Conditions: Acute Lymphoblastic Leukemia Acute Undifferentiated Leukemia Childhood T Acute Lymphoblastic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 218
Healthy volunteers: no

Brief summary:
This phase III trial studies combination chemotherapy with or without lestaurtinib with to see how well they work in treating younger patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of stop cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without lestaurtinib in treating acute lymphoblastic leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the 3-year event-free survival (EFS) of infants with mixed lineage leukemia-rearranged (MLL-R) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus the fms-related tyrosine kinase 3 (FLT3) inhibitor lestaurtinib.

SECONDARY OBJECTIVES:

I. To compare the 3-year EFS of infants with MLL-R ALL treated with chemotherapy plus the FLT3 inhibitor lestaurtinib to MLL-R patients treated with chemotherapy alone.

II. To determine a safe, tolerable and biologically active dose of lestaurtinib given in sequential combination with chemotherapy in MLL-R infants.

III. To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants when given at the proposed dose in sequential combination with chemotherapy.

IV. To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts.

V. To describe levels of minimal residual disease in infants with ALL within the context of the proposed therapy, and correlate with outcome.

VI. To identify gene expression patterns in diagnostic infant leukemia samples that correlate with outcome within the context of the proposed therapy.

VII. To describe the outcome of infants with MLL-G ALL treated with a modified P9407 chemotherapy backbone that includes an extended continuation phase.

OUTLINE:

INDUCTION THERAPY (WEEKS 1-5): All patients receive induction therapy comprising vincristine sulfate intravenously (IV) over 1 minute on days 8, 15, 22, and 29; daunorubicin hydrochloride IV over 30 minutes on days 8 and 9; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4 (closed as of 05/19/09); pegaspargase or asparaginase intramuscularly (IM) on days 15, 18, 22, 25, 29, and 33; prednisone orally (PO) thrice daily (TID) or methylprednisolone IV on days 1-7; dexamethasone IV or PO TID on days 8-28; cytarabine IV over 30 minutes on days 8-21; methotrexate intrathecally (IT) on days 1 and 29; cytarabine IT on day 15; hydrocortisone IT on days 15 and 29; and filgrastim IV or subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. Standard-risk patients are non-randomly assigned to receive a less intensive chemotherapy regimen without lestaurtinib (post-induction therapy A). Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), blood sample collection and bone marrow biopsy on day 1 week 1.

POST-INDUCTION THERAPY A: (for standard-risk patients MLL-germline \[G\])

INDUCTION INTENSIFICATION (WEEKS 6-9): Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; triple IT chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on days 1 and 8; leucovorin calcium IV or PO every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is \< 0.1 uM; cyclophosphamide IV over 30 minutes on days 15-19; etoposide IV over 2 hours on days 15-19; and filgrastim IV or SC beginning on day 20 and continuing until blood counts recover. Patients in morphologic remission proceed to re-induction therapy. Patients may undergo bone marrow biopsy on day 1 week 6.

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase IM on day 4; dexamethasone IV or PO twice daily (BID) on days 1-7 and 15-21; triple IT chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on days 1 and 15; and filgrastim IV or SC beginning on day 5 and continuing until blood counts recover. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10.

CONSOLIDATION (WEEKS 13-19): Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is \< 0.1 uM; triple IT chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on day 1; etoposide IV over 2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19; high-dose cytarabine IV over 3 hours every 12 hours on days 29 and 30; pegaspargase or asparaginase IM on day 30; and filgrastim IV or SC beginning on day 20 and day 31 and continuing until blood counts recover.

CONTINUATION I (WEEKS 20-41): Patients receive vincristine sulfate IV on day 1 in weeks 20 and 24; dexamethasone IV or PO BID on days 1-5 in weeks 20, and 24; triple IT chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on day 1 in weeks 20 and 24; methotrexate IV on day 1 in weeks 21-24 and 25-27; etoposide IV over 2 hours on day 1-5 in week 28; cyclophosphamide IV over 30 minutes on days 1-5 in week 28; mercaptopurine PO on days 1-7 in weeks 21-23 and 25-27; and filgrastim SC or IV beginning on day 6 in week 28 and continuing until blood counts recover. Patients may undergo bone marrow biopsy on day 1 week 20.

CONTINUATION II (WEEKS 42-104): Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone IV or PO BID on days 1-5, 29-33, and 57-61; methotrexate IT on day 1; methotrexate PO on days 8, 15, 22, 36, 43, 50, 64, 71, and 78; and mercaptopurine PO on days 8-28, 36-56, and 64-84. Treatment repeats every 12 weeks for 2 years from diagnosis.

A safety/activity phase is conducted separately for the intermediate-risk (IR) and high-risk (HR) patients to identify a safe, tolerable, and biologically active dose of lestaurtinib combined with chemotherapy backbone. Once a tolerable/active dose of lestaurtinib has been identified for IR patients, subsequent IR patients are eligible to proceed to an efficacy phase, where they are randomized (or non-randomly assigned as of 7/16/2014) to chemotherapy with or without lestaurtinib. HR patients separately proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR stratum. IR and HR patients are randomized (or non-randomly assigned as of 7/16/2014) to 1 of 2 post-induction therapy regimens (post-induction therapy B or C).

POST-INDUCTION THERAPY B: (chemotherapy only for IR/HR patients classified as MLL-R; age \>= 90 days at diagnosis):

INDUCTION INTENSIFICATION (WEEKS 6-9): Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy A induction intensification. Patients in morphologic remission proceed to re-induction Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 6. (Retired as of 7/16/2014)

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy A re-induction. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10. (Retired as of 7/16/2014)

CONSOLIDATION (WEEKS 13-19): Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy A consolidation. (Retired as of 7/16/2014)

CONTINUATION I (WEEKS 20-49): Patients receive vincristine sulfate IV over 1 minute on day 1 in weeks 20, 24, 33, 37, and 46; dexamethasone PO or IV BID on days 1-5 in weeks 20, 24, 33, 37, and 46; triple IT chemotherapy on day 1 in weeks 20, 24, 33, 37, and 46; methotrexate IV on day 1 in weeks 21-23, 25-26 and 37-45; mercaptopurine PO on days 1-7 in weeks 21-23, 25-26 and 37-45; etoposide IV over 2 hours on days 1-5 in week 27; cyclophosphamide IV over 2 hours on days 1-5 in week 27: high-dose cytarabine IV over 3 hours every 12 hours on days 1 and 2 in week 30; pegaspargase or asparaginase IM on day 2 in week 30: and filgrastim SC or IV beginning on day 3 in weeks 30 and continuing until blood counts recover. Patients may undergo bone marrow biopsy on day 1 of weeks 20, 33 and 46. (Retired as of 7/16/2014)

CONTINUATION II (WEEKS 50-104): Patients receive vincristine sulfate, dexamethasone, IT methotrexate, methotrexate PO, and mercaptopurine PO as in post-induction therapy A continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis. (Retired as of 7/16/2014)

POST-INDUCTION THERAPY C: (chemotherapy and lestaurtinib for IR/HR patients classified as MLL-R; age \< 90 days at diagnosis)

INDUCTION INTENSIFICATION THERAPY (WEEKS 6-9): Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy B induction intensification. Patients also receive lestaurtinib PO BID on days 20-27. Patients in morphologic remission proceed to re-induction.Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 6.

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy B re-induction. Patients also receive lestaurtinib PO on days 5-20. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10.

CONSOLIDATION (WEEKS 13-19) Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B consolidation. Patients also receive lestaurtinib PO on days 20-27 and 31-42.

CONTINUATION I (WEEKS 20-49): Patients receive vincristine sulfate, dexamethasone, triple IT chemotherapy, methotrexate, mercaptopurine, etoposide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B continuation I. Patients also receive lestaurtinib PO on days 2-6 in weeks 20 and 24; days 27-41 in weeks 27-29; days 45-56 in weeks 30-32. Patients may undergo bone marrow biopsy on day 1 of weeks 20, 33 and 46.

CONTINUATION II (WEEKS 50-104): Patients receive vincristine sulfate, dexamethasone, IT methotrexate, methotrexate PO, and mercaptopurine PO as in post-induction therapy B continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis.

After completion of study treatment, all patients are followed up every 1-6 months for 4 years and then annually thereafter.

Arms:
arm 1: Population Description: Eligible patients with MLL-G (germline, or non-rearranged) arm 2: Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis. arm 3: Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.

Interventions: intervention 1: Asparaginase intervention 2: Biospecimen Collection intervention 3: Bone Marrow Biopsy intervention 4: Cyclophosphamide intervention 5: Cytarabine intervention 6: Daunorubicin Hydrochloride intervention 7: Dexamethasone intervention 8: Echocardiography intervention 9: Etoposide intervention 10: Filgrastim intervention 11: Laboratory Biomarker Analysis intervention 12: Lestaurtinib intervention 13: Leucovorin Calcium intervention 14: Mercaptopurine intervention 15: Methotrexate intervention 16: Methylprednisolone intervention 17: Multigated Acquisition Scan intervention 18: Pegaspargase intervention 19: Pharmacological Study intervention 20: Prednisone intervention 21: Therapeutic Hydrocortisone intervention 22: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV, IM, or PO intervention 2: Undergo blood sample collection intervention 3: Undergo bone marrow biopsy intervention 4: Given IV intervention 5: Given IV or IT intervention 6: Given IV intervention 7: Given IV or PO intervention 8: Undergo ECHO intervention 9: Given IV intervention 10: Given IV or SC intervention 11: Correlative studies intervention 12: Given PO intervention 13: Given IV intervention 14: Given PO intervention 15: Given IV, IT, or PO intervention 16: Given IV intervention 17: Undergo MUGA intervention 18: Given IM intervention 19: Correlative studies intervention 20: Given PO intervention 21: Given IT intervention 22: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
AALL0631 
 
Version Date: 04/05/13                                                                                                                 Page 1 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
AALL0631 
 
A Phase III Study of Risk Directed Therapy for Infants with Acute Lymphoblastic Leukemia (ALL): 
Randomization of Highest Risk Infants to Intensive Chemotherapy ± FLT3 Inhibition  
(CEP-701, Lestaurtinib; IND#76431; NSC#617807) 
 
 
 
A Groupwide Phase III Study 
 
IND Sponsor: COG 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org  
Activated: 
01/14/08 
Version Date: 
04/05/13 
Closed: 
   06/30/14 
 
      
 
Amendment: 
5 


 
 
 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 2 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Objectives 
9 
1.2 
Secondary Objectives 
9 
2.0 
BACKGROUND 
9 
2.1 
Importance of this Study 
9 
2.2 
Risk Stratification in Infant ALL 
9 
2.3 
Rationale for FLT3 Inhibition as a Novel Treatment for MLL-rearranged Infant ALL 10 
2.4 
Hematopoeitic Stem Cell Transplantation (HSCT) 
12 
2.5 
Rationale for Chemotherapy 
13 
2.6 
Rationale for Study Design 
17 
2.7 
Rationale for Correlative Studies 
19 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
22 
3.1 
Study Enrollment 
22 
3.2 
Patient Criteria 
23 
4.0 
TREATMENT PLAN 
25 
4.1 
Overview 
25 
4.2 
Safety/Activity Phase (Completed) 
28 
4.3 
Efficacy Phase 
31 
4.4 
Induction Chemotherapy: Weeks 1-5 
32 
4.5 
Post-Induction Arm A [for SR Patients (MLL-G)] 
38 
4.6 
Post-Induction Arm B [Chemotherapy ONLY for IR/HR Patients (MLL-R)] (RETIRED)54 
4.6.2 
Re-Induction: Weeks 10-12 (Arm B) (RETIRED) 
57 
4.7 
Post-Induction Arm C [Chemotherapy + Lestaurtinib for IR /HR Patients (MLL-R)] 
71 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
89 
5.1 
Asparaginase [E. coli, Pegaspargase (PEG-Asparaginase) or Erwinia] 
89 
5.2 
Cyclophosphamide 
90 
5.3 
Cytarabine (ARAC) 
91 
5.4 
Daunorubicin 
91 
5.5 
Etoposide (VP-16) 
91 
5.6 
Lestaurtinib 
92 
5.7 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
92 
5.8 
High-Dose Methotrexate (HD MTX) and Leucovorin Rescue 
93 
5.9 
Weekly IV or PO/NG Methotrexate (MTX) and 6-Mercaptopurine (6-MP) 
95 
5.10 
Steroids (Dexamethasone and Prednisone) 
97 
5.11 
Vincristine 
98 
5.12 
Drug Interactions 
99 
6.0 
DRUG INFORMATION 
101 
6.1 
ASPARAGINASE (E.coli L-asparaginase) 
101 
6.2 
ASPARAGINASE (ERWINIA CHRYSANTHEMI) 
102 
6.3 
CYCLOPHOSPHAMIDE  
104 


 
 
