/or sodium hydroxide may be added to adjust 
the pH. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Cytarabine 
solutions should be protected from light. 
 
Guidelines for Administration:  See Treatment and Dose 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 
predniso(lo)ne), 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. 
 
Intrathecal: 
For intrathecal administration, dilute with 5-10 mL (or volume per institutional practice) 
preservative free 0.9% sodium chloride injection, lactated Ringer’s injection, Elliot’s B 
solution. The volume of CSF removed should be equal to at least ½ the volume delivered. 
 
Patient 
Age 
(years) 
Recommended 
volume 
10% CSF volume 
CSF Volume * 
1 – 1.99 
5 – 10 mL 
5 mL 
50 + 10 mL (babies) 
2 – 2.99 
5 – 10 mL 
8 mL 
80 + 20 mL (younger children) 
3 – 8.99 
5 – 10 mL 
10 mL 
100 + 20 mL (older children) 


   
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9 or greater 
5 – 10 mL 
13 mL 
130 + 30 mL (adults) 
 
*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 cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution 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. 
 
6.4 
DAUNORUBICIN  
Daunomycin, rubidomycin, Cerubidine®)  NSC #82151  
 
(05/09/11) 
   
 
 
 
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. 
 
 


   
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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 
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. 
 
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. 
 


   
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Guidelines for Administration: See Treatment and Dose Modifications 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   
(Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521  
(05/09/11) 
 
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 which are found in larger numbers on leukemic 
lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors and 
inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose 
transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Elimination half-lives for the following age groups have been reported to be: infants and 
children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults 
(age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is primarily 
metabolized in the liver and excreted by the kidneys. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Immunosuppression, personality 
changes (mood swings, euphoria, 
anxiety, depression), pituitary-
adrenal axis suppression, acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections (bacterial, 
fungal, parasitic, viral), edema 
Pancreatitis (L), 
increased intraocular 
pressure (L), 
hypertension, psychosis, 
vertigo, headache 
Delayed: 
Any time later 
during therapy 
Cushing’s syndrome (moon facies, 
truncal obesity) 
Striae and thinning of the 
skin, easy bruising, muscle 
weakness, osteopenia  
Spontaneous fractures 
(L), growth suppression, 
peptic ulcer and GI 
bleeding, pseudotumor 
cerebri (increased 
intracranial pressure with 
papilledema, headache), 
aseptic necrosis of the 
femoral and humeral 


   
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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 section of the 
protocol. 
 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV 
use, it may be further diluted in dextrose or saline containing solutions. Avoid using benzyl 
alcohol-containing dexamethasone solutions in neonates. Diluted solutions that contain no 
preservatives should be used within 24 hours, but maintain stability for at least 14 days in 
PVC bags at room temperature protected from light. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.6 
HYDROCORTISONE - INTRATHECAL  
(Hydrocortisone sodium succinate, Solu-cortef®) NSC #010483  
(07/30/14) 
 
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 


   
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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 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus and 
pleocytosis)  
Rash, anaphylaxis (L), paresis, 
bleeding into subarachnoid or 
subdural space (risk > with platelet 
counts < 20,000), confusion, fatigue, 
disorientation, seizures 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
 
 
Myelosuppression, somnolence, 
ataxia, cranial nerve palsy, transient 
paraplegia,(L) speech disorders 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive disturbances (L), 
learning disabilities(L) 
Demyelating 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. 
 
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 


   
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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  
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 
 
6.7 
LEUCOVORIN CALCIUM  
(LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590  
(05/09/11) 
 
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 


   
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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 
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. 


   
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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. 
 
6.8 
MERCAPTOPURINE  
(6-MP, Purinethol®, PurixanTM, 6-mercaptopurine) NSC #000755 
(11/27/17) 
 
Source and Pharmacology:  
Mercaptopurine is an analogue of the purine bases adenine and hypoxanthine. The main 
intracellular pathway for MP activation is catalyzed by the enzyme hypoxanthine-guanine 
phosphoribosyl transferase (HGPRT) which catalyzes the conversion of MP to several 
active nucleotide metabolites including thioinosinic acid, a ribonucleotide which can 
interfere with various metabolic reactions necessary for nucleic acid (RNA and DNA) 
biosynthesis. It can also cause pseudofeedback inhibition of the first step in de novo purine 
biosynthesis or convert to another ribonucleotide which can cause feedback inhibition. 
Mercaptopurine can be incorporated into DNA in the form of TG nucleotides as well and 
thus produce toxicity. The absorption of an oral dose of MP is incomplete and variable, 
with only about 16%-50% of an administered dose reaching the systemic circulation 
secondary to a first pass metabolism in the liver. Food intake and co-administration with 
cotrimoxazole (TMP/SMX) significantly reduces absorption of MP. After IV 
administration, MP has a plasma half-life of 21 minutes in children and 47 minutes in adults. 
Approximately 19% is bound to protein. Mercaptopurine is well distributed into most body 
compartments except the CSF. (With high dose IV MP the CSF to plasma ratio is 0.15.) MP 
is metabolized by xanthine oxidase in the liver to 6-Thiouric acid an inactive metabolite. In 
patients receiving both MP and allopurinol (a xanthine oxidase inhibitor) the dose of MP 
must be reduced by 50-75%. Since TPMT, 6-thiopurine methyltransferase, is also one of 
the enzymes involved in the metabolism of MP, those individuals who have an inherited 
deficiency of the enzyme may be unusually sensitive to the myelosuppressive effects of 
MP and prone to develop rapid bone marrow suppression following the initiation of 
treatment. Mercaptopurine is excreted in urine as metabolites and some unchanged drug; 
about half an oral dose has been recovered in 24 hours. A small proportion is excreted over 
several weeks. 
 
Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of 
patients) 
Neutrophil count decreased, white blood cell decreased, anorexia, fatigue 
Occasional 
(4 - 20% of 
patients) 
Diarrhea, nausea, vomiting, malaise, oligospermia, infection, fever, platelet count decreased, 
anemia, mucositis, stomach pain, ulcerative bowel lesion, skin rash, alanine aminotransferase 
increased, aspartate aminotransferase increased 


   
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Incidence 
Toxicities 
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 be reduced in patients with a TPMT defect. Patients with the rare 
homozygous deficient TPMT phenotype may tolerate only 1/10th to 1/20th the average 
mercaptopurine dose. TPMT testing and thiopurine metabolite measurements are 
commercially available. 
 
Suspension: 
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be 
compounded. The suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a 
mortar and adding 8.5 mL sterile water for irrigation. The mixture is triturated to form a 
smooth paste. Next, 16.5 mL simple syrup (pH=7) are added with continuous mixing and 
finally cherry syrup (pH=7.1) is added to a total volume of 50 mL. The suspension is stable 
in amber glass bottles at room temperature (19ºC -23ºC) for up to 5 weeks. The suspension 
should be shaken well before each use. Procedures for proper handling and disposal of 
cytotoxic drugs should be used when preparing the suspension. (Aliabadi HM, Romanick 
M, Desai S et al. Effect of buffer and antioxidant on stability of mercaptopurine suspension. 
Am J Heath-Syst Pharm. 65:441-7, 2008.) 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. PLEASE NOTE there is a difference in the concentration of the 
commercially available (20 mg/mL) and extemporaneously compounded (50 mg/mL) 
oral suspensions. 


   
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6.9 
METHOTREXATE – ALL ROUTES  
(MTX, amethopterin, Trexall ®, Xatmep ®) NSC#000740 
 
(11/27/17) 
 
Source and Pharmacology:  
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces 
folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the 
availability of one carbon fragments necessary for the synthesis of purines and the conversion 
of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The 
polyglutamated metabolites of MTX also contribute to the cytotoxic effect of MTX on DNA 
repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute drug 
concentration and the duration of drug exposure. MTX is actively transported across cell 
membranes. At serum methotrexate concentrations exceeding 0.1 µmol/mL, passive 
diffusion becomes a major means of intracellular transport of MTX. The drug is widely 
distributed throughout the body with the highest concentration in the kidney, liver, spleen, 
gallbladder and skin. Plasma concentrations following high dose IV MTX decline in a 
biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of 
8-15 hours. About 50% is bound to protein. After oral administration, approximately 60% of 
a 30 mg/m2 dose is rapidly 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, pruritis, 
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: 
 
Learning disability1 (L) 
Pneumonitis, pulmonary fibrosis 
(L), hepatic fibrosis (L), 


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


   
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high-density polyethylene (HDPE) bottle with a child-resistant cap and tamper-evident 
seal. Store oral solution under refrigeration (2°C to 8°C/36°F to 46°F) prior to dispensing. 
Avoid freezing and excessive heat. After dispensing, patients may store methotrexate oral 
solution at room temperature (20°C to 25°C/68°F to 77°F) for up to 60 days; excursions 
permitted to 15°C to 30°C (59°F to 86°F). 
 
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg 
vials. The powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. 
Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL 
preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL 
solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, 
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative. 
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions 
permitted to 15º-30ºC (59º- 86 Fº). Protect from light 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of 
protocol.  Leucovorin rescue may be necessary with certain doses of methotrexate. 
 
Oral administration: Food or milk delays absorption and reduces peak concentration. 
Methotrexate for oral use should preferentially be given on an empty stomach, 1 hour 
before or 2 hours after food or milk and at the same time each day. Methotrexate injection 
diluted in water can be used for oral administration if an oral solution formulation is not 
readily available (Marshall PS, Gertner E. Oral administration of an easily prepared 
solution of injectable methotrexate diluted in water: a comparison of serum concentrations 
vs methotrexate tablets and clinical utility. J Rheumatol 23:455-8, 1996). 
 
For IM/IV use:  Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative 
free SWFI, D5W or NS to a 50 mg/mL concentration. The powder for injection may be 
further diluted in NS or dextrose containing solutions to a concentration of ≤ 25mg/mL for 
IV use. 
 
The 25 mg/mL solution may be given directly for IM administration or further diluted in 
Saline or Dextrose containing solutions for IV use. Do not use the preserved solution for 
high dose methotrexate administration due to risk of benzyl alcohol toxicity. 
Methotrexate dilutions are chemically stable for at least 7 days at room temperature but 
contain no preservative and should be used within 24 hours. Diluted solutions especially 
those containing bicarbonate exposed to direct sunlight for periods exceeding 4 hours 
should be protected from light. 
 
High dose methotrexate requires alkalinization of the urine, adequate hydration and 
leucovorin rescue. Avoid sulfamethoxazole/trimethoprim, probenecid, penicillins, 
cephalosporins, aspirin, proton pump inhibitors, and NSAIDS as renal excretion of MTX is 
inhibited by these agents. 
 
For Intrathecal use: Use preservative free 25 mg/mL solution. 
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s, 
or Elliot’s B solution as per institutional standard of practice. The volume of CSF removed 
should be equal to at least half the volume delivered. 
 