 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 3 
6.4 
CYTARABINE 
105 
6.5 
DAUNORUBICIN 
107 
6.6 
DEXAMETHASONE   
6.7 
ETOPOSIDE  
110 
6.8 
FILGRASTIM 
112 
6.9 
INTRATHECAL TRIPLES 
113 
6.10 
LESTAURTINIB  
114 
6.11 
LEUCOVORIN CALCIUM 
116 
6.12 
MERCAPTOPURINE   
117 
6.13 
MESNA  
119 
6.14 
METHOTREXATE  
120 
6.15 
METHYLPREDNISOLONE  
122 
6.16 
PEGASPARGASE  
124 
6.17 
PREDNISONE 
126 
6.18 
VINCRISTINE SULFATE  
127 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
129 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations  
129 
7.2 
Recommended Follow-up 
130 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
130 
8.1 
Criteria for Removal from Protocol Therapy 
130 
8.2 
Off Study Criteria 
131 
9.0 
STATISTICAL CONSIDERATIONS 
131 
9.1 
Statistical Design 
131 
9.2 
Patient Accrual and Expected Duration of Trial 
131 
9.3 
Statistical Analysis Methods 
133 
9.4 
Gender and Minority Accrual Estimates 
136 
10.0 
EVALUATION CRITERIA 
136 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
136 
10.2 
Response Criteria 
136 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
137 
11.1 
Purpose 
137 
11.2 
Determination of reporting requirements 
137 
11.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
137 
11.4 
Reporting methods 
138 
11.5 
When to report an event in an expedited manner 
139 
11.6 
Other recipients of adverse event reports 
139 
11.7 
Reporting of Adverse Events for investigational agents 
139 
11.8 
Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 140 
11.9 
Routine Adverse Event Reporting 
141 
12.0 
RECORDS AND REPORTING 
141 
12.1 
Categories of Research Records 
141 
12.2 
CDUS 
141 
13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
142 
13.1 
Blood for Lestaurtinib PK/PIA (required) 
142 
13.2 
Bone Marrow for AALL08B1 (required) 
142 
13.3 
Bone Marrow for Flow MRD, Molecular MRD and Resistance Mechanisms (optional)143 


 
 
 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 4 
14.0 
DESCRIPTION OF CORRELATIVE LABORATORY ASSAYS 
143 
14.1 
Lestaurtinib Pharmacokinetic (PK)/Plasma Inhibitory Activity (PIA) Assay 
143 
14.2 
Correlating Clinical Responses with PIA and In Vitro Lestaurtinib Sensitivity 
144 
14.3 
Determining Mechanisms of Resistance to Lestaurtinib 
144 
14.4 
Minimal Residual Disease (MRD) Testing 
146 
14.5 
Gene Expression Analysis 
146 
APPENDIX I:  SUPPORTIVE CARE GUIDELINES 
147 
APPENDIX II: CYP3A4/5 INHIBITORS AND INDUCERS 
154 
APPENDIX III: P-GLYCOPROTEIN SUBSTRATES/INDUCERS (OVER 
TIME)/INHIBITORS 
155 
APPENDIX IV: INSTRUCTIONS TO PATIENT/CAREGIVER FOR ADMINISTERING 
LESTAURTINIB (CEP-701) AT A 5 MG/ML DILUTION 
156 
APPENDIX V: HIGH DOSE METHOTREXATE FLOW CHART 
158 
APPENDIX VI: MERCAPTOPURINE DOSING GUIDELINES 
159 
REFERENCES 
160 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
                                
                       
 
 
 
                           
           
 
 
 
 
 
 
 
 
            
  
 
 
 
            
  
 
 
              
  
  
 
            
  
 
 
 
              
  
 
 
              
  
 
 
            
  
 
 
 
            
  
 
 
 
            
  
 
 
 
            
  
 
 
            
  
 
 
            
  
 
 
              
  
 
 
            
  
 
 
            
  
 
 
              
  
 
 
 
SEE SECTION 13 FOR SPECIMEN SHIPPING ADDRESSES 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 7 
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 
 
Infants with acute lymphoblastic leukemia (ALL), and in particular those with mixed lineage leukemia 
(MLL) gene rearrangement, have experienced poor outcomes. Results from Children’s Oncology Group 
(COG) study P9407 suggest that attempts to intensify chemotherapeutics have reached the limits of 
acceptable toxicity, and that hematopoeitic stem cell transplantation does not improve outcome for these 
patients. Thus, novel treatment approaches are required. 
 
The FLT3 kinase has been shown to be consistently highly expressed and activated in MLL-R ALL. 
FLT3 inhibitors, such as lestaurtinib (CEP-701), selectively kill MLL-R ALL cells in vitro and in vivo, 
and synergize with chemotherapy. Lestaurtinib is in clinical development for adult and pediatric AML.  
 
This study will be done in two phases: a safety/activity phase, which will determine the dose of 
lestaurtinib that, in combination with P9407-based chemotherapy, is safe, tolerable and biologically active 
in infants with MLL-R ALL; and an efficacy phase, in which infants with MLL-R ALL will receive the 
modified chemotherapy regimen with the incorporation of lestaurtinib. Infants with MLL-G ALL will be 
non-randomly assigned to receive a less intensive chemotherapy regimen without lestaurtinib. 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 8 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
All institutions 
MLL 
 
- 
Mixed lineage leukemia gene 
MLL-G 
 
- 
MLL Germline (non-rearranged) 
MLL-R 
 
- 
MLL Rearranged 
SR 
 
- 
Standard Risk 
IR 
 
- 
Intermediate Risk 
HR 
 
- 
High Risk 
A 
 
- 
Post-Induction Arm A (SR chemo) 
B 
 
- 
Post-Induction Arm B (IR/HR chemo) 
C 
 
- 
Post-Induction Arm C (IR/HR chemo + lestaurtinib) 
Induction
A
Enroll
B
MLL-G
(SR)
MLL-R
(IR/HR)
Induction
A
Enroll
MLL-G
(SR)
MLL-R (IR/HR)
Closed 
for toxicity 
assessment?
B
C 
(@ current
dose level)
Y
N
During Safety/Activity Phase
Phase I (+)
Institutions
All Other 
Institutions
Closed 
for toxicity 
assessment?
B
C 
(@ current
dose level)
Y
N
Age 
@ dx?
< 90d (HR)
≥90d (IR)
Completed as of 01/28/11 
for IR patients and 02/03/12 
for HR patients 
On-going 
Randomize 
Induction 
A 
Enroll 
MLL - G (SR) 
MLL - 
B 
C 
All institutions 
Efficacy Phase: Pre-Amendment #5 
Enroll 
C 
MLL-R (IR/HR) 
MLL-G (SR) 
A 
Induction 
R (IR/HR) 
Efficacy Phase: Post-Amendment #5 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 9 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
 
1.1.1 
To estimate the 3-year event-free survival (EFS) of infants with MLL-R ALL treated with 
chemotherapy plus the FLT3 inhibitor lestaurtinib. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To compare the 3-year EFS of infants with MLL-R ALL treated with chemotherapy plus the FLT3 
inhibitor lestaurtinib to MLL-R patients treated with chemotherapy alone. 
 
1.2.2 
To determine a safe, tolerable and biologically active dose of lestaurtinib given in sequential 
combination with chemotherapy in MLL-R infants. 
 
1.2.3 
To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants when 
given at the proposed dose in sequential combination with chemotherapy. 
 
1.2.4 
To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts. 
 
1.2.5 
To describe levels of minimal residual disease in infants with ALL within the context of the 
proposed therapy, and correlate with outcome.  
 
1.2.6 
To identify gene expression patterns in diagnostic infant leukemia samples that correlate with 
outcome within the context of the proposed therapy. 
 
1.2.7 
To describe the outcome of infants with MLL-G ALL treated with a modified P9407 
chemotherapy backbone that includes an extended Continuation phase. 
 
 
2.0 
BACKGROUND  
 
2.1 
Importance of this Study 
This trial will test a novel therapeutic intervention that may improve outcome for one of the highest risk 
groups in pediatric oncology -- infants with MLL gene rearrangements. The specific intervention (FLT3 
inhibition) is based on a strong biological rationale with supporting pre-clinical evaluation.  
 
2.2 
Risk Stratification in Infant ALL 
Infants with ALL have experienced poor event-free survival (EFS), particularly in MLL-rearranged 
disease. International published results show 22% to 43% 3- to 6-year EFS.1-6 Historically, the high 
failure rate in infant ALL has been due to recurrent disease, particularly early relapse < 6-12 months post 
diagnosis.1,4,5 Thus, therapeutic efforts in COG for infant ALL have centered on providing shortened, 
intensified therapy including early Induction Intensification and elimination of age-related dose 
reductions typical of infant therapy in the past. Compared to prior studies, POG 9407 (Cohorts 1 and 2) 
and CCG 1953 (concurrent infant ALL studies in the former POG and CCG) significantly reduced early 
relapse. However, the toxic death rate during Induction exceeded historical controls. As a result, the 
successor study COG P9407 (Cohort 3) was modified by substituting prednisone for dexamethasone 
during Induction, and decreasing dose intensity of anthracyclines, successfully reducing Induction 
toxicity from 17 Induction toxic deaths in 68 patients in POG 9407 (Cohorts 1 and 2) to 8 Induction toxic 
deaths in 141 patients in COG P9407 (Cohort 3).   
 


 
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Results of POG 9407 (Cohorts 1 and 2) and COG P9407 (Cohort 3) have been used to define risk groups 
and provide the chemotherapy backbone to be used in this protocol: 
 
 
 
3-year EFS (n) 
 
Cohorts 1+2 
Cohort 3 
All patients 
50% (68) 
45% (141) 
MLL-R  
40% (48) 
38% (100) 
MLL-G  
81% (16) 
74% (35) 
0-90 days  
18% (17) 
15% (27) 
91+ days  
61% (51) 
52% (114) 
91+ days (MLL-R only) 
53% (34) 
47% (78) 
 
In POG 9407 (Cohorts 1 and 2), age greater or less than 90 days at diagnosis was the most important 
prognostic factor. The presence of a MLL rearrangement was also prognostic. Preliminary data suggests 
age </> 90 days at diagnosis and MLL rearrangement status continue to be important prognostic factors in 
Cohort 3.   
 
The CCG-1953 infant ALL study ran concurrently with POG 9407 (Cohorts 1 and 2), and the results 
confirm the prognostic significance of age and MLL rearrangement status. The study had a 4-year EFS 
and overall survival (OS) of 43.7% and 49.5%, respectively. Age has a very strong effect within the 
MLL-rearranged group (RHR = 4.42) with a 4-year EFS of 55.7% (standard error (SE) = 8.7) in the older 
infants (> 90 days) versus an EFS of only 10.6% (SE = 10.0) in the younger group. The CCG-1953 study 
was designed to test all MLL-rearranged infants (as determined by Southern blot and/or cytogenetics) by 
RT-PCR for fusion transcripts for t(4;11), t(11;19), and t(9;11). The 5-year EFS for these groups on CCG-
1953 therapy (identical to P9407 but without the elimination of decadron, with higher dose methotrexate, 
longer Maintenance and mandated BMT for MLL-rearranged), was as follows: t(4;11): n = 35, EFS = 
29.0% ; t(11;19): n = 20, EFS = 30.0%; t(9;11): n = 9, EFS = 22.2%; and other 11q23: n = 15, EFS = 
53.3%.7  
 
Based on the above experience, groups identified for risk-directed therapy are listed below. MLL-
rearranged infants are all selected for eligibility for FLT3 inhibitor therapy based upon their uniformly 
high expression of FLT3, and their uniformly inferior EFS compared to that of ALL patients older than 
1 year of age. The population proportion and 3-year EFS range from Cohorts 1 + 2 and Cohort 3 are given 
in parentheses. 
 
Infant Standard Risk (SR): MLL non-rearranged (24% of patients, 3 year EFS 74%-81%) 
 
Infant Intermediate Risk (IR): MLL-rearranged, ≥ 90 days at diagnosis (54% of patients, 3 year EFS 
47%-53%) 
 
Infant High Risk (HR): MLL-rearranged, < 90 days at diagnosis (17% of patients, 3 year EFS 5%-7%) 
 
2.3 
Rationale for FLT3 Inhibition as a Novel Treatment for MLL-rearranged Infant ALL  
 
2.3.1 
FLT3 Background  
The FLT3 tyrosine kinase is an important oncogene in adult and pediatric AML, and FLT3 inhibition as a 
therapeutic strategy is being actively explored. FLT3 has recently been implicated in the pathogenesis of 
infant and childhood ALL, as well. Gene expression studies have shown that the highest levels of FLT3 
mRNA expression occur in cases of infant and childhood ALL with rearrangements of the MLL gene, 
which account for 80% of infant and 5% of childhood ALL cases.8,9 The correlation of high FLT3 
expression and MLL rearrangement in these studies is very strong. Moreover, several laboratories have 
demonstrated that leukemic blasts from cases of MLL-rearranged infant ALL also express high levels of 


 
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FLT3 at the protein level, and that FLT3 is constitutively phosphorylated in these cases, even in the 
absence of FLT3 activating mutations, suggesting autocrine activation via coexpression of FLT3 ligand 
(FL) in these cases.10-12 In addition, activating mutations of FLT3 (specifically, point mutations in the 
activation loop of the kinase domain) occur in approximately 15% of infants and children with ALL with 
MLL gene rearrangements.9,11,13   
 
2.3.2 
Pre-Clinical Data with FLT3 Inhibitors  
The demonstrated importance of FLT3 signaling in the pathogenesis of human leukemia has led to the 
development of FLT3-targeted agents. Lestaurtinib (CEP-701) is a highly selective small molecule FLT3 
tyrosine kinase inhibitor (TKI) with excellent oral bioavailability and an IC50 of 3 nM.14 In vitro, 
lestaurtinib selectively kills primary infant and childhood ALL cells with high-level expression of 
constitutively activated FLT3, especially those with MLL rearrangements, so that marked lestaurtinib 
sensitivity was seen in 82% (9 of 11) of MLL-rearranged samples vs. 8% (1 of 13) of samples that lacked 
MLL rearrangement and expressed low levels of FLT3.10 
 
2.3.3 
Pre-Clinical Data with Combinations of Chemotherapy and FLT3 Inhibitors  
Since monotherapy with any single molecularly targeted agent is unlikely to be curative in acute 
leukemia, targeted agents are more likely to be effective as components of combination chemotherapy 
regimens. Lestaurtinib has been shown to result in synergistic killing of MLL-rearranged ALL cells when 
combined with multiple chemotherapy agents.15 The degree of synergy is markedly dependent upon 
sequence of exposure to the agents. Exposure to chemotherapy followed by lestaurtinib results in 
consistent and strong synergistic cell killing, while simultaneous exposure is in most cases additive.  
Exposure to lestaurtinib followed by chemotherapy is, in many cases, antagonistic. This sequence 
dependence is due to the effects of FLT3 inhibition on cell cycle progression. The design of this study 
takes these important biological findings into account, as lestaurtinib will be given immediately following 
exposure to standard cytotoxic chemotherapy in an effort to maximize potential synergy, and will not be 
given for at least 24 hours prior to chemotherapy to avoid potential antagonism. 
 
2.3.4 
Clinical Experience with Lestaurtinib  
 
2.3.4.1 Adult Lestaurtinib Phase I 
A total of 30 adult patients with advanced solid tumors were enrolled at twice-daily doses of 5 mg (n = 3), 
10 mg (n = 3), 20 mg (n = 3), 40 mg (n = 13), 80 mg (n = 7), and 120 mg (n = 1).16 The majority of 
patients (67%) received a single 28-day cycle of lestaurtinib. However, 7 patients received study drug for 
at least 3 months, including 3 patients who were treated for more than 6 months. One patient received 13 
cycles of treatment. The most frequently reported adverse events were nausea (63%), diarrhea (47%), 
anorexia (37%), asthenia (30%), constipation (27%), and vomiting (27%). The incidence of adverse 
events tended to be greater in patients who received at least 40 mg BID. Most of these events were 
intermittent, but lasted several days. Dose-limiting toxicities (DLTs) were reported for 1 patient at 80 mg 
BID (Grade 3 nausea) and 1 patient at 120 mg BID (Grade 3 hypotension). The formal definition of MTD 
was not met for either of these dosages.  Lestaurtinib was rapidly absorbed, with mean tmax values ranging 
from 0.8 to 2.7 hours on Days 1 and 28 across all dosages. At 40 mg BID, the Day 28 mean Cmax was 
3973 ng/mL, and the mean AUC12 was 26630 ng-hr/mL. At 80 mg BID, the Day 28 mean Cmax was 
12117 ng/mL, and the mean AUC12 was 114857 ng-hr/mL. Lestaurtinib did not produce an objective 
tumor response in any patient. The median duration of treatment was 5 weeks. Three patients had stable 
disease for more than 6 months and 1 of the patients with small cell lung cancer was stable for almost a 
year. 
 
2.3.4.2   Adult Lestaurtinib Phase II Single Agent 
The activity of lestaurtinib was studied in 18 adults with refractory or relapsed AML with activating 
mutations of the receptor tyrosine kinase FLT3.17 The starting dosage of lestaurtinib was raised in this 


 
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study from 40 mg BID to 60 mg BID after the first 4 patients showed no response and a cell-based ex-
vivo assay of plasma indicated that the inhibition of the FLT3 target may have been suboptimal. Fourteen 
patients were subsequently enrolled at 60 mg BID, and the dosage for 3 patients was increased to 80 mg 
BID after approximately 1 month of treatment. The higher doses of 60 and 80 mg BID were well tolerated 
in this group of patients. At a dosage of 60 mg BID, the ex-vivo assay indicated that a high degree of 
inhibition (> 90%) of the FLT3 target was maintained over the 12-hour interval between doses. Clinical 
responses (reduction in peripheral blood or bone marrow blast percentage) were seen in 5 of 14 patients, 
all of whom had been shown to be refractory to chemotherapy. Serious adverse events of gastrointestinal 
hemorrhage, fatigue and congestive heart failure in 1 patient each were considered possibly related to 
lestaurtinib. These events were also considered possibly related to the patients' disease and/or prior 
treatment. 
 
2.3.4.3   Adult Lestaurtinib Phase II Chemotherapy Combination 
An ongoing study randomizes adults with refractory or relapsed FLT3-mutant AML to receive 
chemotherapy alone or chemotherapy in sequential combination with lestaurtinib (80 mg PO BID).18 
Forty-two patients have been enrolled and 34 have completed the primary endpoint assessment (12 males 
and 22 females, median age = 58, age range = 26-72). In general, lestaurtinib was well tolerated, with 
mild to moderate gastrointestinal symptoms and fatigue attributed to the drug. Of the pretreatment 
leukemia samples available for cytotoxicity analysis, 78% were sensitive to lestaurtinib in vitro. Thirteen 
of 17 (76%) patients achieved a plasma FLT3 inhibitory activity of greater than 85%. All patients who 
achieved this degree of plasma FLT3 inhibitory activity and whose pretreatment leukemia cells were 
sensitive in vitro to lestaurtinib achieved a clinical response. Conversely, patients with insensitive cells or 
low drug plasma levels did not respond. Ten of 17 patients randomized to lestaurtinib showed evidence of 
response (CR or partial response [PR]); while 4 of 17 patients randomized to receive chemotherapy alone 
had achieved a response. Accrual is ongoing. Lestaurtinib has been well-tolerated in this trial, with mild 
to moderate gastrointestinal symptoms and fatigue attributed to the drug. 
 
2.3.4.4  Pediatric Lestaurtinib Phase I 
A Phase I study of single agent lestaurtinib in children with refractory neuroblastoma (lestaurtinib is also 
an inhibitor of the Trk family of neurotrophin receptors) is underway. Twenty-two patients (median 
age = 10.3 yrs, age range = 3.6 - 19.8) have been enrolled (John Maris et al, personal communication). All 
have been heavily pretreated, with a median of 6 prior regimens (range = 2-11), all 22 patients have 
received at least 1 autologous bone marrow transplant, and 21 of 22 patients have received radiation 
therapy. Patients are given lestaurtinib orally twice daily for 5 days, then 2 days off, for 4 weeks (each 
course is 28 days). Fifty-four courses have been given to the 22 patients (mean age = 2.6, age range = 1-
12). No toxicity was seen at doses up to 50 mg/m2/dose twice daily. Reversible transaminase elevations 
were seen at 70 mg/m2/dose twice daily. Accrual continues at 62.5 mg/m2/dose twice daily. No 
hematologic toxicity has been seen at any dose level. Trough plasma samples taken from patients on this 
trial have consistently demonstrated > 90% FLT3 inhibitory activity in ex-vivo plasma bioassays, a level 
which has been positively correlated with anti-tumor response in the adult AML trials (Patrick Brown, 
personal communication).18 
 
2.4 
Hematopoeitic Stem Cell Transplantation (HSCT) 
There are single institution reports of outcome of hematopoeitic stem cell rescue (HSCR) in infant ALL 
showing good outcomes, but they are uncontrolled, have small numbers, and include non-High Risk 
infants.19-22 There are also reports of lack of benefit to BMT.3,23,24 The largest of these reports, concluding 
that HSCT shows no advantage over chemotherapy, comes from the Ponti de Legno group. This group 
performed a retrospective comparison of outcomes following treatment with chemotherapy vs. HSCT for 
214 infants with t(4;11) ALL treated between 1983 and 1995, which showed a hazard ratio of 1.8 for 
HSCT compared to chemotherapy.23,24 This study, while it is a retrospective analysis of 11 groups, does 


 
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analyze chemotherapy and HSCT patients in a way that adjusts for “time to transplant”, avoiding the bias 
of reporting HSCT patient survival without comparison to chemotherapy patients. 
 
Approximately 14 (of 74, or 19%) infants registered on POG 9407 and 34 (of 115, or 30%) enrolled on 
CCG 1953 underwent HSCT. There was no difference in outcome observed for High Risk patients with 
the MLL gene rearrangement who received conventional chemotherapy (5-year EFS = 48.7% with 
SE = 10.1%) compared with those who underwent stem cell transplant (5-year EFS = 50.9% with 
SE = 9.9%; RHR = 1.13). The interfant-99 protocol allowed BMT for High Risk (prednisone-poor 
responders regardless of MLL) infants. Forty-one infants were transplanted (28 MLL-rearranged, 8 MLL 
germline, 5 MLL unknown). The DFS was not statistically different for transplants (50%) versus those 
treated with chemotherapy alone (37%), adjusted for time to transplant (P = 0.19) (R. Pieters, personal 
communication, submitted). 
 
Based on these data, HSCT in first remission is not a therapeutic option for infants with ALL enrolled on 
this study. 
 
2.5 
Rationale for Chemotherapy 
 
2.5.1 
Induction Chemotherapy 
AALL0631 Induction chemotherapy was initially based on the COG P9407 (Cohort 3) protocol, which 
‘passed’ specific safety monitoring rules incorporated into that trial after excessive infectious toxicity was 
encountered during Cohorts 1 and 2, particularly among infants less than 90 days of age. There were 2 
changes made to Induction therapy in AALL0631: (1) The daunomycin dose was reduced by 15% (Days 
1 and 2) in order to reduce the incidence of mucositis and delay in proceeding to the subsequent phase of 
therapy; (2) E. coli asparaginase was replaced with pegaspargase. 
 
Four of the first 26 patients enrolled on AALL0631 have died of infections during Induction, and 
1 patient has discontinued protocol therapy due to severe non-fatal Induction toxicity.25 The details of the 
5 Induction toxicities on AALL0631 are below (Table 1): 
 
TABLE 1 
Age at dx 
(days) 
Type of toxicity 
Fatal? 
Timing of toxicity 
1 
Infection (fungal – Aspergillus fumigatus) 
Y 
Became ill Day 15, died Day 23 
2 
Severe hepatotoxicity/hyperbilirubinemia 
N 
Bili began rising Day 23, progressed over 
next 2 weeks 
92 
Infection (fungal – Candida tropicalis) 
Y 
First + cx Day 17, progressed over next 2-
3 weeks, died Day 33 
285 
Infection (bacterial – Pseudomonas 
aeruginosa) 
Y 
Became ill Day 10, died Day 16 
308 
Infection (bacterial – Bacillus species) 
Y 
Became ill Day 18, died Day 19 
 
This prompted a comprehensive review of toxicity for infants with ALL treated on AALL0631, P9407 
(Cohort 3 only) and Interfant-99 (a European cooperative group study). The following tables summarize 
relative Induction death rates for patients in various age groups (based on age in days at diagnosis) on 
P9407 (Cohort 3), AALL0631 and Interfant-99 (data provided by Rob Pieters). 
 
Age 0 to 6 days 
Protocol 
N 
Deaths  
Rate 
P9407 c3 
2 
1 
50% 
Interfant-99 
9 
2 
22% 
AALL0631 
2 
1 
50% 
 


 
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We have concluded that for patients less than one week old at diagnosis, the risk of toxic death is high 
with all regimens. While numbers are small, the risk appears to be unacceptably high with AALL0631 
and P9407 (Cohort 3) protocol therapy, and this risk appears to be less with Interfant-99 protocol therapy. 
 
Age 7 to 29 days 
Protocol 
N 
Deaths  
Rate 
P9407 c3 
3 
0 
0% 
Interfant-99 
21 
1 
5% 
AALL0631 
0 
- 
- 
 
We have concluded that for patients from 7 to 29 days of age at diagnosis, we have very little data to 
assess the risk of toxic death with AALL0631 or P9407 (Cohort 3) protocol therapy, but cannot exclude 
the possibility that these risks may be excessive. The risk of Induction death appears to be within the 
expected range with Interfant-99 protocol therapy in this age group. 
 
Age > 30 days 
Protocol 
N 
Deaths  
Rate 
P9407 c3 
137 
5 
4% 
Interfant-99 
452 
19 
4% 
AALL0631 
24 
3 
13% 
 
While numbers are small, we are concerned that for patients at least 30 days of age at diagnosis, the risk 
of toxic death may be excessive with AALL0631 protocol therapy, while the risk of toxic death appears to 
be lower for both P9407 (Cohort 3) and Interfant-99 in this age group. Notably, the Interfant-99 data are 
based on a significantly larger number of patients. 
 
In summary: For infants less than 30 days old at diagnosis, it appears that Interfant-99 Induction therapy 
is associated with lower Induction toxic death rates than either P9407 (Cohort 3) or AALL0631 therapy. 
For infants greater than 30 days old at diagnosis, it appears that there may be increased risk with 
AALL0631 Induction therapy compared to P9407 (Cohort 3) or Interfant-99. While P9407 (Cohort 3) 
passed prospective safety monitoring rules in this population, this is based on a significantly smaller 
number of patients than the Interfant-99 protocol. Therefore, we have concluded that the most prudent 
approach will be to adopt the Interfant-99 Induction regimen for all age groups. 
 
It is important to emphasize that long term outcomes for infants with MLL rearrangements are 
unsatisfactory with either P9407 or Interfant-99 therapy. The primary goal of AALL0631 is to determine 
if treatment with a modified P9407 chemotherapy backbone with the FLT3 inhibitor (lestaurtinib) 
improves outcome for these infants. With this is mind, we believe that it is critical to have an Induction 
regimen that is safe and well tolerated, thereby allowing us to evaluate the potential efficacy of 
lestaurtinib, which is the primary objective of the AALL0631 trial. 
 
An important consideration is whether we will be sacrificing efficacy by adopting the Interfant-99 
Induction regimen. The available data are encouraging in this regard. For patients less than 30 days old, 
the Induction complete remission (CR) rate was 87% (26 of 30, with 2 failures due to toxic deaths) on 
Interfant-99, which was not significantly different than the CR rate of 93% (394/424) for older patients on 
Interfant-99, or the CR rate of 90% (97/108) for all patients on P9407 Cohort 3 (where remission status 
was determined at the end of the Induction Intensification course at Week 8). 