   
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*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 
267:1273-8 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric 
delivery, with the patient remaining prone after the procedure may facilitate drug distribution. 
These procedures have not been validated in clinical trials. They are allowed but not mandated 
for patients on COG studies. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains 
no preservative and should be administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
 
 
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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6.10 
PEGASPARGASE 
(PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase, 
Oncaspar®)  
NSC #624239   
 
 
 
 
 
 
 
(06/05/17) 
 
Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase is modified by 
covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 
5000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-
asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is 
derived from Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a 
reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is 
notably lacking in malignancies of lymphoid origin. Asparaginase depletes L-asparagine from 
leukemic cells (especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic 
acid and ammonia. In predominately L-asparaginase naive adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of 
pegaspargase were determined. Apparent volume of distribution was equal to estimated plasma 
volume. L-asparaginase was measurable for at least 15 days following the initial treatment with 
Pegaspargase. The approximate t½ in adult patients is 5.73 days. The enzyme could not be detected 
in the urine. The half-life is independent of the dose administered, disease status, renal or hepatic 
function, age, or gender. In a study of newly diagnosed pediatric patients with ALL who received 
either a single intramuscular injection of pegaspargase (2500 IU/m2), E. coli L-asparaginase 
(25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-lives for the three forms of 
L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The 
plasma half-life of pegaspargase is shortened in patients who are previously hypersensitive to native 
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is cleared by the 
reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal fluid levels 
are < 1% of plasma levels. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Allergic reactions (total 
likelihood of local, and or 
systemic reaction especially if 
previous hypersensitivity 
reaction to native 
asparaginase), pain at 
injection site, weakness, 
fatigue, diarrhea  
Allergic reactions (total 
likelihood of local, and 
or systemic reaction if no 
previous hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, hyper/hypotension, 
tachycardia, periorbital edema, 
chills, fever, dizziness, dyspnea, 
bronchospasm, lip edema, arthralgia, 
myalgia, urticaria, mild 
nausea/vomiting, abdominal pain, 
flatulence, somnolence, lethargy, 
headache, seizures (L), 
hyperuricemia  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT and 
bleeding times (secondary to 
decreased 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, 


   
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paresthesias, hypertriglyceridemia, 
hyperlipidemia, Parkinson-like 
syndrome with tremor and increase 
in muscular tone, 
hyperbilirubinemia, chest pain  
Delayed: 
Any time later 
during therapy 
 
 
Renal failure, urinary frequency, 
hemorrhagic cystitis, elevated 
creatinine and BUN, fatty liver 
deposits, hepatomegaly, liver failure 
Unknown 
Frequency and 
Timing:  
Animal reproduction studies have not been conducted with pegaspargase. It is not known whether 
pegaspargase can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity. However, fetal toxicities and teratogenic effects of asparaginase have been 
noted in animals. It is unknown whether the drug is excreted in breast milk. 
(L)Toxicity may also occur later. 
 
Formulation and Stability: 
Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic sodium 
phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%, sodium chloride, 
USP 8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific activity of pegaspargase is 
at least 85 IU per milligram protein. Available in 5 mL vials as Sterile Solution for Injection in 
ready to use single-use vials, preservative free. Keep refrigerated at 2°-8°C (36°-46°F). Do not use 
if stored at room temperature for more than 48 hours. DO NOT FREEZE. Do not use product if it 
is known to have been frozen. Freezing destroys activity, which cannot be detected visually.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
For IM administration: the volume at a single injection site should be limited to 2 mL. If the volume 
to be administered is greater than 2 mL, multiple injection sites should be used.  
 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to 2 hours 
through a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of NS or D5W is 
stable for 48 hours at room temperature. Pegaspargase diluted in 100 mL of NS is stable for up to 
72 hours refrigerated (4ºC [39°F]) (refrigerated stability data on file with Sigma-Tau).  Avoid 
excessive agitation. DO NOT SHAKE. Do not use if cloudy of if precipitate is present.  
 
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 further information. 
 
 
6.11 
PREDNISO(LO)NE  
(11/16/17) 
(Deltasone®, PredniSONE Intensol®, Rayos®, Meticorten®, Liquid Pred, Pediapred®, 
Millipred®, OraPred ODT®) NSC #010023 (prednisome), NSC# 9151 (prednisolone)  
       
 
Source and Pharmacology: 
Prednisone and prednisolone are a synthetic compounds closely related to hydrocortisone. 
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 


   
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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. Peak blood levels occur 
within 2 hours of oral intake. Prednisone is approximately 75% protein bound with a plasma t½ of 3.2 
to 4 hours. (Biologic half-life is 12-36 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 
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), electrolyte 
imbalance (Na retention, 
hypokalemia, hypocalcemia) (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 
prednisone in children) 
 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities: Corticosteroids cross the placenta (prednisone has the 
poorest transport). 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. Prednisone is 
excreted into breast milk in humans; however, several studies suggest that amounts excreted 
in breast milk are negligible with prednisone doses ≤ 20 mg/day.  
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: 
Prednisone is available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg tablets. Also available as a 
solution in 1 mg/1 mL or 5 mg/mL concentrations. Inactive ingredients vary depending on 
manufacturer but tablet formulations may include calcium or magnesium stearate, corn starch, 
lactose, erythrosine sodium, mineral oil, sorbic acid, sucrose, talc and various dyes. The solution may 
include 5-30% alcohol, fructose, sucrose, saccharin, and sorbitol. 
 
Prednisolone is available as 5 mg scored tablets (base) and 10 mg, 15 mg, and 30 mg orally 
disintergrating tablets (ODT; sodium phosphate [strength expressed as base]). Liquid formulations 
of prednisolone are available as 15 mg/5 mL oral solution (base); 5 mg/5 mL, 10 mg/5 mL, 15 mg/5 


   
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mL, 20 mg/5 mL oral solution (sodium phosphate [strength expressed as base]; and 15 mg/5 mL 
oral syrup (base).  Inactive ingredients vary depending on manufacturer. Tablet formulations may 
contain dyes and liquid formulations may contain edetate disodium, methylparaben, saccharin 
sodium. 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
PredniSONE and prednisolone are equipotent corticosteroids. 
 
Supplier: Commercially available from various sources. See package insert for further information. 
 
6.12 
THIOGUANINE  
(6-thioguanine, tioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141, Tabloid®, 
Lanvis®) 
NSC #752 
 
 
 
 
 
 
 
 
(12/05/16) 
 
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. 
 
6.13 
VINCRISTINE SULFATE 
(Oncovin®, VCR, LCR) NSC #67574 
 
 
 
 
 
(08/16/12) 
 
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. 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
7.1 
End of Therapy & Follow-up 
 
 
STUDIES TO BE OBTAINED 
End of Therapy 
History 
X 
Physical Exam with VS 
X 
Ht, Wt, BSA 
X 
Performance Status 
X 
CBC, differential, platelets 
X 
Urinalysis 
 X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Creatinine, SGPT, bilirubin 
X 
Total protein/albumin 
X 
ECHO 
X 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
7.2 
Correlative Biology Studies 
The pharmacodynamic (PD) assessment of DNA methylation (Section 14.1) is a required 
correlative study. All other studies in the table below require patient consent. 
 
For patients that consented to cell banking on AALL08B1 or APEC14B1 (if open), submit 
required samples. 
 
Note: If the volume of blood required for correlative studies exceeds safe limits of blood 
draw over a 24 hour period, the priority for peripheral blood sampling for infants on this 
study is as follows: 
 


   
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• 
Test required for clinical care 
• 
Pharmacodynamics of DNA methylation (Section 14.1) 
• 
Banking for future research (Section 14.3) 
• 
Pharmacokinetics of Azacitidine (Section 14.4) 
• 
(CAR) T cell expansion (Section 14.5) 
 
SAMPLES TO BE 
OBTAINED 
Diagnosis 
Induction 
EPI #1 
Consolidation 
EPI #2 
IM 
DI PT. 1 
Relapse 
PD Assessment of 
DNA Methylation: 
Peripheral Blood 
Section 14.1 
 
 
X 
 
X 
 
 
 
MRD Results 
Reporting 
Section 14.2 
 
X 
 
X 
 
X 
 
 
Banking for Future 
Research 
Section 14.3 
X 
X 
 
X 
 
X 
 
X 
PK of Aza: 
Peripheral Blood 
Appendix VIII 
 
 
X 
 
 
 
 
 
Assessment of 
Infant T cell 
Proliferative 
Capacity: 
Peripheral Blood 
Section 14.5 
X 
X 
 
X 
 
 
 
 
PD of Peg: 
Report Results 
Section 14.6 
 
X 
 
 
 
X 
X 
 
 
7.3 
Shipping Information for MRD Flow Cytometry Laboratories 
 
For a list of COG-approved Flow Cytometry Labs, see: 
https://members.childrensoncologygroup.org/_files/admin/mrdflowlabs.pdf  
 
 
 


   
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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) Patients without KMT2A-R leukemia following Induction and prior to EPI Block #1. 
b) Patients with KMT2A-R leukemia who do not meet the criteria to start EPI Block #1 by 
Day 64. 
c) Two or more dose limiting toxicities (DLTs) in an individual patient. 
d) Failure to achieve M1 marrow status following completion of Consolidation therapy. 
e) Relapse at any site after achieving remission. 
f) Adverse Events/ Side Effects/ Complications. 
g) Refusal of further protocol therapy by patient/parent/guardian. 
h) Completion of planned therapy. 
i) Physician determines it is in patient’s best interest. 
j) Development of a second malignancy. 
k) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2). 
l) Inevaluable. 
m) Patients with KMT2A-R leukemia who meet criteria to start EPI Block #1, following 
the treatment of 6 patients with azacitidine, but prior to completion of interim toxicity 
analysis. 
 
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 patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death 
b) Lost to follow-up 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
This study will accrue infant patients with ALL for approximately 1.5 to 3.0 years (3.0 if 
there is a dose reduction). Based on review of infant patient accrual onto COG protocol 
AALL0631, and since this protocol will be open group-wide, we expect an enrollment rate 
of approximately 40 patients/year. The study will enroll a minimum of 4 and maximum of 
up to 116 patients. A minimum of 2 and a maximum of 58 infants with ALL will be enrolled 
at the first dose level (DL1; Azacitidine 2.5 mg/kg). If a dose reduction is required, then a 
minimum of 2 and maximum of 58 infants would be enrolled on the reduced dose level 
(DL0; Azacitidine 1.8 mg/kg). 
 


   
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The maximum accrual of 116 is to ensure the goal of at least 30 evaluable KMT2A-R 
patients for a given dose level.  This accounts for the assumptions of 80% KMT2A-R, 90% 
eligibility, and up to 25% drop out before conclusion of the evaluability period. 
 
Amendment # 3 
The study was temporarily closed to enrollment on October 30, 2018, when the accrual 
goal was met for dose level 1 (DL1).  
 
With this amendment the study accrual is increased to allow enrollment of an additional 20 
subjects at DL1 to reach accrual of 30 evaluable subjects to ensure fulfillment of the 
primary study aim. If we use the actual study rates of 71% KMT2A-r rate, 90% eligibility 
rate, and 43% drop-out rate, 20 additional subjects will result in about 7 additional 
evaluable subjects. Duration of extended accrual is expected to be 6 months. 
 
9.2 
Study Design 
9.2.1 
Primary Endpoint 
To assess tolerability of azacitidine in combination with Interfant-06 standard 
chemotherapy in 30 evaluable infant patients with newly diagnosed ALL with 
KMT2A gene rearrangement (KMT2A-R). 
 
9.2.2 
Secondary Endpoint 
To evaluate the biologic activity of azacitidine by pharmacodynamic assessment 
of global DNA methylation in peripheral blood mononuclear cells (PBMCs) of 
infants treated with azacitidine. 
 