 
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The following table shows a direct comparison of the Induction therapy given on these protocols. A key 
part of the Interfant-99 Induction regimen that will be new to COG trials is a 7-day prednisone prophase. 
 
 
Interfant 
AALL0631/P9407 c3 
Comparison 
Drug 
Details 
Cum 
Details 
Cum 
PRED/ 
DEX 
PRED 45 mg/m2 Days 1-7, 
DEX 4.5 mg/m2 Days 8-28, 
taper Days 29-35 
PRED 
315 mg/m2, 
DEX 
94.5 mg/m2 
(plus taper) 
PRED 40 mg/m2 Days 1-21 
PRED 
840 mg/m2 
similar 
VCR 
1.125 mg/m2 Days 8,15,22,29 
4.5 mg/m2 
0.05 mg/kg Day 1, 15, 
0.03 mg/kg Day 8 
0.13 mg/kg  
(~4 mg/m2) 
similar 
DAUN 
22.5 mg/m2 Days 8,9 
45 mg/m2 
2.6 mg/kg Days 1,2 
(9407: 3 mg/kg) 
5.2 mg/kg 
(~150 mg/m2) 
(9407: 
6 mg/kg, 
~180 mg/m2) 
0631 >> 
interfant 
PEG- 
ASP 
E.coli L-ASP 7500 IU/m2 
(Elspar) 
IV or IM 
Days 15,18,22,25,29,33 
45,000 IU/m2 
0631: PEG-ASP 2500 IU/m2 IM 
Day 4 
9407: E.coli L-ASP 6000 IU/m2 
IM x 8 
(Days 4,6,8,10,12,15,17,19) 
0631: PEG-
ASP 
2500 IU/m2 
9407: E.coli 
L-ASP 
48,000 IU/m2 
similar 
ARAC 
56.25/m2 Days 8-21 
787.5/m2 
- 
- 
interfant >> 
0631 
CPM 
- 
- 
250 mg/m2 q12 x 4 Days 3, 4 
1000 mg/m2 
0631 >> 
interfant 
IT 
MTX (6 mg) Day 1, 
ARAC (15 mg) + HC (12 mg) 
Day 15, 
MTX + HC Day 29 
MTX 12 mg, 
ARAC 15 mg, 
HC 24 mg 
ITT Days 1, 8, 15 
MTX 
22.5 mg,  
ARAC 45 mg,  
HC 22.5 mg 
0631 >> 
interfant 
 
NOTES:  
1. For Interfant, non-IT drugs dose reduced 11% for patients < 6 months old at diagnosis. 
2. For AALL0631, dauno dose reduced to 2.1 mg/kg for 6-9 months old at diagnosis, and to 1.7 mg/kg 
for < 6 months old at diagnosis. 
 
Based on these data, we are adopting the Interfant-99 Induction regimen for all patients, with the 
following modifications: 
 
1. The steroid taper that is included in the Interfant-99 Induction regimen will be eliminated. 
2. E. coli asparaginase (ASP; Elspar) will be given IM (not IV or IM, as in Interfant-99) if available.  
If unavailable, Erwinia is to be substituted as per Section 5.1.  
3. For patients less than 7 days old at diagnosis, an additional 25% dose reduction will be applied to 
all non-intrathecal chemotherapy. 


 
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The table below summarizes the amended Induction regimen: 
 
Amended AALL0631 
Drug 
Details 
Cumulative 
PRED/DEX 
PRED 45 mg/m2 Days 1-7,  
DEX 4.5 mg/m2 Days 8-28 
PRED 315 mg/m2, DEX 
94.5 mg/m2  
VCR 
1.125 mg/m2 Days 8,15,22,29 
4.5 mg/m2 
DAUN 
22.5 mg/m2 Days 8,9 
45 mg/m2 
E.coli L-ASP 
7500 IU/m2 IM Days 
15,18,22,25,29,33 
45,000 IU/m2 
ARAC 
56.25 mg/m2 Days 8-21 
787.5 mg/m2 
CPM 
- 
- 
IT 
MTX (6 mg) Day 1 
ARAC (15 mg) + HC (12 mg) Day 
15, 
MTX + HC Day 29 
MTX 12 mg, ARAC 
15 mg, HC 24 mg 
 
NOTES:  
1. Non-IT drugs dose reduced 11% for patients < 6 months old at diagnosis.   
2. Non-IT drugs dose reduced an additional 25% for patients < 7 days old at diagnosis. 
 
Following this change, induction mortality was significantly lower for patients in Cohort 2 (modified 
Induction) versus Cohort 1 (original Induction), 2/67 (3%) vs. 4/26 (15.4%), p=0.049.26 All deaths during 
Induction were infection related except one from progressive disease (Cohort 2).  Sterile site infections 
were also more common in Cohort 1 (Table 1).  There were no clinically significant Grade 3-4 non-
infectious toxicity differences between Cohorts 1 and 2.   
 
2.5.2 
Post-Induction Chemotherapy Backbone for MLL-R Patients 
The post-Induction chemotherapy to be given to all patients in this study will continue to be based upon 
the post-Induction chemotherapy regimen given on P9407, Cohort 3. 
 
Several modifications have been made to post-Induction chemotherapy with the goal of improving 
outcome by reducing relapse risk without significantly increasing regimen-related toxicity. 
 
 
Replace E coli asparaginase with pegaspargase in Re-Induction, Consolidation and Continuation I 
 
Currently the asparaginase of choice in all COG ALL protocols is pegaspargase, due to reduced 
toxicity and ease of delivery. We will incorporate this change into this protocol for uniformity among 
ALL protocols, and will monitor for unexpected toxicities. 
 
 
Change post-Induction steroids from prednisone to dexamethasone  
 
No dexamethasone-related deaths were observed during Re-Induction for Cohorts 1 and 2 of P9407, 
and minimal toxicity has been observed during Re-Induction for Cohort 3 of P9407. Dexamethasone 
is likely to enhance disease (marrow and CNS) control. 
 
 
Intensify Continuation with modifications of VP/CTX pulses 
 
P9407 Continuation included 2 5-day pulses of VP/CTX. As of March 2006, there have been 23 
relapses for Cohort 3. Thirteen (57%) of these (7 BM, 4 CNS and 2 testicular) have occurred between 
Week 18 (beginning of Continuation) and Week 48 (end of therapy evaluation), with 3 of these being 
noted with the end of therapy marrow/LP (1 CNS relapse, 2 BM relapses). This is a greater relapse 
rate than was noted for Cohorts 1 and 2 (only 2 of 13 relapses occurred during therapy). Therefore, 
intensifying the existing VP/CTX pulses is likely to enhance disease control during this less intensive 


 
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phase of therapy, while also providing additional HDAC exposure which is desirable, given in vitro 
data suggesting that infant ALL cells are more sensitive to Ara-C than ALL cells from older 
children.27,28 Intensive pulses will be modified such that VP/CTX will be followed by 1 week of 
HDAC/PEG-ASP. While the potential for enhanced toxicity during Continuation I is increased, there 
is likely to be a significant advantage to intensifying therapy at this point. 
 
 
Change weekly MTX in Continuation from 20 mg/m2 intramuscular (IM) to 20 mg/m2 intravenous 
(IV) 
 
Methotrexate is changed from IM to IV administration for patient comfort and uniformity among 
ALL protocols. 
 
 
Extend Continuation, resulting in 24 months of total therapy 
 
Concern has been raised that the Continuation in P9407 (total 46 weeks of therapy) is of insufficient 
duration. There have been 3 relapses noted at “off-protocol therapy” marrow in Cohort 3 of P9407. In 
addition, there have been an additional 5 relapses within 5 months of stopping therapy. Extended 
Continuation may enhance disease control with minimal risk of increased toxicity. 
 
2.5.3 
Post-Induction Chemotherapy Backbone for MLL-G Patients 
Given the small number of MLL-G infants that will enroll in this trial, we do not anticipate being able to 
ask and answer a rigorous efficacy question. We propose to treat these patients with an Interfant-99 based 
Induction chemotherapy regimen identical to that given to the MLL-R infants. MLL-G infants receive a 
post-Induction chemotherapy regimen identical to Cohort 3 of P9407 until Week 42, except for 3 
modifications: (1) change post-Induction steroid to dexamethasone, (2) replace E coli asparaginase with 
pegaspargase in Re-Induction and Consolidation, and (3) change weekly MTX in Continuation from IM 
to IV. After Week 42, MLL-G patients will begin an extended Continuation period similar to 
Maintenance therapy that is given in standard ALL protocols, for a total duration of therapy of 2 years. 
This change is being made both to address the risk of late relapse that has been seen for MLL-G patients 
enrolled in prior studies. 
 
2.6 
Rationale for Study Design 
 
2.6.1 
Overview 
Lestaurtinib has never been tested in infants, and so this study will be conducted in two phases: a 
safety/activity phase, with the objective of determining a safe, tolerable and biologically active dose of 
lestaurtinib given in sequential combination with chemotherapy in MLL-R infants, and an efficacy phase, 
with the objective of estimating the 3-year EFS of infants with MLL-R ALL treated with chemotherapy 
plus the FLT3 inhibitor lestaurtinib. 
 
2.6.2 
Rationale for Design of Safety/Activity Phase 
During the safety/activity phase, MLL-R infants enrolled at the institutions listed on the AALL0631 
protocol website (COG Phase I/Pilot Consortium plus a number of additional institutions) will receive 
chemotherapy plus lestaurtinib. MLL-R infants enrolled at other institutions during this phase will be 
treated with chemotherapy only.  MLL-R infants treated with lestaurtinib during the safety/activity phase 
will be stratified into IR (≥ 90 days of age at diagnosis) and HR (< 90 days of age at diagnosis) arms to 
facilitate independent toxicity assessments and dose adjustments, which will allow for potentially 
different pharmacokinetic and toxicity profiles of older and younger infants. Decisions regarding dose 
adjustments based on toxicity and biologic activity will be made according to the algorithm in 
Section 4.2.1. The presence or absence of a DLT attributable to lestaurtinib will be determined for each 
patient after the first 2 courses of lestaurtinib (i.e., during the Induction Intensification and Re-Induction 


 
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Age group
Wt (kg)
BSA 
(m2)
Dose 
(mg/m2/day)
Dose 
(mg/kg/day) 
Dose 
(mg/day) 
Volume of dose 
of 5 mg/mL mixture
(mL/dose)
Neonate
3.2 
0.2
56
3.5
11 
1.1
6 wk old
4.6 
0.27
60
3.5
16 
1.6
3 mo old (89 days)
6
0.32
66
3.5
21 
2.1
3 mo old (90 days)
6
0.32
75
4 
24 
2.4
6 mo old
7.8 
0.38
82
4 
31 
3.1
9 mo old
9.1 
0.43
85
4 
36 
3.6
12 mo old
10.1
0.46
88
4 
40 
4
9 yr old (Nb patient)
28.5
1.03
125
4.5
129 
N/A 
Adult (AML trials) 
70
1.73
92.5 
2.3
160 
N/A 
phases), which will facilitate timely assessment of safety and need for dose adjustment. The definition of 
DLTs attributable to lestaurtinib to be used in this study is detailed in Section 4.2.3.   
 
2.6.3 
Rationale for Starting Dose of Lestaurtinib 
 
The starting dose of lestaurtinib on this study will be 3.5 mg/kg/day divided BID for < 90 days of age, 
and 4 mg/kg/day divided BID for > 90 days of age. Due to the lack of clinical experience with lestaurtinib 
in infants (who have proven to be unpredictable in terms of pharmacokinetics and pharmacodynamics), 
dosing on a per kg basis seems the most appropriate initial strategy. The dose tolerated in older children 
in the lestaurtinib single agent Phase I neuroblastoma trial was 125 mg/m2/day divided BID, and the dose 
tolerated in adults in the combination lestaurtinib and chemotherapy Phase II AML trial was 160 mg/day 
divided BID. The table above shows a comparison of these doses with the proposed starting doses in this 
trial for infants of various weights and BSA (based on average for males at listed age). Compared to the 
Phase I pediatric dose, which is a more relevant dose comparison group for this trial than the adult group, 
our proposed starting doses are 11%-23% lower on a per kg basis, and 30%-55% lower on a per m2 basis. 
Compared to the adult dose, the starting doses on this trial are 5%-39% lower on a per m2 basis and 52%-
74% higher on a per kg basis (which is less relevant than m2 when comparing adult and pediatric dosing). 
 
2.6.4 
Rationale for Design of Efficacy Phase 
This study initially used a randomized design (prior to Amendment #5) to evaluate whether the addition 
of lestaurtinib to a modified P9407 chemotherapy backbone results in improved outcome for MLL-R 
infant ALL. A randomized design allows for a direct comparison of the 2 arms, minimizing confounders 
unrelated to lestaurtinib (such as improvements in supportive care). In addition, it allows for several 
modifications to the P9407 chemotherapy backbone which may improve overall outcome. The specific 
modifications, and the rationale for each, are detailed in Section 2.5.  
 
As of the activation of Amendment #5, the design of the efficacy phase is changed to accommodate the 
lack of drug availability for the duration of the planned randomized study. MLL-R patients will be non-
randomly assigned to receive lestaurtinib at the dose proven to be safe and achieve biologically active 
levels in the safety phase. In addition, the duration of lestaurtinib treatment will be reduced such that 
patients will discontinue lestaurtinib after Continuation I (Week 45), which will be 1 year from diagnosis. 
 
2.6.5  Successful Completion of Safety/Activity Phase 
 
2.6.5.1 IR patients 
Ten evaluable IR patients received lestaurtinib, 5 patients each at dose levels (DL) 1 (4 mg/kg/day) and 
DL2 (5 mg/kg/day). There were no DLTs at either dose level during the first 2 courses of lestaurtinib. 
Results from the plasma inhibitory assay (PIA) were used to assess the biologic activity of lestaurtinib. 
There were a total of 5 trough time points for each patient: Days 24 and 27 of Induction Intensification; 


 
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Days 9, 12, and 19 of Re-Induction. For the 5 IR patients treated at DL2, 4 out of 5 had adequate FLT3 
inhibitory plasma levels for the majority of the 5 trough samples: 1 patient had adequate levels at 1 time 
point, 2 patients had adequate levels at 3 time points, and 2 patients had adequate levels at 5 time points. 
Thus DL2 (5 mg/kg/day divided BID) was identified as a tolerable and biologically active dose for IR 
patients, and the efficacy phase began for IR patients on 01/28/11.29 
 
2.6.5.2 HR patients 
Ten evaluable HR patients received lestaurtinib, 5 patients each at dose levels (DL) 1 (3.5 mg/kg/day) and 
2 (4.25 mg/kg/day). There were no DLTs at DL1 and 1 DLT at DL2 during the first 2 courses of 
lestaurtinib. The DLT was Grade 4 intestinal perforation secondary to severe typhlitis during neutropenia 
following re-Induction, possibly related to lestaurtinib. The patient was taken off protocol due to inability 
to tolerate further chemotherapy and died of progressive disease. Results from the plasma inhibitory assay 
(PIA) were used to assess the biologic activity of lestaurtinib. There were a total of 5 trough time points 
for each patient: Days 24 and 27 of Induction Intensification; Days 9, 12, and 19 of re-Induction. For the 
5 HR patients treated at DL2, 4 out of 5 had adequate FLT3 inhibitory plasma levels for the majority of 
the 5 trough samples: 1 patient did not have adequate levels at any time point, 1 patient had adequate 
levels at 3 time points, 2 patients had adequate levels at 4 time points and 1 patient had adequate levels at 
5 time points. Thus DL2 (4.25 mg/kg/day divided BID) was identified as a tolerable and biologically 
active dose for HR patients, and the efficacy phase began for HR patients on 02/03/12.30 
 
2.7 
Rationale for Correlative Studies 
 
2.7.1 
Assessing Biologic Activity of Lestaurtinib Using FLT3 Plasma Inhibitory Activity (PIA) Assay 
The advent of molecularly targeted agents has created a need for new early phase trial designs that are 
based primarily on determining the dose necessary to achieve the desired biologic activity, rather than the 
MTD. In practice, directly assessing whether a targeted agent is consistently “hitting the target” in the 
context of a clinical trial is challenging, requiring not only multiple invasive procedures to obtain 
sufficient numbers of tumor cells for evaluation, but also the availability of a validated, technically 
feasible, real-time assay of functional target inhibition. The few cases where this type of assessment has 
been attempted have been leukemia clinical trials where persistently high peripheral leukemic blast counts 
despite exposure to the investigational drug have allowed collection of tumor cells at multiple time points 
with simple blood draws. Even in these rare (and unenviable) situations, such assessments have been 
largely unsuccessful for a variety of reasons. In the trial described here, patients will have already been 
exposed to 54 days of intensive Induction chemotherapy prior to the onset of lestaurtinib therapy on 
Day 55. In the vast majority of these cases, there will be inadequate numbers of circulating leukemic cells 
on Day 55 to allow direct assessment of FLT3 inhibition by collecting peripheral blood, and it would be 
neither feasible nor ethically acceptable to perform bone marrow aspiration on patients at the multiple 
time points necessary for adequate evaluation of consistent FLT3 inhibition in tumor cells. Standard 
pharmacokinetic assays accurately measure the concentration of total drug in plasma, but do not measure 
the amount of free drug, which varies widely depending upon the affinity of a drug for the various plasma 
proteins (e.g., albumin, alpha-1-acid glycoprotein (AGP) and the concentration of these proteins in an 
individual patient’s plasma. Since only the free, unbound fraction of lestaurtinib is available to inhibit 
FLT3 in target cells, and since lestaurtinib is known to be greater than 99% bound to plasma proteins, 
pharmacokinetic values cannot be used as a valid surrogate for lestaurtinib biologic activity. While direct 
measurement of free lestaurtinib levels in patient plasma would be expected to correlate nicely with the 
degree of FLT3 inhibition achieved in target leukemic cells, reliable assays of free lestaurtinib levels are 
not available. 
 
In light of these limitations, we have developed an assay which can act as a powerful surrogate for in vivo 
FLT3 inhibition in patients receiving lestaurtinib by measuring FLT3 plasma inhibitory activity (PIA).31 


 
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The results of the PIA assay will be used to assess the biologic activity of lestaurtinib in this novel clinical 
trial design. 
 
2.7.2 
Correlating Clinical Responses with PIA and In Vitro Lestaurtinib Sensitivity 
In order for a leukemia patient to have a favorable response to a molecularly targeted therapeutic agent, 2 
requirements must be met: (1) the leukemia cells must be dependent, at least in part, upon the activity of 
the molecular target for its survival; and (2) sufficient levels of the agent must be delivered to the 
leukemia cells to inhibit the target. Using the MTT cytotoxicity and annexin V binding apoptosis assays, 
we have demonstrated that in over 80% of cases, leukemic cells isolated from patients with MLL-R ALL 
are dependent on activated FLT3 signaling for their survival, since when FLT3 is selectively inhibited by 
exposure to lestaurtinib, the cells undergo apoptosis and die (and are therefore considered “sensitive” to 
lestaurtinib). The degree of inhibition of FLT3 activity required to achieve this cytotoxicity is 
approximately 90% relative to untreated control, and this degree of inhibition must be sustained over at 
least 48 hours. A minority of MLL-R samples demonstrate in vitro resistance to FLT3 inhibition, a 
phenomenon that will be explored in detail in correlative studies introduced in Section 2.7.3. We have 
also developed an assay that is able to reliably measure the FLT3 inhibitory activity in patient plasma 
(plasma inhibitory activity, or PIA) while receiving lestaurtinib. The major significance of this assay is 
that it has proven to be a reliable surrogate for the degree of FLT3 inhibition achieved in the patient’s 
leukemia cells, which is often not amenable to direct assessment. Thus, with the availability of in vitro 
assays of lestaurtinib sensitivity and the ex vivo PIA assay, we will be able to test whether the 2 
requirements for a favorable response are met for each patient. We hypothesize that consistently 
achieving ≥ 90% FLT3 PIA at trough time points in a patient whose diagnostic blasts are lestaurtinib-
sensitive in vitro will be predictive of clinical response, and that a lack of in vitro sensitivity or a failure 
to consistently achieve these levels of inhibition will be predictive of treatment failure. If the model 
proves to be predictive, we may be able to use it in future trials to select appropriate patients for treatment 
with lestaurtinib, and to individualize dosing to ensure that each patient has a chance to derive maximal 
benefit from the therapy. 
 
2.7.3 
Determining Mechanisms of Resistance to Lestaurtinib  
Approximately 15% of MLL-R samples obtained at the time of diagnosis are resistant to the in vitro 
cytotoxic effects of lestaurtinib. There has been good correlation between in vitro resistance and clinical 
resistance in adults treated thus far on the ongoing Phase II trial of chemotherapy plus lestaurtinib in 
adults with relapsed and refractory FLT3-mutant AML. In a limited number of these resistant samples, we 
have seen persistent phosphorylation/activation of one or more of the signaling proteins known to be 
downstream of FLT3 (such as STAT5, MAP kinase, or AKT) despite inhibition of FLT3 phosphorylation, 
suggesting that the underlying basis of lestaurtinib resistance in some cases may be mutations in one or 
more signal transduction proteins other than FLT3. The correlative studies proposed here will more fully 
explore the phenomenon of inherent resistance to FLT3-inihibtor induced cytotoxicity. Acquired 
resistance during therapy is another potential problem. Acquired resistance to imatinib in chronic 
myelogenous leukemia (CML) patients is most often due to emergence of CML clones with point 
mutations that disrupt binding of imatinib to BCR-ABL, resulting in reactivation of BCR-ABL kinase 
activity in these cells. Recognition of this fact has led to the development of a second generation of BCR-
ABL inhibitors that are active against the known resistance-inducing mutations. This experience suggests 
that acquired resistance-inducing mutations in FLT3 or one of its downstream signaling proteins are likely 
to be present in samples obtained from patients with progressive or relapsed disease on lestaurtinib 
therapy, particularly in those whose pre-therapy samples demonstrate in vitro sensitivity. Other potential 
mechanisms of acquired resistance include factors independent of the leukemic cells, such as an increase 
in the clearance of lestaurtinib (due to upregulation of metabolizing pathways, for example) or a decrease 
in free drug levels due to increases in plasma protein binding. The correlative studies in this trial will 
investigate these potential molecular bases of acquired resistance in patients that relapse or progress 
during or after lestaurtinib therapy. Successfully identifying one or more of these inherent or acquired 


 
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resistance mechanisms may potentially allow for selection of patients most likely to respond to 
lestaurtinib, and could lead to novel therapies able to overcome resistance. 
 
2.7.4 
Minimal Residual Disease  
While no studies have yet been completed using MRD in infant ALL, all studies in childhood ALL using 
MRD techniques have shown significant correlations between end-Induction tumor burden and 
outcome.31-37 Incorporation of MRD assessments into this study will provide additional data and 
understanding of the role of MRD in predicting disease recurrence and response to therapeutic 
interventions in infant ALL. As novel agents become available, MRD analysis may lay the groundwork 
for evaluation of new agents in infant ALL when added to this therapeutic backbone. Studies in childhood 
ALL show that patients can be divided into 3 groups: 1) no end-Induction MRD detected (42% to 75% of 
the total); 2) intermediate levels of MRD (10-3 – 10-2, 42% to 20%); 3) and MRD high levels (> 10-2, 5% 
to 16%). Patients without evidence of MRD have an excellent outcome (3-year EFS > 90%) whereas 
those with high levels have an exceedingly high relapse rate (3-year EFS = 26%-28%). 
 
Over the past decade, a number of strategies have been developed to monitor MRD in ALL.38-40 Flow-
cytometric detection of residual blast cells has a sensitivity of 10-3 to 10-4 and relies on 3 and 4 color 
antigen detection of 1 (or preferably 2) surface phenotypes unique to leukemia and not present on normal 
cells. This technique can be applied to 98% of all newly-diagnosed children with ALL.32,33,41,42 Drs. 
Brown and Murphy at Johns Hopkins have developed a sensitive and reliable multiplex quantitative RT-
PCR assay to detect the 3 most common MLL gene rearrangements in infant ALL (MLL-AF4, MLL-
ENL and MLL-AF9), adapted from a published technique.43 
 
Flow MRD data were collected prospectively on P9407 (measured at Week 8, Week 18 and end therapy). 
Molecular MRD data are being generated retrospectively at these same timepoints for patients with 
banked specimens. Comparisons will be made between the Week 10, Week 20/21 and off therapy MRD 
between the current study and P9407 to determine whether the changes in therapy are associated with 
changes in MRD patterns at the various timepoints. We will also determine whether MRD by either 
methodology at any timepoint is predictive of outcome. This analysis will be performed on patients from 
the 2 studies individually, and with patients from the 2 studies combined for the shared timepoints. The 
Week 6 MRD determination has been added in this population specifically to: (1) compare the impact of 
end Induction MRD between infants and older children with ALL, and (2) characterize the impact of the 
addition of lestaurtinib to MRD patterns between Arm B and Arm C [Week 6 MRD is pre-lestaurtinib, 
Weeks 10 and 20 MRD are after the lestaurtinib doses in Induction Intensification (Week 10 MRD), and 
Re-Induction/Consolidation (Week 20 MRD)]. 
 
2.7.5 
Gene Expression Profiling  
The gene expression profiling studies associated with this protocol are based on 2 hypotheses: (1) that we 
can identify gene expression profiles and develop classifiers predictive of in vitro sensitivity or resistance 
of infant ALL samples to the FLT3 inhibitor lestaurtinib; and (2) that we can extend and validate a novel 
molecular classification scheme we have developed for infant leukemia in this prospective cohort of 
infant leukemia patients. Using Affymetrix oligonucleotide microarrays, Dr. Cheryl Willman’s laboratory 
obtained expression profiles from an initial retrospective cohort of 126 infants with acute leukemia (78 
ALL, 48 AML). Using unsupervised learning algorithms and novel data visualization tools (VxInsight 
and Principal Component Analysis (PCA)), they discovered 3 novel, statistically robust clusters of infant 
leukemia that did not correlate with traditional morphologic (AML vs. ALL) or cytogenetic (presence or 
absence of MLL rearrangements) parameters (Cheryl Willman, personal communication). We now 
propose to determine if this molecular classification scheme is reproducible by validating it in a new 
prospective cohort of infant patients registered to COG leukemia trials using newer high density 
Affymetrix HG_U133 Plus2.0 Arrays, including the infant leukemia cases registered to this trial. 
 


 
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3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration via Remote Data Entry (RDE) 
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained. The COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help. 
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs 
to be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The 
Childhood Cancer Research Network (CCRN). 
 
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. 
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites must 
submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory Office and allow 
3 business days for processing. The submission must include a fax coversheet (or optional CTSU IRB 
Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may be 
submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the CTSU web 
page (https://www.ctsu.org). Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the RSS Tab. 
 