9.2.3 
Exploratory Endpoints 
9.2.3.1 
To determine the 5 year event free survival (EFS) of infants with 
KMT2A-R treated with azacitidine in addition to Interfant-06 standard 
chemotherapy. 
9.2.3.2 
To correlate minimal residual disease with outcome in the context of the 
protocol therapy. 
9.2.3.3 
To perform pharmacokinetic (PK) testing of azacitidine in infants.  
9.2.3.4 
To test the expansion of infant T lymphocytes by stimulation with 
artificial antigen presenting cells identical to those used in CART-19 
production. 
9.2.3.5 
To collect pharmacodynamic (PD) data for asparaginase activity 
following Pegaspargase administration in infants. 
 
9.2.4 
Analysis for Primary Endpoint 
A single dose level design, with continuous enrollment, will be used for dose level 
tolerability and biologic activity determination. Enrollment will begin on DL1, 
with reduction to DL0 only if DL1 is deemed too toxic. Up to 58 patients will be 
enrolled at DL1, with the goal of evaluating 30 patients with KMT2A-R for 
tolerability and biologic activity (see Section 9.5 for definition of evaluability for 
primary endpoint). If dose reduction to DL0 is required, then up to 58 additional 


   
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patients will be enrolled at DL0, with the goal of evaluating 30 patients with 
KMT2A-R for tolerability and biologic activity. 
 
With Amendment #3, the study accrual is increased to allow enrollment of an 
additional 20 subjects at DL1 (total 78 patients) to reach accrual of 30 evaluable 
subjects to ensure fulfillment of the primary study aim. If we use the actual study 
rates of 71% KMT2A-r rate, 90% eligibility rate, and 43% drop-out rate, 20 
additional subjects will result in about 7 additional evaluable subjects. 
 
DL1 and/or DL0 will be considered intolerable at any time if the number of patients 
with a DLT meets or exceeds pre-determined stopping boundaries. In the event that 
DL1 is deemed too toxic, any patient with remaining doses of azacitidine planned at 
DL1 will instead receive DL0. If neither dose level is tolerable, then the investigators 
will review the biologic correlates to determine if there is sufficient evidence of 
epigenetic modification to propose amending the study to test a lower DL.   
 
After the 6th evaluable patient, DLTs will be monitored continuously using Pocock 
stopping bounds as described by Ivanova et al.77 As detailed in Section 5.1.1, a 
DLT is defined such that we expect chemotherapy alone would result in a DLT 
rate of approximately 10% (including a < 10% rate of delays in subsequent courses 
and a toxic death rate of approximately 3%). The stopping bounds for DLTs are 
designed to stop the study early with probability of 5% when the true DLT rate is 
10%. The dose level stopping bounds that will deem a dose level excessively toxic 
are based on the number of evaluable patients and the number of patients with 
DLTs at any given time (Table 2). Table 2 assumes evaluation of 6 patients prior 
to initiation of stopping boundaries. The intent of this design is to allow the trial to 
progress in the event of a spuriously high rate of DLT during early enrollment, 
while maintaining safety by creating boundaries that become more conservative as 
the study progresses. With 30 evaluable patients, the probabilities of declaring the 
dose level as too toxic are approximately 82.5%, 40.1%, and 4.3% when the true 
DLT rates are 30%, 20%, and 10%, respectively. 
 
Table 2. Continuous monitoring table for DLT 
n 
b(n) 
≤6 
3 
7-10 
4 
11-16 
5 
17-21 
6 
22-28 
7 
29-30 
8 
 
n = number of evaluable patients treated on any single dose level 
b(n) = toxicity boundary (If the number of patients with at least one DLT is ≥ b(n) 
on any single dose level, then that dose level will be deemed excessively toxic) 
 
Toxic deaths will be considered DLT events (see definition of DLT in Section 5.1) 
and will also be monitored independently of DLT. Toxic death will be defined as 
any Grade 5 toxicity that occurs as a first event during protocol therapy. The 
expected toxic death rate during the DLT evaluation period is 3%. The study will 


   
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be stopped for toxicity and safety review if 2 of the first 15 or any 3 infants 
experience a toxic death during the evaluation period. Using 3% as the planning 
rate, the study will have a 75.8% probability of stopping if the true death rate is 
12% and a 10.0% chance of stopping for review if the true death rate is 3%. 
Pending the outcome of the toxicity and safety review, the study may progress with 
further enrollment, with amendments if necessary. 
 
An informal interim analysis of toxicity and safety will be conducted after 3 
patients complete EPI #1 and Consolidation. Prior to the completion of this interim 
analysis, no more than 6 patients will be exposed to azacitidine (i.e., if a 7th patient 
is due to receive the first dose of azacitidine prior to the interim analysis of the first 
3 patients, this patient will be removed from protocol therapy). The study 
committee will convene to review the toxicity data for each of these 3 patients, and 
will formulate an adjusted plan for further enrollment, if necessary. 
 
9.2.5 
Analysis for Secondary Endpoint 
LINE-1 global methylation assessment of peripheral blood mononuclear cells 
(PBMCs) on Day 1 prior to azacitidine and on Day 5 of the first two courses of 
azacitidine will be performed. We will observe for relative changes in methylation 
in infant PBMCs. We will calculate the mean LINE-1 methylation for all patients 
before and after azacitidine and perform paired t-test analysis to determine if there 
is significant demethylation in the study population for the tested dose level. 
 
9.2.6 
Analysis for Exploratory Endpoints 
Five year EFS will be estimated for infants with KMT2A-R treated with azacitidine 
in addition to Interfant-06 standard chemotherapy. With a sample size of 30 we 
would be able to estimate this with a maximum standard error of 9.1%.  
 
The following are all optional studies and hence sample size availability for 
analyses cannot be accurately assessed.  Statistical analyses will be primarily 
descriptive. Minimal Residual Disease evaluations are optional studies; hence it is 
not possible to estimate how many patients will be evaluable for this endpoint. 
Descriptive analysis will be conducted to correlate MRD with the EFS for the 
KMT2A-R patients. Pharmacokinetic (PK) testing and analysis of azacitidine in 
infants will be performed by Covance as described in Appendix VIII. Optional 
biological study participation will explore the feasibility of T-cell collection for 
the purposes of chimeric antigen receptor (CAR) T-cell production from the 
peripheral blood in infants with ALL as described in Section 14.5. 
Pharmacodynamic (PD) data for asparaginase activity following pegaspargase 
administration in infants will be collected and correlated with EFS for the KMT2A-
R patients (see Section 14.6). 
 
9.3 
Methods of Analysis 
Toxicity monitoring will be performed using Pocock continuous stopping bounds as 
described by Ivanova et al.77 Toxic deaths will also be monitored with guidelines in place 
for toxicity and safety review as detailed above. Paired t-tests will be used to test 
demethylation levels before and after the first course of azacitidine. Five year EFS 
estimation will be calculated from time of enrollment. Standard errors and confidence 
intervals for EFS will be calculated using Peto’s method.78 
 


   
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9.4 
Evaluability for Response  
Response will be evaluated at the end of Induction. All patients on study at end of Induction 
will be evaluated for response. 
 
9.5 
Evaluability for Toxicity 
The presence or absence of a DLT will be determined for each patient during each of the 
first 3 courses of azacitidine in combination with chemotherapy and until the patient meets 
count requirements to begin the fourth course of azacitidine therapy. Course 4 will not be 
included in the DLT evaluation period because it includes a repeat of drug combinations 
used in the prior blocks. Patients who do not experience a DLT but go off protocol therapy 
prior to completion of Course 3 of azacitidine will be inevaluable for DLT and will be 
replaced. 
 
In addition to monitoring for DLT, distinct stopping rules will be in place for an 
unexpectedly high rate of deaths due to toxicity during the evaluation period (see Section 
5.1.1). 
 
 
 
9.6 
Gender and Minority Accrual Estimates  
 
The gender and minority distribution of the study population is expected to be: 
 
DOMESTIC PLANNED ENROLLMENT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
1 
1 
0 
0 
2 
Asian 
4 
1 
0 
0 
5 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
7 
2 
0 
0 
9 
White 
47 
31 
14 
15 
107 
More Than One Race 
1 
0 
1 
0 
2 
Total 
60 
35 
15 
15 
125 


   
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This distribution was derived from enrollment distributions on AALL0631 with known 
Ethnic/Race categories. 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
0 
0 
0 
0 
White 
4 
6 
0 
0 
10 
More Than One Race 
0 
0 
0 
0 
0 
Total 
4 
7 
0 
0 
11 
This distribution was derived from enrollment distributions on AALL0631 with known 
Ethnic/Race categories. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Response Criteria for Patients with Leukemia 
See definitions in Section 3.4 
 
 


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


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


   
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Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
11.5 
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. 
 


   
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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. 
 
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.  
 


   
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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 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.  


   
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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.   
 
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.  
 


   
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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 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 
require expedited reporting.  
• 
Grades 1-2 AST/ALT elevations 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 
 
 
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. 


   
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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, non-hematologic Grade 4 and higher Adverse Events, Grade 3 
and higher Infectious Events, Adverse Events resulting in Dose Limiting Toxicities (DLTs, 
Section 5.1), as well as the following specific toxicities identified by the ALL Toxicity 
Reporting Task Force to be collected on all future COG ALL trials:: 
 
1. CNS hemorrhage requiring medical intervention (Grade 2 or 3)  
2. GI bleed requiring operative or interventional radiology intervention (Grade 3)  
3. Pancreatitis requiring medical intervention (Grade 2 or 3)  
4. Osteonecrosis interfering with function (Grade 2 or 3)  
5. Transient ischemic attacks (All grades)  
6. Stroke (All grades)  
7. Encephalopathy (Grade 3)  
8. Neuropathy; motor or sensory, interfering with ADL (Grade 3)  
9. Seizure (Grade 2 or 3)  
10. Allergic reaction (Grade 3)  
11 Ileus (Grade 3)  
12. Mucositis/stomatitis; functional (Grade 3)  
13. Bilirubin (Grade 3)  
14. Thrombosis (Grade 3) 
 
11.13 Syndrome Reporting 
Unless otherwise specified in this protocol, syndromes should be reported as a single event 
using the CTCAE term for the composite syndrome, and not as the individual events that 
make up the syndrome. For example, Tumor Lysis Syndrome should be reported under the 
composite definition rather than reporting the component events (hyperkalemia, 
hyperphosphatemia, hypocalcemia, hyperuricemia) separately. 
 
12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are 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) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 


   
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Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
12.3.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI. If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement. A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
12.3.2. 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 


   
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will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own Agent. 
 
12.3.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator:  
 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
12.3.4 When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
12.3.5 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
12.3.6 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 AND SPECIMEN REQUIREMENTS 
No pathology review is planned for this study. 
 
 


   
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14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
14.1 
Pharmacodynamic Assessment of DNA Methylation (Required) 
14.1.1 Timing of Pharmacodynamic Sampling 
Collect peripheral blood from patients just prior to the dose of azacitidine on Day 
1 and again on Day 5, for the first 2 courses of azacitidine. Please refer to Appendix 
VI for additional details. 
• 
EPI Block #1  
o Day 1 
o Day 5 
 
• 
EPI Block #2 
o Day 1 
o Day 5 
 
14.1.2 Sample Collection and Processing  
• 
Collect 3-4 mL of peripheral blood in a sodium heparin tube (green top). 
• 
Samples can be stored for up to 48 hours at room temperature. 
 
14.1.3 Sample Labeling and Shipping 
• 
Label specimens with study #, COG patient ID#, BPC #, time point (course and 
day), and date/time of collection. 
• 
Ship the specimens overnight to the Brown Laboratory at room temperature. 
Please email Dr. Patrick Brown before shipping. 
• 
Do not batch the specimens. 
• 
Deliveries are accepted on weekend and holiday, please contact Pat Brown prior 
to shipping. If shipping on a Saturday, please indicate on delivery sheet. 
• 
Please include the transmittal form. 
• 
See the AALL15P1 Correlative Studies Shipment sheet on the AALL15P1 web 
page for the shipping account number. 
 