IRB/REB 
approval 
documents 
may 
be 
faxed 
(1-215-569-0206), 
emailed 
(CTSURegulatory@ctsu.coccg.org), or mailed to the CTSU Regulatory office.   
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of 
Need” registration. For Time of Need registrations, in addition to marking your submissions as 
‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-651-
CTSU. For general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have 
problems with enrollment, refer to online help in the Applications area of the COG website. 
 
3.1.4 
Timing 
PATIENTS MUST BE ENROLLED ON A COG ALL CLASSIFICATION STUDY (AALL08B1) 
BEFORE TREATMENT ON AALL0631 BEGINS. PATIENTS THAT BEGIN PROTOCOL 
THERAPY FOR LEUKEMIA, PRIOR TO ENROLLMENT ON THE CLASSIFICATION 
STUDY, ARE INELIGIBLE FOR BOTH THE CLASSIFICATION AND COG ALL 
THERAPEUTIC TRIALS. The AALL08B1 Institutional Pre-Induction Data Form should be completed 
within 72 hours of enrolling on this study. If the data is not completed in a timely fashion, the patient will 
be made inevaluable for the classification and therapeutic trials. Study enrollment must take place within 
five (5) calendar days of beginning protocol therapy. If enrollment takes place before starting therapy, the 
date protocol therapy is projected to start must be no later than five (5) calendar days after enrollment. 


 
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Systemic chemotherapy must start within 72 hours of initial intrathecal (IT) therapy specified in 
Section 4.4.   
 
3.1.5 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.1.6 
Treatment Assignment (Callback) 
The Callback CRF must be submitted for all patients in order to obtain a post-Induction treatment 
assignment. Note: In order to complete this CRF, the MLL gene rearrangement status must have been 
previously entered into eRDE. The Callback CRF should be submitted when the patient’s counts have 
recovered and he/she is ready to proceed to Induction Intensification (Day 1 Week 6 of therapy). All 
patients with MLL-G (SR) will be assigned to Arm A; all patients (in the US and Canada, see 
Section 3.1.7 below) with MLL-R (IR and HR) will be assigned to Arm C. Week 6 therapy must begin 
within 5 days of treatment assignment.  
 
3.1.7 
Institutional Participation 
This study is open to COG member sites in the US and Canada for the lestaurtinib efficacy phase. Patients 
from sites outside the US and Canada can enroll on the study but if they are found to be MLL-R are not 
eligible to continue on study post-Induction (lestaurtinib is not available for distribution outside of the US 
and Canada). 
 
3.2 
Patient Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy posted 5/11/01). All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record which will serve 
as the source document for verification at the time of audit.  
 
3.2.1 
Classification Study 
Patients must be enrolled on a COG ALL Classification Study (AALL08B1) prior to enrollment on 
AALL0631. 
 
3.2.2 
Age 
Patients must be < 366 days of age at the time of diagnosis; for neonates in the first month of life, patients 
must be > 36 weeks gestational age at the time of diagnosis. 
 
3.2.3 
Diagnosis 
 
3.2.3.1 
Patients must be newly diagnosed with acute lymphoblastic leukemia (ALL) or acute undifferentiated 
leukemia (AUL). Patients with T-cell ALL are eligible. Patients with bilineage or biphenotypic acute 
leukemia are eligible, provided the morphology and immunophenotype are predominately lymphoid. 
 
3.2.3.2 
Patients with mature B-cell ALL or acute myelogenous leukemia (AML) are NOT eligible. 
 
3.2.3.3 
Patients with Down syndrome are NOT eligible. 
 


 
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3.2.4 
Prior Therapy 
Patients must be previously untreated with the exception of steroids and intrathecal chemotherapy. No 
other systemic chemotherapy may have been administered. Patients receiving prior steroid therapy are 
eligible for study. Any amount of steroid pretreatment will not affect initial Induction assignment as long 
as the patient meets all other eligibility criteria. IT chemotherapy per protocol is allowed for patient 
convenience at the time of the diagnostic bone marrow or venous line placement to avoid second lumbar 
puncture. (Note: the CNS status must be determined based on a sample obtained prior to administration of 
any systemic or intrathecal chemotherapy, except for steroid pretreatment as discussed in Section 4.1.1.) 
Systemic chemotherapy must begin within 72 hours of this IT therapy. 
 
3.2.5 
Regulatory 
 
3.2.5.1 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.5.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 


 
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4.0 
TREATMENT PLAN 
 
 
 
4.1 
Overview 
All patients will be treated with a common 5-week Induction course after enrollment, as detailed in 
Section 4.4. Based on age at diagnosis and MLL gene rearrangement status, patients will be stratified into 
risk groups as follows: 
 
Standard Risk (SR):  
MLL-G (germline, or non-rearranged) 
 
Intermediate Risk (IR): MLL-R (rearranged), age ≥ 90 days at diagnosis 
 
High Risk (HR): 
MLL-R, age < 90 days at diagnosis 
 
SR patients will be non-randomly assigned to receive chemotherapy alone as detailed in Section 4.5. 
There will be some patients for whom MLL status is indeterminate. These patients are to be taken off 
study. 
 
During the initial safety/activity phase, IR and HR patients who enroll at institutions other than those 
listed on the AALL0631 protocol website (COG Phase I/Pilot Consortium plus additional institutions) or 
who enroll during periods where lestaurtinib is unavailable due to toxicity evaluations, will receive 
chemotherapy alone as detailed in Section 4.6. Please note that IR/HR patient transfers to an institution 
listed on the AALL0631 protocol website are allowed, if the patient’s family wishes to receive 
lestaurtinib. IR and HR patients who enroll at one of the institutions listed on the AALL0631 protocol 
website will be assigned to receive a combination of chemotherapy and lestaurtinib as detailed in 
Section 4.7, with the dose of lestaurtinib determined according to Section 4.2. The safety/activity phase 
will be done separately and independently for IR and HR patients. 
 
When the safety/activity phase identifies a dose of lestaurtinib that is safe, tolerable and biologically 
active for the IR and HR arms, then the study will proceed to an efficacy phase for that arm. During the 
efficacy phase, IR and HR patients enrolled at institutions in the US and Canada will non-randomly be 
assigned to receive a combination of chemotherapy and lestaurtinib (at the dose identified in the 
safety/activity phase) as detailed in Section 4.7. 
 
Note: as of 01/28/11 the safety/activity phase for Intermediate Risk patients was completed, and the 
randomized efficacy phase began at DL2 (5 mg/kg/day). 
 
Note: as of 02/03/12, the safety/activity phase for High Risk patients was completed, and the randomized 
efficacy phase began at DL2 (4.25 mg/kg/day).  
 
4.1.1 
Definitions 
 
INITIAL WBC:  
The first WBC at the treating COG institution. If prior therapy (i.e., steroids) has been administered, then 
the initial WBC prior to therapy should be used. 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable 
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for 
surgery) for valid clinical, patient and family logistical, or facility,  procedure and/or anesthesia scheduling issues 
are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol).  


 
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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 patient meets all other eligibility requirements. The “presteroid” age of the patient 
will be used to determine risk classification (IR vs. HR) for MLL-R patients. Inhalational steroids are not 
considered as pretreatment. 
 
CNS LEUKEMIA AT DIAGNOSIS: 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the number 
of white blood cells (WBCs). 
 
CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or > 5/uL WBCs but negative by 
Steinherz/Bleyer algorithm: 
CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and 
CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer 
algorithm (see below). 
 
CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical signs of CNS 
leukemia: 
CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm (see below); 
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 (Steinherz/Bleyer 
algorithm): 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and contains 
≥ 5 WBC/μL and blasts, the following algorithm should be used to distinguish between CNS2 and CNS3 
disease: 
 
 
CSF WBC    >    2   X  Blood WBC 
 
 
CSF RBC  
 
Blood RBC 
 
A patient with CSF WBC ≥ 5/μL, CSF RBC ≥ 10/μL, and cytospin positive for blasts, whose CSF 
WBC/RBC ratio is at least 2 X greater than the blood WBC/RBC ratio, has CNS3b disease at diagnosis. 
Otherwise, the patient has CNS2c disease. 
 
Example: CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 3.0 X 
106/μL: 
 
  60      =   0.04   >   2 X     46000      = 0.015    (patient has CNS3b disease) 
 
1500  
3.0 X 106 
 


 
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TESTICULAR LEUKEMIA AT DIAGNOSIS:  
Unilateral or bilateral testiculomegaly. Biopsy is required if clinical findings are equivocal or suggestive 
of hydrocele or a non-leukemic mass. 
 
BONE MARROW STATUS: 
M1: < 5% lymphoblasts 
M2: 5 - 25% lymphoblasts 
M3: > 25% lymphoblasts. 
 
RELAPSE: Any recurrence of disease whether in marrow or extramedullary site. Relapse should be 
histopathologically confirmed. 
 
CNS Relapse: Positive cytomorphology and > 5 WBC/μL OR positive cytomorphology with CSF WBC 
0-4/μL on two successive occasions one month apart. If any CSF evaluation shows positive 
cytomorphology and < 5 WBC/μL, a second CSF evaluation is required in greater or equal to 4 weeks. 
Identification of leukemic clone in CSF by flow cytometry (TdT, CD19, CD10, etc) or FISH for 
diagnostic karyotypic abnormality is encouraged. 
 
Testicular Relapse: Must be documented by testicular biopsy, in the absence of concomitant bone marrow 
relapse. 
 
Bone Marrow Relapse: Patients with an M3 marrow at any point after the beginning of Re-Induction 
(Week 10). 
 
4.1.2 
Concomitant Medications Restrictions 
 
4.1.2.1 
Patients cannot receive any non-protocol chemotherapy or investigational therapy while on this study. 
 
4.1.2.2 CYP3A4/5 Inhibitors:  
Lestaurtinib is metabolized by the cytochrome P450 isoform CYP3A4/5. Potent inhibitors of CYP3A4/5 are 
likely to inhibit lestaurtinib metabolism and increase systemic exposure. Therefore, concomitant treatment 
with lestaurtinib and the following medications should be avoided: azole antifungals (e.g., fluconazole and 
voriconazole), cyclosporine, erythromycin, clarithromycin, troleandomycin, HIV (human immunodeficiency 
virus) protease inhibitors, and nefazodone (see Appendices I and II for additional details).  
 
4.1.2.3 CYP3A4/5 Inducers: 
It is also likely that inducers of CYP3A4/5, such as carbamazapine, dexamethasone, rifampin, phenobarbital, 
phenytoin and St. John’s Wort will reduce the plasma exposure to lestaurtinib. Concomitant administration of 
these drugs is also discouraged, except for dexamethasone as prescribed in the treatment regimen (see 
Appendix II for additional details).  
 


 
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4.2 
Safety/Activity Phase (Completed) 
 
4.2.1 
Schematic 
 
 
 
< 90 days old 
(mg/kg/day divided BID) 
≥ 90 days old 
(mg/kg/day divided BID) 
DL 0 
2.75 
3 
DL 1 
3.5 
4 
DL 2 
4.25 
5 
 
4.2.2 
Definition of Dose-Limiting Toxicity (DLT) 
Defining DLT of a novel agent added to a backbone of intensive chemotherapy is challenging, due to the 
high baseline toxicity rate associated with the chemotherapy alone. This is particularly true for infants, 
who have been especially vulnerable to chemotherapy-related toxicities. The major toxicity noted with the 
chemotherapy backbone (P9407 Cohort 3) was infectious toxicity associated with chemotherapy-induced 
myelosuppression. Grade 3 or greater infectious toxicity was reported in the majority of patients, and 
Grade 3 or greater myelosuppression was universal, during Phase I (defined as Weeks 1-7 of therapy, 
including Induction and Induction Intensification blocks), but both were significantly less common after 
Phase I. Most of the post-Phase I serious infectious toxicities and myelosuppression were associated with 
high dose cytarabine in Consolidation. Brief (< 2 weeks) delays in the scheduled start of subsequent 
chemotherapy courses due to delayed neutrophil and/or platelet recovery was common, but it was rare for 
chemotherapy-induced myelosuppression to cause delays of 3 weeks of greater. Non-hematologic and 
non-infectious toxicities that were severe (≥ Grade 3) and occurred with a frequency of ≥ 10% included: 
stomatitis (24% for all phases of therapy, mostly in Phase I), diarrhea (17% for all phases, mostly in 
Phase I), AST/ALT elevation (17% for all phases, about half in Phase I) and neurologic toxicities (10%, 
about one-third in Phase I), which were primarily seizures related to intrathecal or high dose methotrexate 
and peripheral neuropathy related to vincristine. In addition to these “serious and unexpected” toxicities, 
other toxicities are expected in infants undergoing intensive chemotherapy, including constitutional 
symptoms, transient laboratory abnormalities (e.g., electrolytes, liver function tests, and coagulation 
tests), transient hypertension or hypotension, selected skin toxicities (ulceration/rashes in the diaper area, 
petechiae/purpura), and tumor lysis syndrome. The major toxicities that were attributable to lestaurtinib 
during previous clinical trials in children and adults have included nausea and vomiting (primarily in 
adults), and asymptomatic, transient transaminase elevation (primarily in children). 
 