Dr. Patrick Brown 
Johns Hopkins Oncology 
Cancer Research Building I, Room 262 
1650 Orleans Street 
Baltimore, MD 21231 
Email:pbrown2@jhmi.edu 
Phone:(410) 955-8688 
Fax: (410) 955-8897 
 
14.2 
Minimal Residual Disease (MRD) Results Reporting (Optional) 
14.2.1 Reporting of MRD Results 
MRD by flow cytometry in a COG-approved laboratory is required with bone 
marrow evaluations at the end of Induction, Consolidation, and Interim 
Maintenance. If the patient consents, enter MRD data into RAVE. MRD results will 
be correlated with disease outcome. 
 


   
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14.3 
Banking for Future Research (Optional) 
14.3.1 Timing of Molecular profiling sampling 
For patients who consent, collect a bone marrow aspirate from all time points when 
a bone marrow evaluation is clinically indicated (at diagnosis, at the end of 
Induction, at the end of Consolidation, at the end of Interim Maintenance, and at 
the time of relapse). If apheresis is performed pre-treatment, please submit the 
apheresis sample in addition to the bone marrow sample (if performed). 
 
14.3.2 Sample Collection and Processing 
• 
Collect 3-5 mLs of fresh bone marrow in shipping media (SM) tube. 
• 
If the absolute circulating blast count is at least 2,500/µL, peripheral blood can 
be substituted for diagnostic and relapse samples. 
o At least 2 mL of blood may be substituted for each 1 mL of required bone 
marrow. 
• 
If apheresis is performed for clinical purposes, also submit an apheresis 
sample. 
o If there is a small volume of pheresate, mix 3 mL of SM with every 1 mL 
of pheresis sample. Use multiple SM tubes as needed. 
o If there is a large volume of pheresate or exchange transfusion product, 
process as above with a maximum of 10 SM tubes of pheresis sample. 
• 
If samples cannot be shipped on the day of collection, please store at 4◦C 
until shipment on the next business day. 
 
 
14.3.3 Sample Labeling and Shipping 
• 
Label specimens with study #, COG patient ID#, BPC #, patient name/initials 
and date of birth, collection date, time point (course and day), and specimen 
type (bone marrow, blood, pheresis). 
• 
Do not batch the specimens. 
• 
Samples may be shipped Monday through Friday. If shipped on a Friday, mark 
Saturday delivery on the air bill and email the laboratory prior to shipment. 
• 
Please include the transmittal form. 
• 
Each samples should be prepared in accordance with IATA regulations. 
• 
Ship samples via FedEx priority overnight. Utilize the COG Federal Express 
account found on the members site: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf  
 
Shipping Media (SM)  
To request prepared and pre-packaged sample shipping tubes, order tubes 
through the Biopathology Center Kit Management system. Select AALL08B1 or 
APEC14B1 (if available for ALL patients). 
 
https://ricapps.nationwidechildrens.org/KitManagement/ 


   
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Laboratory Contact Information: 
Molecular Genetics Laboratory 
mglab@nationwidechildrens.org 
Phone: 
(614) 722-2866 
Fax: 
(614) 722-2887 
 
Shipping Address: 
COG ALL Molecular Reference Laboratory 
Nationwide Children’s Hospital 
575 Children’s Crossroads, Room WB2255 
Columbus, OH 43215 
 
14.4 
Pharmacokinetics of azacitidine (Optional) 
When a patient consents to this study, contact Clinical Logistics for a sample collection kit 
containing the supplies required for blood collection. Please refer to the PK of Aza 
information packet on the AALL15P1 study webpage for details related to kit ordering. 
Peripheral blood samples will be collected during the first course of azacitidine. Please 
refer to Appendix VIII for details 
 
14.4.1 Timing of pharmacokinetic sampling 
• 
Please refer to Appendix VIII for details. 
 
14.4.2 Sample Collection and Processing  
Azacitidine is unstable in blood and therefore, all blood samples must be processed 
and plasma harvested immediately. Please refer to Appendix VIII. 
 
14.4.3 Sample Labeling and Shipping 
• 
Refer to Appendix VIII for sample preparation details. 
• 
See the PK of Aza information packet on the AALL15P1 study webpage 
for the shipping account number and details. 
 
Lab Contacts: 
 
 
Karen Yazell  
Project Manager, Bioanalytical 
Email: Karen.yazell@covance.com 
Phone: (317) 273-5218 
 
Ryan Hill 
Email: ryan.hill1@covance.com 
Phone: (317) 273-7409 
 
 
BioA Sample Management (ATTN: Ryan Hill) 
Covance Bioanalytical Services, LLC  
8211 SciCor Drive, D19 (Suite B)  
Indianapolis, IN 46214 


   
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14.5 
Assessment of Infant T cell Proliferative Capacity (Optional) 
AALL15P1 includes an optional biological correlative study testing the feasibility of T-cell 
collection for the purposes of chimeric antigen receptor (CAR) T-cell production from the 
peripheral blood in infants with ALL.  
 
T-cells from the peripheral blood will be enumerated and stimulated with artificial antigen 
presenting cells as they would be in the production phase of CART 19. Measured outcome 
will be a positive test expansion defined as an increase in cell number > 5 fold within 10 
days from diagnosis and end-Induction. Secondary outcomes will assess the ability to 
expand to a potential number for CART-19 manufacturing and the ALC associated with 
potential expansion. Please refer to Appendix VII for additional details.  
 
14.5.1 Timing of (CAR) T-cell sampling 
For consenting patients, collect peripheral blood samples at the following time 
points: 
 
• 
Pretreatment/Diagnosis 
• 
End of Induction (pre-azacitidine) 
• 
End of Consolidation  
 
14.5.2 Sample Collection and Processing  
• 
5-10 mL of peripheral blood is required 
• 
Peripheral blood should be collected in purple top tubes 
• 
Refrigerate at 4◦C for no more than 72 hours 
 
Note: Exchange transfusion leukemia rich peripheral blood collected in purple top tubes may 
be substituted. No more than 2mL/kg should be drawn, with the exception of peripheral blood 
removed for exchange that would have been discarded.  
 
14.5.3 Sample Labeling and Shipping 
• Label tubes with study #, COG patient ID #, BPC #, source (peripheral or 
exchange), and timing (diagnosis, end of Induction, or end of Consolidation). 
• Submit CBC including differential closest to time point of study lab draw 
• Do not batch specimens 
• Ship on a cold pack via overnight courier 
• Ship specimens Tuesday through Thursday  
Note: If samples are collected on a Friday, store until Monday for shipping 
• Do not deliver on a weekend or Holiday. 
• Please include the transmittal form. 
• See the AALL15P1 Correlative Studies Shipment sheet on the AALL15P1 web 
page for the shipping account number. 
 
Contact laboratory before specimens are shipped. 
 
Contact: Jessica Perazelli 
Email: HULITTJ@email.chop.edu 


   
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Phone: (267) 426-5692 
Fax: (215) 590-3770 
 
Shipping Address: 
 
David Barrett, M.D., Ph.D. 
Colket Translational Research Building, Lab 3100 
Children’s Hospital of Philadelphia 
3501 Civic Center Blvd. 
Philadelphia, PA, 19104 
 
 
14.6 
Pharmacodynamics of Pegaspargase (Optional) 
14.6.1 Timing of pharmacodynamic sampling 
It is recommended that asparaginase activity levels are measured on the 7th day 
following the administration of pegaspargase during Induction, Interim 
Maintenance, and Delayed Intensification part I. 
 
Based on the activity level results and/or clinical findings of hypersensitivity or 
other adverse reaction to pegaspargase (per each institution’s standard practice), 
investigators may substitute Erwinia asparaginase. 
 
For those patients who consent, institutional data will be submitted via RAVE and 
correlated with outcome. 
 
14.7 
Bone Marrow: Central review of Cytogenetics/FISH (Required) 
Local bone marrow evaluation must be completed to confirm KMT2A-R to remain on 
AALL15P1. Both standard cytogenetic studies and FISH analysis must be performed at a 
COG-approved cytogenetics lab, and results submitted for central review. The local 
institution obtains the COG cytogenetics report forms and original karyotypes (not copies) 
from 2 different cells from each abnormal clone from the approved laboratory and sends 
them by email to Dr Carroll (Western Division) or Dr Nyla Heerema (Eastern Division) 
per the address information below (please refer to map). The COG FISH reporting forms 
and representative FISH images of all FISH analyses should also be included at this time. 
The cytogenetics data must be submitted for review on time (by Induction Day 10) in 
order for the information to be used for proper post-Induction therapy. 
 
IT IS ESSENTIAL THAT KMT2A FISH DATA FOR INFANTS ENROLLED ON 
AALL15P1 BE ENTERED BY THE LOCAL INSTITUTION IN RAVE BY DAY 10 OF 
INDUCTION. If there is any discrepancy between local cytogenetic results and COG-
approved Laboratory review results, local institutions should contact the appropriate 
COG-approved Laboratory Director or the Study Chairs in order to resolve 
discrepancies. 
 
Please refer to Appendix X for information regarding specimens, recommended assays, 
and entry of date into the RAVE system. 
 


   
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Please see the following link for a list of COG approved cytogenetics labs: 
https://www.cogmembers.org/uploadedFiles/Site/Admin/Uploaded_Documents/Cytogene
tics_Approved_Labs.pdf  
 
 
EASTERN DIVISION 
Nyla A Heerema, PhD 
Ohio State University 
Director of Cytogenetics 
1645 Neil Avenue 
Hamilton Hall, Room 129 
Columbus, OH  43210-1228 
Phone: (614) 292-7815 
Fax: (614) 293-9919 
E-mail: nyla.heerema@osumc.edu 
WESTERN DIVISION 
Andrew J Carroll, PhD 
University of Alabama at Birmingham 
Department of Genetics 
1720 20TH St. South 
Kaul Bldg, Room 314B 
Birmingham, AL  35294-2050 
Phone: (205) 934-0665 
Fax: (205) 934-1078 
E-mail: acarroll@uab.edu 
 
 
 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
No imaging studies are planned for this study.  
 
 
16.0 
RADIATION THERAPY GUIDELINES 
No radiation therapy is planned for this study. 
 
 
 


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


   
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Site registration forms may be downloaded from the AALL15P1 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Either enter the protocol # in the search field at the top of the protocol tree, or 
▪ 
Click on the By Lead Organization folder to expand 
▪ 
Click on the COG link to expand, then select trial protocol #AALL15P1 
Click on LPO Documents, select the Site Registration documents link, and download and complete 
the forms provided. 
 
Requirements for AALL15P1 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS. 
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission 
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 


   
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compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 
 


   
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APPENDIX II:  CYP3A4/5 SUBSTRATES, INHIBITORS AND INDUCERS 
This is not an all-inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently-updated medical references. 
 
CYP3A4 substrates  
Strong 
Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers  
Moderate 
Inducers  
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 eplerenone5 
ergotamine4 erlotinib 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
graperfruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
idelalisib 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 


   
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isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4 
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5 
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 6.5 and Section 6.6 regarding the use of corticosteroids.  


   
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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 (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors)


   
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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, 
and continue 
q6hrs until MTX 
level < 0.1 µM 
 
-- Repeat MTX 
levels q12-24 hrs 
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 III:  HIGH-DOSE METHOTREXATE FLOWCHART 
 
 
 


   
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APPENDIX IV: SUPPORTIVE CARE GUIDELINES 
General 
These are provided for institutional consideration. Investigator discretion should be used, and individual 
considerations made for specific patient situations and institutional practices. Study Chairs must be notified 
of any Serious Adverse Events, an Investigator’s decision to deviate in a major way from protocol directed 
therapy, or a patient taken off study. 
 
Aggressive supportive care improves outcome, particularly in high-risk patient populations receiving very 
intensive therapy as incorporated in this trial. The following guidelines are intended to give general 
direction for optimal patient care and to encourage uniformity in the treatment of this study population. 
 
The 
Children’s 
Oncology 
Group 
Supportive 
Care 
Guidelines 
may 
be 
found 
at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-endorsed-guidelines. 
 
Hydration/Allopurinol/Rasburicase (recombinant urate oxidase) 
All infants should be placed on allopurinol (150-300 mg/m2/day or 10 mg/kg/day in 2-3 divided doses) 
when the diagnosis of leukemia is made or strongly suspected.  In some situations it may be appropriate to 
use rasburicase (recombinant urate oxidase). Prior to instituting Induction therapy, all patients should be 
well hydrated. Potassium should not be added to the hydration fluids. Urine alkalinization is NOT necessary 
for TLS prophylaxis. There is paucity of evidence demonstrating benefit of urine alkalinization and it can 
potentially lead to calcium phosphate precipitation and/or metabolic acidosis. If the patient has oliguria or 
severe renal dysfunction, consider the use of rasburicase at 0.1 to 0.2 mg/kg/dose (or as per institutional 
guidelines) and obtaining a nephrology consult. In patients with a prior history of glucose-6-phosphate 
dehydrogenase (G-6PD) deficiency, rasburicase is contraindicated and allopurinol should be utilized 
instead of rasburicase. Evidence of severe tumor lysis syndrome should be stabilized prior to the institution 
of therapy. In patients with extremely elevated WBC (> 300,000/µL), exchange transfusion is strongly 
recommended. 
 
Venous Access 
Due to the need for frequent blood sampling, intensive chemotherapy, nutritional support and vesicant use, 
it is essential that all patients have a central venous catheter placed. 
 
Blood Components 
Blood products should be irradiated following current FDA guidelines found at: 
http://www.fda.gov/OHRMS/DOCKETS/98fr/981218g2.pdf  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components 
CAN/CSA-Z902-10 issued in February 2010 and available at: http://www.shopcsa.ca 
 
Red blood cells (RBCs) 
Transfusion with RBCs is indicated to correct severe or symptomatic anemia or acute blood loss. In the 
setting of extreme hyperleukocytosis investigators should be mindful that packed RBC transfusion may 
contribute to hyperviscosity. 
 
Platelets 
Transfusion with platelets is indicated to correct bleeding manifestations and may be indicated for severe 
thrombocytopenia without bleeding particularly in the setting of an invasive procedure. 
 


   
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Nutrition 
Protein-calorie malnutrition due to chemotherapy induced loss of appetite, nausea, vomiting, mucositis, and 
sepsis is a major concern. Aggressive nutritional support should be instituted when patient’s weight/height 
ratio ÷ median weight/median height ratio for age and sex falls below 80% or when the serum albumin is 
less than 3 mg/dL. 
 
Caution is advised with the use of early feeding / tube feeding in patients with difficult early courses or 
extensive mucositis/diaper area skin ulceration. Necrotizing enterocolitis and intestinal perforation have 
been observed in such infants. Total parenteral nutrition (TPN) should be strongly considered in such 
infants until it is certain there is no risk to the gut. 
 
Fever and Neutropenia 
Aggressively manage episodes of fever (≥ 100.5ºF or 38.0oC), particularly during Induction, Consolidation, 
Interim Maintenance, and Delayed Intensification, or when the patient is neutropenic with an ANC ≤ 1000. 
The risk of life threatening infection is particularly high during the first 4-6 weeks of therapy or when 
patients are neutropenic with an ANC ≤ 1000. It is strongly advised that patients with fever and neutropenia 
(ANC < 1000) not be managed with an outpatient antibiotic regimen. It is mandatory that patients with an 
ANC < 500 and fever be hospitalized with immediate institution of broad spectrum IV antibiotics adjusted 
appropriately for the causative organism. 
 
See 
COG 
endorsed 
Fever 
and 
Neutropenia 
Guidelines 
at 
http://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document.pdf 
for 
empiric 
treatment of febrile neutropenia. 
 
Infants with ALL are also at high risk for life-threatening viral infections, particularly RSV (see RSV 
Prophylaxis and Treatment sections below), during respiratory season. 
 
Use of filgrastim (G-CSF) 
Filgrastim or biosimilar may be used for severe infections with neutropenia, but routine use is discouraged. 
Filgrastim should not be given concurrently with azacitidine or chemotherapy and it must be discontinued 
at least 48 hours prior to the start of an azacitidine or chemotherapy course. 
 
Infection Prophylaxis and Treatment 
Bacterial and fungal infections are prevalent and severe among infants with ALL.  It is strongly 
recommended that patients remain hospitalized during Induction therapy until there is evidence of marrow 
recovery and that all potential bacterial infections be treated promptly with empiric antibiotic therapy with 
broad coverage for BOTH gram-positive and gram-negative organisms. As the predominant pathogenic 
bacteria are gram-positive organisms including viridians streptococci, the empiric gram-positive coverage 
should include vancomycin, clindamycin or a drug appropriate for the treatment of viridians streptococci. 
 
Intravenous Immunoglobulin  
All patients are to receive intravenous immunoglobulin (IVIG) at a dose of 400 mg/kg if serum IgG level 
is below 500 mg/dL. Doses should be repeated every 4 weeks as needed to keep IgG level at 500 mg/dL or 
greater. 
 
Antibiotic and Antifungal Prophylaxis 
Infection related mortality is high during all phases prior to Maintenance.  Interfant-06 mandates antibiotic 
and antifungal prophylaxis and hospitalization until count recovery for all patients during and after the 
intensive chemotherapy courses (Induction, Consolidation, Interim Maintenance, and Delayed 
Intensification).  There are insufficient data to make specific recommendations regarding the choice of 


   
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antibiotic and antifungal prophylaxis for infants enrolled on AALL15P1. Azole antifungal agents (i.e., 
fluconazole, itraconazole, voriconazole) given concurrently with vincristine may increase the risk of 
neurotoxicity. Investigator caution is advised if azole antifungals are used. 
 
The following are strongly recommended for infants enrolled on AALL15P1, during the intensive phases 
of therapy (Induction, Consolidation, Delayed Intensification, and Interim Maintenance). 
 
1) Monitor the patient in the hospital from the start of the respective treatment phase until 
he/she shows signs of bone marrow recovery (specifically evidence that the absolute 
neutrophil count is rising for 2 consecutive days after the nadir) and the patient is afebrile 
and clinically stable.  
2) Consider antibiotic prophylaxis against gram-positive and gram-negative organisms. 
3) Consider antifungal prophylaxis.  Options include an echinocandin such as caspofungin or 
micafungin, or azoles.  Concomitant administration of an azole with vincristine should be 
avoided. 
 
Pneumocystis Prophylaxis 
PCP prophylaxis should be started as soon as possible after the diagnosis of ALL is confirmed and 
continued until 6 months after all therapy is completed. 
 
1. The drug of choice is trimethoprim-sulfamethoxazole at a dosage of 150 mg TMP/m2/day in 2 divided 
doses on 2 or 3 consecutive days per week in infants > 4 weeks of age.  
 
a. Trimethoprim-sulfamethoxazole must be held on the days of HD MTX infusion and for at least 
72 hours after the start of the HD MTX infusion and until the MTX level is less than 0.1 μM.  
 
2. Second line options include: Dapsone 2 mg/kg/day or 4mg/kg once a week in infants ≥ 1 month of age, 
IV pentamidine for infants ≥ 5 months of age, Aerosolized pentamidine for all ages. 
 
RSV Prophylaxis  
Palivizumab 15 mg/kg IM every month should be initiated at the start of the RSV season and terminated at 
the end of the RSV season. 
 
RSV Treatment  
All RSV infections (upper and lower respiratory) should be treated. Follow institutional guidelines for RSV 
treatment in high risk patients. 
 
Additionally, palivizumab 15 mg/kg IM should be administered, if not already given as prophylaxis.  
 
Influenza Immunization  
Infants ≥ 6 months of age should receive 2 doses of the influenza immunization per CDC guidelines. 
Household contacts and out-of-home caregivers should also receive the influenza immunization. 
 
Varicella Infection and Prophylaxis  
Varicella-Zoster Virus (VZV) immunization should be avoided until at least 3 months following the end of 
Maintenance chemotherapy. Patients with exposure to VZV should be treated with Varicella Zoster 
Immunoglobulin (VZIG) within 10 days of exposure, preferably within the first 96 hours. If VZIG is not 
available, patients should be treated with IVIG 400 mg/kg.  Consideration may be given to oral acyclovir 
prophylaxis, beginning 7 to 10 days after exposure and continuing for 7 days. Patients with symptoms of 


   
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VZV infection should be treated promptly with intravenous acyclovir, and monitored closely for the 
development of invasive systemic disease. Consultation with an infectious disease specialist is advised for 
the treatment of infants with VZV infection. The use of oral acyclovir for prophylaxis is recommended after 
completion of treatment for VZV infection. 
 
Empiric Management of Pulmonary Infiltrates  
Pulmonary infiltrates should be evaluated in the context of the patient’s clinical and laboratory profile as 
well as institutional infection pattern. If the patient is not neutropenic and the pulmonary lesions on CT 
scan are not particularly suggestive of a mold infection (Aspergillus, Mucor), consider coverage with broad 
spectrum antibiotics and evaluate for viral causes of pulmonary infiltrates including RSV, influenza, and 
CMV. If the patient develops progressively worsening clinical or laboratory features or if the pulmonary 
lesions on CT scan are suggestive of a fungal infection (Aspergillus, Mucor), more aggressive diagnostic 
measures should be undertaken. Pulmonary infiltrates may be evaluated with bronchoscopy and biopsy, 
lavage, or open lung biopsy. If a procedure cannot be tolerated and/or if there is high clinical suspicion of 
fungal disease, begin empiric treatment with amphotericin B, given the high likelihood of fungal disease.  
Empiric coverage should consider gram-negative and positive bacteria, fungi, RSV, influenza, CMV, 
Pneumocystis, and Legionella. If fungal pulmonary disease is documented, surveillance radiographic 
imaging studies of the sinuses, abdomen/pelvis, and brain are indicated. Surgical excision should be 
considered and is at the discretion of the treatment physician. Treatment of fungal infections with 
amphotericin B and/or other antifungal agents will be at the discretion of the treating physician.  Azole 
antifungal agents (i.e. fluconazole, voriconazole) given concurrently with vincristine may INCREASE the 
risk of neurotoxicity. Caution is advised if azole antifungals are used. It is advisable to seek an infectious 
disease consult during the evaluation and treatment of an infant with pulmonary infiltrates and/or suspected 
invasive fungal infection. 
 
Stress Steroid Support  
If serious illness (particularly a potentially life-threatening infection) should occur in close proximity to the 
completion of the Induction or Delayed Intensification, consider additional "stress steroid" support.  
 