DL 1
N=5
DLT
FLT3 inhib
at DL 1?
DL 0
N=5
DLT
Proceed 
at DL 0
DL 2
N=5
DLT
Proceed 
at DL 2
Y
N
Y
Y
N
STOP
FLT3 inhib
at DL 0?
FLT3 inhib
at DL 2?
Proceed 
at DL 1
Consider amendment for 
further dose escalation
FLT3 inhib
at DL 0?
Consider amendment for 
further dose de-escalation
N
Y
HR
IR
>1/5
0/5 or 
1/5
0/5 or 
1/5
>1/5
N
STOP
0/5 or 
1/5
>1/5


 
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Since toxicities that cause therapy omissions or delays are the most significant in terms of potentially 
compromising patient outcome, and are the most relevant to the determination of whether the addition of 
a novel agent to a chemotherapy regimen is “tolerable”, we will use this criterion as the basis for a 
definition of lestaurtinib-related DLT. With a few exceptions, post-Induction toxicities of sufficient 
severity to cause prolonged (greater than 1 week) omissions or delays in therapy on P9407 Cohort 3 were 
uncommon. Exceptions include: febrile neutropenia/infection, myelosuppression, mucositis and diaper 
area skin ulceration, where omissions or delays of greater than 1 week were common, but omissions or 
delays of greater than 2-3 weeks were rare. 
 
A lestaurtinib-related DLT is therefore defined as follows: 
 
 
Any Grade 4 non-hematologic (i.e., excluding blood/bone marrow) toxicity that occurs after the first 
dose of lestaurtinib and is at least possibly related to lestaurtinib, with the following specific 
exceptions: 
o Febrile neutropenia or infection 
o Fever 
o Metabolic/laboratory abnormalities (see CTCAE v4 category Investigations) that resolve to 
≤ Grade 2 within: 
 
14 days, for ALT/SGPT, AST/SGOT, alkaline phosphatase 
 
7 days, for amylase, lipase, total bilirubin 
 
48 hours for all others 
o Coagulation abnormalities (see CTCAE v4 category Investigations): INR, PTT or fibrinogen AEs 
that resolve to ≤ Grade 2 within 48 hours 
 
 
Any Grade 3 non-hematologic (i.e., excluding blood/bone marrow) toxicity that occurs after the first 
dose of lestaurtinib, is at least possibly attributable to lestaurtinib and results in omission or delay of 
the beginning of the subsequent course of chemotherapy for greater than 7 days, with the following 
specific exceptions: 
o Febrile neutropenia or infection 
o Mucositis or diaper area skin ulceration must result in omission or delay of the beginning of the 
subsequent course of chemotherapy for greater than 14 days to be considered a DLT 
 
 
No hematologic toxicity will be considered a DLT while a patient is receiving scheduled doses of 
lestaurtinib. After completion of a lestaurtinib course, persistent Grade 3 or greater neutrophils and/or 
platelets that results in a greater than 21 day delay in the start of the following course of 
chemotherapy will be considered a DLT (unless the delay in neutrophil or platelet recovery is due to 
another clearly identifiable factor such as leukemic relapse or documented myelosuppressive 
infection). 
 
The definitions of lestaurtinib-related DLTs are based in part on the duration of delays in the beginning of 
subsequent courses of chemotherapy. If the actual start date is later than the expected start date as listed in 
the table below, then the course would be delayed by the difference between the actual and expected start 
dates. 


 
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Course 
Expected Start Date 
Re-Induction (Week 10 VCR/DAUN/CPM/PEG-ASP) 
21 days AFTER Week 8, Day 15 
Consolidation (Week 13 HD MTX) 
28 days AFTER Week 10, Day 1 
Consolidation (Week 17 HD ARAC/PEG-ASP) 
21 days AFTER Week 15, Day 15 
Continuation I (Week 20 VCR/DEX) 
21 days AFTER Week 17, Day 29 
Continuation I (Week 27 ETOP/CPM) 
21 days AFTER Week 24, Day 1 
Continuation I (Week 30 HD ARAC/PEG-ASP) 
21 days AFTER Week 27, Day 22 
Continuation I (Week 40 ETOP/CPM) 
21 days AFTER Week 37, Day 1 
Continuation I (Week 43 HD ARAC/PEG-ASP) 
21 days AFTER Week 40, Day 22 
 
NOTE: During the safety/efficacy phase, a study co-chair should be notified in the event of a suspected 
lestaurtinib-related DLT. 
 
4.2.3 
Determining a Safe and Active Dose of Lestaurtinib 
The safety/activity phase will proceed with independent arms for IR and HR patients. The presence or 
absence of a DLT will be determined for each patient during the first 2 courses of lestaurtinib (i.e., during 
the Induction Intensification and Re-Induction phases). Cohorts of 5 patients will be enrolled in each of 
the 2 strata (i.e., < 90 days and > 90 days) at the starting dose level 1 (DL1). Any patient who experiences 
a DLT after receiving at least one dose of lestaurtinib on study will be considered evaluable for toxicity of 
lestaurtinib. A patient will be considered inevaluable for toxicity of lestaurtinib and will be replaced if 
he/she is: (1) removed from protocol therapy for a reason other than a DLT prior to receiving at least 75% 
of the prescribed lestaurtinib doses during the first 2 courses of lestaurtinib (i.e., during the Induction 
Intensification and Re-Induction phases); or (2) does not experience a DLT and receives less than 75% of 
the prescribed lestaurtinib doses during the first 2 courses of lestaurtinib (i.e., during the Induction 
Intensification and Re-Induction phases). As each patient proceeds through treatment on and recovery 
from Induction Intensification and Re-Induction, rapid reporting via eRDES of toxicity data and actual 
number of prescribed lestaurtinib doses received will be required. After the fifth evaluable patient in a 
cohort recovers from the Re-Induction phase (i.e., the patient is ready to begin Consolidation/Week 13), 
toxicity data will be finalized for that cohort. The study committee will then convene a formal conference 
call review and will make a consensus decision regarding dose changes as shown in the schematic in 
Section 4.2.1. Accrual to the study will continue between the time the fifth patient of a cohort enrolls and 
when the committee decision on dose adjustment has been made. IR and HR patients who enroll during 
these periods of toxicity evaluation for their respective arms will receive chemotherapy only as detailed in 
Section 4.6. 
 
Once a tolerable dose has been identified for an arm, the study will proceed to the efficacy phase for that 
arm at that dose level only if adequate FLT3 inhibitory plasma levels have been achieved in at least 3 of 
the patients treated at that dose level (for each patient, “adequate” will be defined as ≥ 90% FLT3 PIA in 
a majority of available trough samples – see Section 14.0 for details). If DL0 or DL1 is the MTD and 
adequate FLT3 inhibitory activity is not seen, then the study of lestaurtinib will stop for that arm. If DL2 
is well-tolerated but adequate FLT3 inhibitory activity is not seen, then consideration will be given to 
amending the trial for that arm to allow further dose escalation. If DL0 is not tolerated but adequate FLT3 
inhibitory activity is seen, then consideration will be given to amending the trial for that arm to allow 
further dose de-escalation. 
 
It is expected that the IR stratum will accrue faster than the HR stratum, and will therefore proceed to the 
randomized phase first (assuming a tolerable and active dose of lestaurtinib is identified). If a tolerable 
and active dose cannot be identified for the IR stratum, the study will close, since the small number of 
patients in the HR stratum would be insufficient to power the efficacy phase. If, on the other hand, a 
tolerable and active dose can be identified for the IR cohort, but not for the HR cohort, the study of 


 
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lestaurtinib will continue with the IR stratum only until accrual goals (n = 162 evaluable MLL-R infants) 
are met. 
 
Note: as of 01/28/11 the safety/activity phase for Intermediate Risk patients was completed, and the 
randomized efficacy phase began at DL2 (5 mg/kg/day). 
 
Note: as of 02/03/12, the safety/activity phase for High Risk patients was completed, and the randomized 
efficacy phase began at DL2 (4.25 mg/kg/day).  
 
4.3 
Efficacy Phase 
Prior to Amendment #5: 
IR and HR patients will be eligible for the randomized efficacy phase once a tolerable and biologically 
active dose has been identified for their respective stratum. Based on the randomization, patients will be 
assigned to post-Induction therapy with either chemotherapy alone (see Section 4.6) or chemotherapy plus 
lestaurtinib (see Section 4.7). 
 
Revised Efficacy Phase as of Amendment #5: 
IR and HR patients (at institutions in the US and Canada) will be eligible for the lestaurtinib efficacy 
phase. Patients will be non-randomly assigned to post-Induction therapy with chemotherapy plus 
lestaurtinib (see Section 4.7). 
 
Arm C Continuation II Updates: 
Lestaurtinib will no longer be administered with Continuation II therapy as of Amendment #5. All newly 
enrolled patients and patients that have not yet reached Continuation II will cease lestaurtinib treatment 
following Continuation I. Patients currently receiving Continuation II as of Amendment #5 will cease 
lestaurtinib as of the activation of the amendment.  
 
Note: as of 01/28/11 the safety/activity phase for Intermediate Risk patients was completed, and the 
randomized efficacy phase began at DL2 (5 mg/kg/day). 
 
Note: as of 02/01/12, the safety/activity phase for High Risk patients was completed, and the randomized 
efficacy phase began at DL2 (4.25 mg/kg/day).  
 


 
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4.4 
Induction Chemotherapy: Weeks 1-5  
All patients will receive the same Induction chemotherapy with regard to agents and schedule; however, 
patients ≥ 7 days and < 6 months old at diagnosis will receive an 11% dose reduction for all non-
intrathecal agents (see Section 4.4.2 below) and patients < 7 days old at diagnosis will receive an 
additional 25% dose reduction for all non-intrathecal agents (see Section 4.4.3 below). 
 
4.4.1 
Induction Chemotherapy for Patients ≥ 6 Months Old at Diagnosis 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.125 mg/m2/dose on Days 8, 15, 22 and 29 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
22.5 mg/m2/dose Days 8 & 9 
 
E. coli L-asparaginase  (e.g., Elspar, Kidrolase): IM 
7500 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
If E.coli L-asparaginase (i.e., Elspar or Kidrolase) is not available, please use Erwinia asparaginase 
(Erwinaze) as follows:  
Erwinia L-asparaginase (Erwinaze): IM 
30,000 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
PredniSONE: PO/NG 
45 mg/m2/day divided TID on Days 1-7 
Give methylprednisolone IV at 80% of the prednisone dose, if needs to be given IV instead of PO/NG 
 
Dexamethasone: PO/NG/IV 
4.5 mg/m2/day divided TID on Days 8-28 
 
Cytarabine: IV over 30 minutes 
56.25 mg/m2/dose Days 8-21 
 
Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
 
Age-based dosing: 
 
Day 1* 
MTX only 
< 1 year  
              ≥ 1 year 
MTX: 6 mg 
 
MTX: 8 mg 
Day 15 
HC and ARAC 
< 1 year  
              ≥ 1 year 
HC: 12 mg 
 
HC: 16 mg 
ARAC: 15 mg  
ARAC: 20 mg 
Day 29 
MTX and HC 
< 1 year  
              ≥ 1 year 
MTX: 6 mg 
 
MTX: 8 mg 
HC: 12 mg 
 
HC: 16 mg 
* Day 1 IT treatment may be given at the time of the diagnostic lumbar puncture. 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 


 
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4.4.2 
Induction Chemotherapy for Patients ≥ 7 Days and < 6 Months Old at Diagnosis 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1 mg/m2/dose on Days 8, 15, 22 and 29 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
20 mg/m2/dose Days 8 and 9 
 
E. coli L-asparaginase (e.g., Elspar, Kidrolase): IM 
6675 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
If E.coli L-asparaginase (i.e., Elspar or Kidrolase) is not available, please use Erwinia asparaginase 
(Erwinaze) as follows:  
Erwinia L-asparaginase (Erwinaze): IM 
27,000 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
PredniSONE: PO/NG 
40 mg/m2/day divided TID on Days 1-7 
Give methylprednisolone IV at 80% of the prednisone dose, if needs to be given IV instead of PO/NG 
 
Dexamethasone: PO/NG/IV 
4 mg/m2/day divided TID on Days 8-28 
 
Cytarabine: IV over 30 minutes 
50 mg/m2/dose Days 8-21 
 
Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
 
Day 1* 
MTX only 
MTX: 6 mg 
Day 15 
HC and ARAC 
HC: 12 mg 
ARAC: 15 mg 
Day 29 
MTX and HC 
MTX: 6 mg 
HC: 12 mg 
* Day 1 IT treatment may be given at the time of the diagnostic lumbar puncture. 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 
 


 
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4.4.3 
Induction Chemotherapy for Patients < 7 Days Old at Diagnosis 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
0.75 mg/m2/dose on Days 8, 15, 22 and 29 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
15 mg/m2/dose Days 8 and 9 
 
E. coli L-asparaginase (e.g., Elspar, Kidrolase): IM 
5000 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
If E.coli L-asparaginase (i.e., Elspar or Kidrolase) is not available, please use Erwinia asparaginase 
(Erwinaze) as follows:  
Erwinia L-asparaginase (Erwinaze): IM 
20,000 International units/m2/dose on Days 15, 18, 22, 25, 29 and 33 
 
PredniSONE: PO/NG 
30 mg/m2/day divided TID on Days 1-7 
Give methylprednisolone IV at 80% of the prednisone dose, if needs to be given IV instead of PO/NG 
 
Dexamethasone: PO/NG/IV 
3 mg/m2/day divided TID on Days 8-28 
 
Cytarabine: IV over 30 minutes 
37.5 mg/m2/dose Days 8-21 
 
Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
 
Day 1* 
MTX only 
MTX: 6 mg 
Day 15 
HC and ARAC 
HC: 12 mg 
ARAC: 15 mg 
Day 29 
MTX and HC 
MTX: 6 mg 
HC: 12 mg 
* Day 1 IT treatment may be given at the time of the diagnostic lumbar puncture. 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 
 
The therapy delivery maps (TDMs) for Induction are on the next 3 pages. The TDM numbered 4.4.4 is for 
patients ≥ 6 months old at diagnosis; the TDM numbered 4.4.5 is for patients ≥ 7 days and < 6 months old 
at diagnosis; the TDM numbered 4.4.6 is for patients < 7 days old at diagnosis. 
 