Mucositis  
Moderate (Grade 3) or severe (Grade 4) mucositis requires vigorous treatment including IV fluids, 
hyperalimentation, and strong consideration of broad spectrum antibiotics if febrile or ill appearing. 
Antifungal and antiviral therapy should be considered based on culture results and clinical evaluation. Daily 
oral antifungal prophylaxis with fluconazole should be strongly considered in patients not receiving 
vincristine. DO NOT PROCEED WITH FURTHER HD MTX or DAUNORUBICIN UNTIL MUCOSITIS 
BEGINS TO HEAL. 
 
Perineal Irritation  
There is a high risk of Grade 3-4 diaper area skin ulceration with daunorubicin and HD MTX. Placement 
of a Foley catheter for 48-72 hours during administration/urinary excretion of these drugs may dramatically 
reduce this diaper area skin ulceration. Use of a strong barrier technique is also recommended. If unable to 
place a Foley catheter, frequent diaper changes are advised during HD MTX/daunorubicin administration. 
If severe skin ulceration occurs, manage skin care aggressively and strongly consider antibiotic coverage 
until skin heals. DO NOT PROCEED WITH FURTHER HD MTX/DAUNORUBICIN UNTIL SKIN 
BEGINS TO HEAL.  
 
Antiemetic Protection  
Azacitidine is moderately emetogenic and antiemetics are strongly advised on Days 1 to 5 of every 
azacitidine course.  Antiemetics should be given as needed during all phases of chemotherapy. The routine 
use of corticosteroids as antiemetics is discouraged. 
 


   
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APPENDIX V: 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. 
 
Some drugs, food, and supplements may interact with cyclophosphamide.  Examples 
include: 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• Amiodarone 
• Carbamazepine 
• 
Cyclosporine 
• 
Digoxin 
• Efavirenz 
• 
Etanercept  
• 
Hydrochlorothiazide 
• Lumacaftor 
• Mifepristone 
• 
Pentostatin  
• Rifampin 
• Ritonavir 
• 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
Some drugs, food, and supplements may interact with daunorubicin.  Examples include: 
 
Drugs that may interact with daunorubicin 
• Some antibiotics and antifungals (clarithromycin, erythromycin, itraconazole, 
ketoconazole, rifampin) 
• Some antiepileptics (carbamazepine, phenobarbital, phenytoin, fosphenytoin) 
• Some antiretrovirals (lapatinib, lopinavir; nelfinavir, ritonavir, saquinavir, telaprevir,  
tipranavir) 
• Some heart medications (amiodarone, carvedilol, digoxin, dronedarone, quinidine, 
propafenone, verapamil) 
• Some chemotherapy (be sure to talk to your doctor about this) 
o Ado-trastuzumab emtansine, bevacizumab, trastuzumab, taxane 
derivatives) 
•  


   
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• Other agents, such as atorvastatin, clozapine, cyclosporine, dexamethasone, ivacaftor, 
leflunomide, lumacaftor, natalizumab, nefazodone, progesterone, ranolazine, 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” 
 
Some drugs, food, and supplements may interact with dexamethasone.  Examples 
include: 
 
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, 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 
 


   
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Some drugs, food, and supplements may interact with leucovorin.  Examples include: 
 
Drugs that may interact with leucovorin 
o Glucarpidase 
o Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
o Trimethoprim 
 
Food and supplements that may interact with leucovorin 
• Folic acid 
 
Some drugs, food, and supplements may interact with mercaptopurine.  Examples 
include: 
 
Drugs that may interact with mercaptopurine 
o Artiritis medications: leflunomide, tofacitinib 
o Other medications, such as adalimumab, allopurinol, azathioprine, certolizumab pegol, 
clozapine, etanercept, febuxostat, golimumab, infliximab, natalizumab, olsalazine, 
sulfasalazine, warfarin 
 
Food and supplements that may interact with mercaptopurine 
• Echinacea 
 
Some drugs, food, and supplements may interact with methotrexate (by mouth or by 
vein).   
Examples include: 
Drugs that may interact with methotrexate 
• 
Some antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, penicillin, piperacillin, 
tetracycline, trimethoprim/sulfamethoxazole) 
• Some anti-inflammatory drugs (aspirin, ibuprofen, naproxen, ketorolac, sulfasalazine, 
sulindac) 
• 
Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole) 
• 
Several other specific agents, including the following: amiodarone, clozapine, 
cyclosporine, eltrombopag, fosphenytoin, gemfibrozil, leflunomide, phenytoin, 
pimecrolimus, probenecid, pyrimethamine, ranolazine, retinoids, teriflunomide, 
theophylline, tolvaptan, warfarin 
 
Food and supplements that may interact with methotrexate 
• 
Alcohol 
• 
Echinacea 
• 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
 
 
 


   
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Some drugs, food, and supplements may interact with pegaspargase.  Examples include: 
 
Drugs that may interact with pegaspargase 
o Leflunomide, natalizumab, pegloticase, tofacitinib 
 
Food and supplements that may interact with pegaspargase 
• Echinacea 
 
Some drugs, food, and supplements may interact with prednisone or prednisolone.  
Examples include: 
Drugs that may interact with prednisone or prednisolone 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Antidiabetic medications 
• Antiretrovirals and antivirals  
o Ritonavir, telaprevir 
• Anti-seizure medications  
o Phenobarbital, phenytoin, primidone 
• Growth hormones 
• Heart medications  
o Diltiazem, 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, aspirin, cyclosporine, deferasirox, desirudin, ibuprofen, 
itraconazole, mifepristone, natalizumab, pimecrolimus, rifampin, warfarin 
 
Food and supplements that may interact with prednisone 
• Echinacea 
 
 
Some drugs, food, and supplements may interact with thioguanine. Examples include: 
 
Drugs that may interact with thioguanine 
o Arthritis medications: leflunomide, tofacitinib 
o Other medications, such as adalimumab, allopurinol, azathioprine, certolizumab 
pegol,clozapine, etanercept, golimumab, infliximab, natalizumab, olsalazine, sulfasalazine 
 
Food and supplements that may interact with thioguanine 
• Echinacea 
 
 
 


   
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Some drugs, food, and supplements may interact with vincristine.  Examples include: 
 
Drugs that may interact with vincristine 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
• Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tenofovir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedenarone, propafenone, quinidine, 
ranolazine,  verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, ivacaftor, 
mifepristone, modafinil, natalizumab, nefazodone, netupitant   
 
Food and supplements that may interact with vincristine 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
 
 


   
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APPENDIX 
VI: 
ADDITIONAL 
INFORMATION 
FOR 
PHARMACODYNAMIC 
ASSESSMENT OF DNA METHYLATION 
a) Rationale 
Preclinical studies of methylation patterns in infant ALL cell lines and patient samples have 
identified DNA hypermethylation as an important pathway driving leukemogenesis and is a 
potential target for testing in infant ALL models.7,9,10 Kostadinov et al., reported the critical role of 
subclonal methylation changes in chemoresistance and relapse of infant ALL.6 Azacitidine has 
established efficacy as a demethylating agent in myelodysplastic syndrome and demonstrated a 
direct cytotoxic effect in vitro against pre-B ALL cells.11 Decitabine and zebularine are similar 
DNA demethylation inhibitors that have demonstrated preclinical efficacy in the treatment of 
KMT2A-R ALL cells. Bhatla et al., described reversal of the gene methylation signature and 
cytotoxicity of the combination of decitabine with vorinostat in B-ALL patient samples and 
KMT2A-R cell lines.12 Stumpel et al., further demonstrated that infant ALL cells with KMT2A -R 
are susceptible to demethylating agents.5 In a study of the methylation patterns of infant ALL, 
Schafer et al. identified significantly more promoter hypermethylation in KMT2A-R patient-
derived cells, compared with KMT2A-wild type infant ALL cells.7 Genes with promoter 
hypermethylation correlated with down-regulated or silenced expression. Treatment with 
decitabine preferentially led to cytotoxicity of KMT2A-R cell lines, compared with KMT2A-wild 
type cell lines, supporting the role for demethylating agents in inducing cytotoxicity and 
chemosensitivity in the treatment of infant KMT2A-R ALL. There is growing clinical experience 
with DNMTis in combination with chemotherapy in acute leukemia in children, but no specific 
treatment experience in infants. Thus, a pilot study in infants to determine the safety of this 
combination with chemotherapy is warranted. For this trial in a highly vulnerable infant population, 
azacitidine has been chosen for study, based upon its availability and preferred profile of safety and 
tolerability in prior pediatric studies. 
 
A secondary endpoint of this trial is to determine if there is biologic activity of azacitidine at a 
tolerable dose level. Dosing of azacitidine and the metabolism of azacitidine may be altered in 
infants, and the starting dose level is reduced from the typical adult BSA-based dosing, so we feel 
that it is important to directly assess for evidence of DNA demethylation at each dose level tested. 
 
This pilot study does not seek to define maximum tolerated dose or to escalate doses to evaluate 
for clinical efficacy. Rather, DL1 (and DL0 if necessary) will be evaluated for tolerability and 
evidence of biologic epigenetic activity in combination with chemotherapy. If both DL1 and DL0 
are too toxic, but show evidence of biologic activity, then consideration will be given to amending 
the study to test lower doses. If no biologic activity is seen, the strategy will not be pursued further. 
If DL1 is tolerable but shows no biologic activity, then consideration will be given to amending the 
study to test higher doses. 
 
b) Hypotheses and specific aims 
We hypothesize that the dose levels of azacitidine to be tested on this trial will lead to reduction of 
global DNA methylation (i.e., 5-methylcytosine content) in peripheral blood mononuclear cells 
when comparing cells collected just prior to the first dose of azacitidine and cells collected after 5 
consecutive days of azacitidine dosing. 
 
• 
Specific Aim 1: To determine, for each patient and for the population of patients as a  
 
 
whole, the total DNA 5-methylcytosine (5mC) content in peripheral blood 
 
 
mononuclear cells (PBMCs) isolated from samples of peripheral blood  


   
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collected on Day 1 prior to the first dose of azacitidine and on Day 5 of  
 
 
the first two courses of azacitidine. 
 
c) Methods 
Refer to Section 14.1 for specimen collection and shipment. All blood samples will be diluted in 
HBSS and centrifuged over Lymphocyte Separation Medium (LSM) to isolate mononuclear cells, 
then suspended in culture medium. Viable cells will be counted by trypan blue exclusion. For yields 
≤ 5e6, all cells will be used for immediate DNA extraction. For yields > 5e6, excess cells will be 
suspended in cryoprotectant solution and viably cryopreserved in liquid nitrogen in aliquots of up 
to 5e6 cells for subsequent batched assays as needed. 
 
Using the freshly isolated PBMCs, total cellular DNA will be extracted using Qiagen commercial 
kits according to manufacturer’s protocol. DNA quantity and quality will be assessed using 
NanoDrop. DNA will be stored at -80 C for subsequent batched assays.  
 
Batched DNA will be thawed and assessed for global DNA methylation using a commercial ELISA 
LINE-1 kit which measures 5-methylcytosine (5mC) content in the long interspersed nucleotide 
element 1 (LINE-1) repeat elements, which is a validated surrogate of global DNA methylation. 
Each sample will be assayed in triplicate using 200 ng of starting DNA for each of the three 
replicates. The endpoint with the assay is a point estimate of the %5-mC in each replicate, ranging 
from 0-100%. 
 
The Brown laboratory routinely processes blood specimens from cooperative group clinical trials 
and performs a wide variety of assays using freshly isolated and/or viably cryopreserved cells. 
Samples are generally received in the laboratory within 48 hours of collection and processed 
immediately. Cells are sufficiently stable in transport under these conditions for the proposed 
assays.  
 
d) Analysis and Statistical Considerations 
The mean and standard error of the %5-mC triplicates will be calculated for each sample.  
 
The difference between the mean %5-mC of each paired pre- and post-treatment sample will be 
calculated and expressed as ΔM (change in methylation). A positive value will represent a decrease 
in methylation after exposure to azacitidine. 
 
Each set of paired pre- and post-treatment %5-mC values will be assessed for statistically 
significant change in methylation using paired t-tests. 
 
Each patient will have 2 sets of pre- and post-treatment samples, one for each of the first two 
courses of azacitidine, so each patient will have two ΔM values (ΔM1 for course 1, and ΔM2 for 
course 2).  
 
There are two possible dose levels that patients will receive on this pilot study. The patients treated 
at DL1 and DL0 will be analyzed separately. 
 
We will first describe the distribution of all ΔM values for the entire cohort for each dose level. 
The anticipated result is that the mean ΔM for the entire cohort will be positive and the paired t-
test will demonstrate statistical significance, reflecting the expected reduction in DNA methylation 
upon exposure to azacitidine. 
 


   
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We will use t-tests to compare the distributions of ΔM1 and ΔM2 within each dose level to assess 
for evidence of changes in pharmacodynamics between the first and second courses of azacitidine. 
While we do not anticipate a significant difference, it is possible that changes in drug clearance 
between the first and second courses may be reflected by a detectable change in biologic activity. 
 
We will use t-tests to compare the ΔM distributions for DL1 and DL0 to assess for evidence of a 
dose-response relationship in terms of demethylation, if both dose levels have been tested in the 
pilot. We anticipate that there will be a detectable dose-response relationship. 
 
In published clinical trials where LINE-1 methylation has been measured in PBMCs before and 
after DNMTi treatment, the reduction in %5-mC has been variable, with most studies showing an 
average reduction in the 3-10% range at standard doses. Given the relative paucity of data available 
and the wide variability, we will simply describe the observed differences in %5-mC before and 
after azacitidine treatment in our patient population, as described above. A strict decision rule in 
terms of the magnitude of %5-mC reduction will not be pre-determined. Similarly, we do not have 
sufficient data to guide formal power calculations. We anticipate that for each dose level, at least 
30 patients will provide a full set of 4 samples (pre- and post-treatment for each of the first two 
courses of azacitidine). We anticipate that this sample size will be sufficient to detect clinically 
significant biologic activity of azacitidine. 
 
 
 
 


   
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APPENDIX VII: ADDITIONAL INFORMATION FOR T CELL PROLIFERATION 
CAPACITY CORELATIVE BIOLOGY STUDY 
 
a) Rationale  
Adoptive immunotherapy with CART-19 has had great early success in pediatric patients with 
acute lymphoblastic leukemia (ALL)79-81. In order for patients to receive this therapy, we must be 
able to harvest functional T cells from the patient. Not all patients who undergo apheresis have 
successful collections or ex vivo T cell expansions, and this corresponds with the absence of early 
memory T cell subsets in the peripheral blood of these patients82. This can be directly related to 
chemotherapy, but is also true at diagnosis in lymphoma and solid tumor patients. Of the first 70 
pediatric patients treated with CART19, only one was less than 3 years old. Prospective data on the 
feasibility of CAR T cell manufacture indicates that very young children (<3 years old) quickly 
lose T cell proliferative capacity after successive chemotherapy cycles, much more quickly and 
completely than older children. At diagnosis, however, >80% of children under age 3 had excellent 
T cell proliferative capacity similar to the rate for children of all ages (81.2%). After 2 cycles of 
chemotherapy, however, only 16% of children under age 3 had suitable T cells for cellular therapy 
compared with 75% of all ages. Only one infant ALL patient has been able to be analyzed in any 
of these studies from a single institution. 
 
This trial includes a correlative study testing the feasibility of T-cell collection for the purposes of 
chimeric antigen receptor (CAR) T-cell production from the peripheral blood in infants with ALL. 
For those patients who consent, peripheral blood samples will be collected prior to therapy 
initiation, at the end of Induction, and at the end of Consolidation therapy. Lymphocyte subsets 
will be quantified, and functional studies will be performed to assess the ability of the lymphocytes 
to expand in response to artificial antigen presenting cell stimulation ex vivo. The ability to expand 
in response to this stimulus is a critical determinant of the feasibility of adoptive immunotherapy, 
specifically for CART-19. 
 
 
b) Hypotheses and specific aims  
The central hypothesis is that infants and very young children with ALL have highly proliferative 
T cells available for collection at diagnosis, and that these cells are rapidly destroyed by cycles of 
chemotherapy. 
 
• Specific Aim 1: Determine the lymphocyte subset and phenotype of T cells from infants with 
ALL. 
 
• Specific Aim 2: Determine the feasibility of CART19 manufacture from infants with ALL 
with T cells collected at diagnosis or after Induction and Consolidation 
therapy. 
 
c) Methods  
Sample receipt and processing. Please refer to Section 14.5 for detail. 
 
The Barrett laboratory routinely processes blood and marrow specimens from cooperative group 
clinical trials and performs a wide variety of assays using fresh and viably cryopreserved cells. 
Samples are generally received in the laboratory within 48-72 hours of collection and processed 
immediately. T cells are sufficiently stable in transport under these conditions for the proposed 
assays. The flow cytometric and T cell expansion assays are also routinely performed in the Barrett 


   
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laboratory. 
 
Multiparameter flow cytometric measurement of lymphocyte subsets and phenotype 
Blood samples will be separated by density centrifugation (Ficoll) the day of receipt. White blood 
cells will be isolated from the buffy coat and plated on plastic overnight at 37◦C to remove adherent 
cells. Cells will then be stained with isotype controls and the following antibody panels, and 
analyzed in triplicate by flow cytometry. 
 
o For lymphocyte subsets: CD3, CD4, CD8, CD19 (to exclude leukemia), CD45RO, 
CD45RA, CCR7, CD62L, CD95, PD-1, Lag-3, Tim-3, VISTA, and TIGIT. 
 
The endpoint for this assay will be the relative percentage of each of the following: 
 
o Naïve T-cells 
o Memory T-cells (stem central memory vs central vs. effector) 
o Terminal effector T cells 
o Number of negative checkpoint regulators (NCRs) on each subset and in total 
 
T cell proliferative capacity 
Small scale manufacture of CART19 replicates the potential of clinical scale manufacturing. 
Samples from 1-4 mL of peripheral blood subjected to the same manufacturing conditions using 
CD3/CD28 Dynabeads (called a test expansion) accurately predict the success of clinical CART19 
manufacture. T cells from the sample will be counted and plated with CD3/CD28 beads at a ratio 
of 3:1, and followed for cell size (by Coulter Counter), number and change in T cell subset 
composition by multiparameter flow cytometry. A cutoff of a 5-fold expansion or higher within 14 
days is used to determine successful potential for CART19 manufacture. 
 
The endpoint for this assay will be pass (≥5 fold expansion) or fail (< 5 fold).  
 
Rationale for selection of methods and laboratories 
The methods described above are performed routinely in the Barrett lab, who published the first 
and most comprehensive analysis of T cell subsets and CART19 potential in children with B cell 
malignancies. Thus use of this lab is likely to optimize the chances that the proposed studies will 
be successful. 
 
d) Analysis and Statistical Considerations 
 
Since we are proposing to use standard assays (flow cytometric quantification of marrow cell 
subsets) in a novel population, we do not have a priori knowledge of the expected range of observed 
values. As such, these studies are exploratory and definitive power calculations are not possible.  
 
Final cell counts from the test expansions will be used to estimate the volume of blood necessary 
for making clinical scale CART19 for patients of this population. In addition, the test expansions 
will be used to judge feasibility of CART19 manufacture from infants at the early time points in 
their therapy. This knowledge will be used to guide future cell therapy studies in this high risk 
population. 
 
 


   
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APPENDIX VIII: PHARMACOKINETIC OF AZACITIDINE 
Pharmacokinetic sampling will be done on Days 3, 4 and 5 of EPI Block #1 for determination of plasma 
azacitidine concentrations. A total of 7 samples (7 mL of blood) will be collected from each patient. 
Azacitidine is unstable in blood, therefore all blood samples will be processed and plasma harvested 
immediately per the instructions provided. Sample collection kits and supplies will be provided by Clinical 
Logistics. Kit ordering details and shipment instructions are provided in the PK of Aza information packet 
found on the AALL15P1 protocol webpage. 
 
To obtain accurate measurements of azacitidine levels in plasma, it is very important that tetrahydrouridine 
(THU) be added to blood collection tubes immediately after obtaining PK blood samples. THU inhibits 
the activity of cytidine deaminase, an enzyme responsible for the breakdown of azacitidine. The following 
preparations should occur in advance of PK blood collections. 
 
Preparation of Tetrahydrouridine 
 
Supplies provided by Clinical Logistics: 
• 
(3) vials containing 0.3 mL THU-Solution A in 10 mL polypropylene capped vial 
 
NOTE: Clinical Logistics will ship the THU- Solution A frozen, in single-use vials, separately from 
the collection kits. The THU-Solution A must be stored at -20C immediately upon receipt. Use one 
vial of THU-Solution A for each PK sampling visit. 
 
1. THU-Solution A: 
a. THU-Solution A will be provided in single-use vials at a concentration of 5 mg/mL in 
methanol. 
 
b. One the day of use remove one single-use vial of THU-Solution A from the -20°C freezer. 
 
c. Mix vigorously and thoroughly using a vortex mixer or sonicator after thawing, 
 
 
2. THU-Solution B - must be prepared on each PK day: 
a. Transfer 5 mL of distilled water into the thoroughly mixed, single-use vial of THU-
Solution A to prepare THU-Solution B. 
 
b. Mix thoroughly. 
 
c. The final concentration of THU-Solution B is 0.3 mg/mL. 
 
d. Store THU-Solution B at 4C. 
 
e. Label the tube “THU-Solution B” with the “date of preparation” and the “expiration 
date” (i.e., expiration date = date of preparation + 1 day). Clinical Logistics will provide 
a label. 
 
f. Discard any remaining THU-Solution B at the end of each day. Prepare a fresh batch of 
THU-Solution B at the beginning of each PK sampling visit. 
 
 


   
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Blood Collection and Processing 
 
Containers: 
Use 1 x 1.2 mL K2EDTA Monovette tube and lavender top EDTA tube per time point. Refer to 
Appendix IX for instructions regarding the Monovette drawing system and use. 
2 x 2 mL polypropylene cryovial, screw cap without ring sterile per time point 
1 x 1 mL Tuberculin syringe per time point 
1 polypropylene tube containing pre-made THU solution B per visit 
 
Blood Collection: 
i. 
Pre-chill blood collection tubes on ice for at least 15 minutes prior to blood draw. 
 
ii. Load tuberculin syringes (one for each PK blood collection tube) with 0.05 mL (50 microliters) of 
THU-Solution B/syringe. Store at 4◦C (i.e., refrigerator or wet ice). 
 
iii. Collect blood samples at the appropriate time points (see below) and place into the appropriately 
labeled 1.2 mL K2EDTA Monovette tube. 
 
iv. NOTE: Record the actual collection dates and times on the worksheet for entry into the CRF. 
Immediately after PK blood collection, add 0.05 mL of THU-Solution B to the blood sample. Use 
one syringe per collection tube. 
 
v. Invert the collection tube 8-10 times and place on wet ice. 
 
Sample Names (Note Primary or Back-Up for each time point): 
SMI/PK PRE-DOSING ≤ 1 HOUR DAY 3 
SM2/PK PRE-DOSING ≤ 1 HOUR DAY 4 
SM3/PK POST-DOSE 5 MIN 
SM4/PK POST-DOSE 30 MIN 
SM5/PK POST-DOSE 1 HOUR 
SM6/PK POST-DOSE 4 HOURS 
SM7/PK POST-DOSE 6 HOURS 
 
Sampling Schedule  
Blood samples (1 mL per time point) will be collected from each patient by in-dwelling catheter or 
peripheral IV, into sample collection tubes. 
 
Days and timing of PK blood sampling will be as follows: 
Pharmacokinetic Sampling Schedule 
Acceptable Deviation 
Window 
EPI Block #1 Day 3 
EPI Block #1 Day 4 
EPI Block #1 Day 5 
Prior to dosing (≤1 hour) 
Prior to dosing (≤1 hour) 
Not applicable 
≤ 60 min 
 
 
Postdose 5 minutes 
± 1 min 
 
 
Postdose 30 minutes 
± 3 min 
 
 
Postdose 1 hour 
± 3 min 
 
 
Postdose 4 hours 
± 3 min 
 
 
Postdose 6 hours 
± 3 min 
 
 
 


   
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Blood Processing: 
i. 
Blood must be processed within 30 minutes of collection. 
 
ii. Separate plasma from blood cells by centrifugation at 2000xg for 10 minutes at 4◦C. 
 
iii. Transfer two aliquots of plasma into 2 cryovials. Transfer approximately equivalent volume into 
the tube designated Primary and into the tube designated Back-Up (BU). 
 
iv. Freeze immediately on dry ice or at -70◦C. Store at -70◦C until shipment. 
 
v. Ship Primary PK plasma samples frozen on dry ice to Covance CLS within 1 month of collection. 
 
vi. Ship BU PK samples frozen on dry ice to Covance CLS upon sponsor’s request. 
 
Shipment instructions are provided in the PK of Aza information packet found on the AALL15P1 protocol 
webpage. 
 
Pharmacokinetics Analysis 
A validated high-performance liquid chromatography/tandem mass spectrometric method (LC-MS/MS) 
will be used for azacitidine plasma concentration analysis by the bioanalytical laboratory. 
 
The PK population will consist of all patients who had sufficient concentration time data to enable the 
calculation of PK parameters for azacitidine. For patients that did not receive adequate azacitidine dose, or 
for patients with incomplete data, a decision as to their inclusion in the analysis will be made on a case-by-
case basis. 
 
Pharmacokinetic parameters of azacitidine will be calculated from plasma concentration-time profiles using 
non-compartmental methods, though compartmental analysis may be employed if appropriate. Plasma PK 
parameters will include, but not be limited to:  
• 
Cmax: observed maximum plasma concentration 
• 
Tmax: observed time to maximum plasma concentration 
• 
AUCt: area under the plasma concentration-time curve from time zero to the last quantifiable 
time point, calculated by the linear trapezoidal rule 
• 
AUCinf: area under the plasma concentration-time curve from time zero to infinity, calculated 
by the linear trapezoidal rule and extrapolated to infinity will be calculated according to the 
following equation: 
AUCinf = AUCt + (Ct/λz), where Ct is the last quantifiable concentration  
• 
λz: terminal phase rate constant, determined by linear regression of the terminal points of the 
log-linear plasma concentration-time curve 
• 
t½: terminal phase half-life, will be calculated according to the following equation:   
t½ = 0.693/λz 
• 
CL: total clearance, calculated as Dose/AUCinf 
• 
Vz: volume of distribution will be calculated according to the equation: Vz = (CL)/λz 


   
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A listing of PK blood sample collection times, derived sampling time deviations, and PK parameters will 
be provided for each patient. Azacitidine plasma concentrations and resulting PK parameters will be 
summarized using descriptive statistics (N, arithmetic mean, standard deviation, minimum, median, 
maximum, percent coefficient of variation, geometric mean, and geometric percent coefficient of variation).  
 
Figures of mean azacitidine concentration-time data will also be illustrated. Individual azacitidine patient 
concentration-time data will be graphically presented on linear and semi-logarithmic scales. 
 
Pharmacokinetic parameters will be derived using WinNonlin® Professional Version 6.3, or higher, 
(Pharsight Corp., Mountain View, California). All PK computations and graphics will be performed using 
WinNonlin Professional Version 6.3, or higher; Excel 2007, or higher (Microsoft Corp., Seattle, 
Washington); SAS Version 9.2, or higher (SAS Institute, Inc., Cary, North Carolina); or R statistical 
software (R Foundation for Statistical Computing; Vienna, Austria; http://www.R-project.org). 


   
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APPENDIX IX: PROCEDURES FOR SARSTEDT MONOVETTE DRAWING SYSTEM 
 


   
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APPENDIX X: FISH TESTING: INFORMATION REGARDING SPECIMENS, 
RECOMMENDED ASSAYS AND ENTRY OF DATA INTO RAVE SYSTEM 
FLUORESCENCE IN SITU HYBRIDIZATION (FISH) TESTING FOR COG AALL15P1  
 
Specimens to be submitted to COG-approved Cytogenetic Laboratory: 
• 
5 mL of BM aspirate obtained prior to initiation of systemic anti-leukemia therapy is optimal. 
• 
If an adequate marrow specimen cannot be aspirated, then a BM biopsy specimen may be substituted 
at the discretion of the cytogenetic laboratory; contact cytogenetic laboratory for questions regarding 
specimen handling. 
• 
If an adequate marrow specimen cannot be aspirated, then PB may be substituted for BM if there are 
at least 1,000 circulating blasts/µL (i.e., a WBC count of 10,000/µL with 10% blasts or a WBC count 
of 5,000/µL with 20% blasts). If only PB is submitted, please obtain and send twice the volume of PB 
as the recommended BM volume specified in the tables. As long as there are at least 1,000/µL PB 
blasts, institutions are encouraged to submit PB in addition to BM samples to make sure that adequate 
material is available to perform the required studies. 
 
Technical Aspects for Cytogenetic Laboratory Directors 
 
Probes: 
BCR-ABL1 dual fusion preferred, extra signal acceptable, single fusion not acceptable 
ETV6-RUNX1 (TEL-AML1) 
KMT2A breakapart. 
Centromeres for chromosomes 4 and 10. Simultaneous (i.e., 2-color) evaluation preferred. 
 
Technique: 
• 
Samples must be unstimulated. 
• 
All probes should be validated prior to use. 
• 
Follow manufacturer’s directions. 
• 
KMT2A (MLL) break-apart should be scored positive if the 5’ and 3’ signals are split OR if the 3’ signal 
is deleted with retention of 5’ signal. Loss or translocation of both the 5’ and 3’ KMT2A signals is NOT 
indicative of an KMT2A (MLL) rearrangement and should NOT be scored as positive. 
• 
Evaluate/count signal patterns in 200 cells. If less than 100 cells are analyzed for any 1 of the probes, 
please call Andrew Carroll (West) at (205) 934-0665 or Nyla Heerema (East) at (614) 292-7815 to 
discuss. 
 
Fill out COG FISH form with results:  
KMT2A (MLL) results must be returned to your CRA and entered into RAVE by Day 10. 
Remaining FISH results must be returned to your CRA by Day 21. 
 
THE FORM INCLUDED ON THE FOLLOWING PAGES WILL PROVIDE THE COG INSTITUTION 
WITH ALL OF THE DATA NEEDED FOR RAVE ENTRY. THE FIRST PAGE SHOULD BE FILLED 
OUT BY THE CRA AND THE SUBSEQUENT PAGES BY THE CYTOGENETICS LABORATORY. 


   
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COG AALL15P1 DIAGNOSTIC SPECIMEN TESTING 
 
Specific FISH tests are REQUIRED for patients on AALL15P1. The results of these tests must be entered 
in RAVE by the treating institution. 
 
Results for KMT2A (MLL) (11q23) for infants MUST be entered in the RAVE by Day 10 of treatment 
for the infant patients enrolled on AALL15P1. 
 
To be completed by the submitting institution – send/FAX to Cytogenetic Lab: 
 
Patient Name: ______________________ (last)    ____________________ (first) 
 
COG Registration Number: _____________ 
Date of birth: __________________ 
 
Treating Institution: _________________________________________________ 
 
 
Contact Person: ________________  Phone Number: ______________________  
 
 
 
 
 
 
Fax Number: ________________________ 
 
 
 
 
 
 
Email: ______________________________ 
 
Cytogenetic Testing Laboratory: _______________________________________ 
 
Specimen Type:      
_____ Bone Marrow (% blasts if available_____) 
 
 
 
 
_____ Peripheral Blood (WBC _____ % blasts if available _____) 
 
Date specimen collected: ________________ 
 
 
Results are needed by Day 10 for KMT2A (MLL):  
______________ 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Name ___________________ 
 
 
COG Registration No. __________________ 


   
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To be completed by the Cytogenetic Laboratory (Return form to contact person, see front page): 
 
t(9;22)(q34;q11.2) 
____ Fusion Positive 
_____ % of cells positive 
 
 
 
BCR-ABL1 
 
____ Fusion Negative 
 
 
 
____ Unsatisfactory 
 
 
 
t(12;21)(p13;q22) 
____ Fusion Positive 
_____ % of cells positive 
 
 
ETV6-RUNX1  
____ Fusion Negative  
 
(TEL-AML1) 
 
____ Unsatisfactory 
 
 
KMT2A rearrangement – Positive if 5’ and 3’ signals are split OR 3’ signal is deleted with retention 
of 5’ signal. Loss or translocation of both the 5’ and 3’ KMT2A signals is NOT considered positive for 
this purpose. 
 
 
 
____ Positive 
_____ % of cells positive 
 
 
 
 
 
____ Negative 
 
 
 
____ Unsatisfactory 
 
 
 
Double trisomy (DT) – best tested by SIMULTANEOUS detection of both centromere probes (orange 
& green) 
 
Trisomy 4 
 
 
____ Positive 
 
_______% of cells with 3 or more signals 
 
____ Negative 
____ Unsatisfactory 
 
 
 
Trisomy 10 
 
 
____ Positive 
 
_______% of cells with 3 or more signals 
 
____ Negative 
____ Unsatisfactory 
 
 
 
Does this case meet the definition of double trisomy? – Yes/No 
 
 


   
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Definition of double trisomy:  
For a case to be “positive” for trisomy 4 & 10 (double trisomy, DT), it must be positive for both 
trisomy 4 and trisomy 10, and the percentage of one trisomy cannot be ≥ 2X the percentage of the 
other. Examples: If trisomy 4 in 20% and trisomy 10 in 40%, the case is not DT. If trisomy 4 in 21% 
and trisomy 10 in 40%, the case is DT. 
 
In addition to completing this form, the cytogenetic laboratory must submit all cytogenetics results and 
karyotypes to Dr Nyla Heerema (Eastern institutions) or Dr Andrew Carroll (Western institutions) prior to 
Day 10 for KMT2A, and Day 21 for all other results. Please see Section 14.7. 
 
 
 
 
 


   
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This 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.,  
74. 
Gastrointestinal 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 


   
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hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC.,  
75. 
Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS 
SOC.,  
76. 
Abnormal breath sounds include rales and rhonchi.,  
77. 
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