Following completion of Induction, the next course (Induction Intensification, Section 4.5.1 or 4.6.1 or 
4.7.1) starts on Day 36 or when counts recover and mucositis and/or diaper area skin ulceration ≥ Grade 3 
has improved to Grade 2 or less (whichever occurs later). 
 


 
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  Version Date: 04/05/13                                                                                                                 Page 35 
 
 
4.4.4 
Induction (for patients ≥ 6 months old at diagnosis) 
Induction lasts 5 weeks (35 days); this Therapy Delivery Map is on one (1) page. 
 
______________________________     _______________ 
           Patient name or initials                           DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
1.125 mg/m2/dose 
Days 8, 15, 22, 29 
+ Or infusion via minibag as 
per institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T bili 
d. CSF cell count, 
cytospin 
e. Serum IgG 
f. Echo or MUGA 
g. CrCl or GFR 
h. Local BM eval 
i. BM per AALL08B1 
j. PB for Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
k. OPTIONAL BM for 
flow MRD, molecular 
MRD & resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
DAUNOrubicin (DAUN) 
IV over 30 min 22.5 mg/m2/dose 
Days 8 & 9 
 
E. coli L-asparginase (E. 
coli L-ASP) 
IM 
7500 International units/m2/dose 
Days 15, 18, 22, 25, 
29, 33 
Erwinia L-asparaginase 
(Erwinaze): 30,000 
International units/m2/dose  
PredniSONE (PRED) 
PO/NG 
(may give IV) 
45 mg/m2 divided TID 
Days 1-7 
See Section 4.4.1 for IV 
administration guidelines 
Dexamethasone (DEX) 
PO/NG 
(may give IV) 
4.5 mg/m2 divided TID 
Days 8-28 
 
Cytarabine (ARAC) 
IV over 30 min 56.25 mg/m2/dose 
Days 8-21 
 
Intrathecal Therapy: 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 6 mg 
 
HC: 12 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 16 mg 
 
ARAC: 20 mg 
Days 1*: MTX only 
Day 15: HC & ARAC 
Day 29: MTX & HC 
Note age-based dosing 
 
* Day 1 IT MTX may be 
given at the time of 
diagnostic lumbar puncture 
 
See Section 5.7 regarding IT 
dose reduction for pts 
requiring Ommaya reservoir 
administration 
 
Therapy Delivery Map  
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
____mg 
DAUN 
____mg 
L-ASP 
____IU 
PRED 
___mg ___mg ___mg 
DEX 
___mg ___mg ___mg 
ARAC 
____mg 
IT Therapy 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
1* 
 
 
 
___mg ___mg ___mg 
 
 
___mg (MTX) (a, b, c, d, e, f, g, 
h, i, j, k)^ 
 
 
 
2 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
3 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
4 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
5 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
6 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
7 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
2 
8 
____mg 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
b 
 
 
 
9 
 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
10 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
11 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
12 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
13-14 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
3 
15 
____mg 
 
____IU 
 
___mg ___mg ___mg 
____mg 
___mg (HC) 
___mg (ARAC) 
b, c, d, e  
 
 
 
16 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
17 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
18 
 
 
____IU 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
19 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
20-21 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
4 
22 
____mg 
 
____IU 
 
___mg ___mg ___mg 
 
 
b 
 
 
 
23-24 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
25 
 
 
____IU 
 
___mg ___mg ___mg 
 
 
 
 
 
 
26-28 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
5 
29 
____mg 
 
____IU 
 
 
 
___mg (MTX) 
___mg (HC) 
b, c, d, e 
 
 
 
30-32 
 
 
 
 
 
 
 
 
 
 
 
33 
 
 
____IU 
 
 
 
 
 
 
 
 
36 
Start next course (Induction Intensification, Section 4.5.1 or 4.6.1 or 4.7.1) on Day 36 or when blood count parameters are met and 
mucositis and/or diaper area skin ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 
Comments may be documented on a separate page. 
* Day 1 IT MTX may be given at the time of diagnostic lumbar puncture 
^ Pretreatment observations (see Section 7.1) may fulfill Day 1 requirements 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
  Version Date: 04/05/13                                                                                                                 Page 36 
 
 
4.4.5 
Induction (for patients ≥ 7 days and < 6 months old at diagnosis) 
Induction lasts 5 weeks (35 days); this Therapy Delivery Map (TDM) is on one (1) page. This TDM 
reflects an 11% dose reduction in all non-intrathecal agents due to age < 6 months old at diagnosis. 
 
 
____________________________     _______________ 
           Patient name or initials                        DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
1 mg/m2/dose 
Days 8, 15, 22, 29 
+ Or infusion via minibag as 
per institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T bili 
d. CSF cell count, 
cytospin 
e. Serum IgG 
f. Echo or MUGA 
g. CrCl or GFR 
h. Local BM eval 
i. BM per AALL08B1 
j. PB for Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
k. OPTIONAL BM for 
flow MRD, molecular 
MRD & resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
DAUNOrubicin 
(DAUN) 
IV over 30 min 20 mg/m2/dose 
Days 8 & 9 
 
E. coli L-asparginase 
(E. coli L-ASP) 
IM 
6675 International units/m2/dose 
Days 15, 18, 22, 25, 29, 33 Erwinia L-asparaginase 
(Erwinaze): 27,000 
International units/m2/dose  
PredniSONE (PRED) 
PO/NG 
(may give IV) 
40 mg/m2/day divided TID 
Days 1-7 
See Section 4.4.2 for IV 
administration guidelines 
Dexamethasone (DEX) 
PO/NG 
(may give IV) 
4 mg/m2/day divided TID 
Days 8-28 
 
Cytarabine (ARAC) 
IV over 30 min 50 mg/m2/dose 
Days 8-21 
 
Intrathecal Therapy: 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX: 6 mg 
HC: 12 mg 
ARAC: 15 mg 
Days 1*: MTX only 
Day 15: HC & ARAC 
Day 29: MTX & HC 
Note age-based dosing 
 
* Day 1 IT MTX may be 
given at the time of diagnostic 
lumbar puncture 
 
See Section 5.7 regarding IT 
dose reduction for pts 
requiring Ommaya reservoir 
administration 
 
Therapy Delivery Map  
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
____mg 
DAUN 
____mg 
L-ASP 
____IU 
PRED 
___mg ___mg ___mg 
DEX 
___mg ___mg ___mg 
ARAC 
____mg 
IT Therapy 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
1* 
 
 
 
___mg ___mg ___mg 
 
 
___mg (MTX) (a, b, c, d, e, f, g, 
h, i, j, k)^ 
 
 
 
2 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
3 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
4 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
5 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
6 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
7 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
2 
8 
____mg 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
b 
 
 
 
9 
 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
10 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
11 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
12 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
13-14 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
3 
15 
____mg 
 
____IU 
 
___mg ___mg ___mg 
____mg 
___mg (HC) 
___mg (ARAC) 
b, c, d, e  
 
 
 
16 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
17 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
18 
 
 
____IU 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
19 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
20-21 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
4 
22 
____mg 
 
____IU 
 
___mg ___mg ___mg 
 
 
b 
 
 
 
23-24 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
25 
 
 
____IU 
 
___mg ___mg ___mg 
 
 
 
 
 
 
26-28 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
5 
29 
____mg 
 
____IU 
 
 
 
___mg (MTX) 
___mg (HC) 
b, c, d, e 
 
 
 
30-32 
 
 
 
 
 
 
 
 
 
 
 
33 
 
 
____IU 
 
 
 
 
 
 
 
 
36 
Start next course (Induction Intensification, Section 4.5.1 or 4.6.1 or 4.7.1) on Day 36 or when blood count parameters are met and 
mucositis and/or diaper area ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 
Comments may be documented on a separate page. 
* Day 1 IT MTX may be given at the time of diagnostic lumbar puncture 
^ Pretreatment observations (see Section 7.1) may fulfill Day 1 requirements 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
  Version Date: 04/05/13                                                                                                                 Page 37 
 
 
4.4.6 
Induction (for patients < 7 days old at diagnosis) 
Induction lasts 5 weeks (35 days); this Therapy Delivery Map is on one (1) page. This TDM reflects a 
25% dose reduction in all non-intrathecal agents due to age < 7 days old at diagnosis. 
 
 
____________________________     _______________ 
           Patient name or initials                        DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
0.75 mg/m2/dose 
Days 8, 15, 22, 29 
+ Or infusion via minibag as 
per institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T bili 
d. CSF cell count, 
cytospin 
e. Serum IgG 
f. Echo or MUGA 
g. CrCl or GFR 
h. Local BM eval 
i. BM per AALL08B1 
j. PB for Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
k. OPTIONAL BM for 
flow MRD, molecular 
MRD & resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
DAUNOrubicin 
(DAUN) 
IV over 30 min 15 mg/m2/dose 
Days 8 & 9 
 
E. coli L-asparginase 
(E. coli L-ASP) 
IM 
5000 International units/m2/dose 
Days 15, 18, 22, 25, 29, 33 Erwinia L-asparaginase 
(Erwinaze): 20,000 
International units/m2/dose  
PredniSONE (PRED) 
PO/NG 
(may give IV) 
30 mg/m2/day divided TID 
 
Days 1-7 
See Section 4.4.3 for IV 
administration guidelines 
Dexamethasone (DEX) 
PO/NG 
(may give IV) 
3 mg/m2/day divided TID 
Days 8-28 
 
Cytarabine (ARAC) 
IV over 30 min 37.5 mg/m2/dose 
Days 8-21 
 
Intrathecal Therapy: 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
MTX: 6 mg 
HC: 12 mg 
ARAC: 15 mg 
Days 1*: MTX only 
Day 15: HC & ARAC 
Day 29: MTX & HC 
Note age-based dosing 
 
* Day 1 IT MTX may be given 
at the time of diagnostic 
lumbar puncture 
 
See Section 5.7 regarding IT 
dose reduction for pts 
requiring Ommaya reservoir 
administration 
 
Therapy Delivery Map  
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
____mg 
DAUN 
____mg 
L-ASP 
____IU 
PRED 
___mg ___mg ___mg 
DEX 
___mg ___mg ___mg 
ARAC 
____mg 
IT Therapy 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
1* 
 
 
 
___mg ___mg ___mg 
 
 
___mg (MTX) (a, b, c, d, e, f, g, 
h, i, j, k)^ 
 
 
 
2 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
3 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
4 
 
 
 
___mg ___mg ___mg  
 
 
 
 
 
 
 
5 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
6 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
 
7 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
2 
8 
____mg 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
b 
 
 
 
9 
 
____mg 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
10 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
11 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
12 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
13-14 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
3 
15 
____mg 
 
____IU 
 
___mg ___mg ___mg 
____mg 
___mg (HC) 
___mg (ARAC) 
b, c, d, e  
 
 
 
16 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
17 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
18 
 
 
____IU 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
 
19 
 
 
 
 
___mg ___mg ___mg  
____mg 
 
 
 
 
 
20-21 
 
 
 
 
___mg ___mg ___mg 
____mg 
 
 
 
 
4 
22 
____mg 
 
____IU 
 
___mg ___mg ___mg 
 
 
b 
 
 
 
23-24 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
 
25 
 
 
____IU 
 
___mg ___mg ___mg 
 
 
 
 
 
 
26-28 
 
 
 
 
___mg ___mg ___mg 
 
 
 
 
 
5 
29 
____mg 
 
____IU 
 
 
 
___mg (MTX) 
___mg (HC) 
b, c, d, e 
 
 
 
30-32 
 
 
 
 
 
 
 
 
 
 
 
33 
 
 
____IU 
 
 
 
 
 
 
 
 
36 
Start next course (Induction Intensification, Section 4.5.1 or 4.6.1 or 4.7.1) on Day 36 or when blood count parameters are met and 
mucositis and/or diaper area skin ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 
Comments may be documented on a separate page. 
* Day 1 IT MTX may be given at the time of diagnostic lumbar puncture 
^ Pretreatment observations (see Section 7.1) may fulfill Day 1 requirements 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 38 
4.5 
Post-Induction Arm A [for SR Patients (MLL-G)] 
To avoid diaper area skin ulceration, especially at Weeks 6 and 7 of HD MTX, please see Appendix I, 
section on Perineal Irritation.  
 
4.5.1 
Induction Intensification: Weeks 6-9 (Arm A) 
 
Begin Induction Intensification when ANC > 750/µL and platelets > 75,000/µL and mucositis 
and/or diaper area skin ulceration ≥ Grade 3 has improved to Grade 2 or less.   
 
To begin Day 8 HD MTX, mucositis or diaper area skin ulceration ≥ Grade 3 must have 
improved to Grade 2 or less. 
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines. 
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO 
q6 hours as long as the T=24 hr methotrexate level is < 150µM, and will continue at this dose as long as 
the T=42 hr and T=48 hr methotrexate levels are < 1µM and < 0.4µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
 
Triple Intrathecal Chemotherapy: IT Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Days 1 & 8; deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19. 


 
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Version Date: 04/05/13                                                                                                                 Page 39 
 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19 
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion (CI) IV over 4 hours following each dose of cyclophosphamide (2 total doses per 
day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 20 and until ANC > 1500/µL x 2 days post nadir. 
Administer undiluted by subcutaneous injection (preferred).  May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
The therapy delivery map (TDM) for Induction Intensification is on the next page. 
 
Following completion of Induction Intensification, the next course (Re-Induction, Section 4.5.2) starts on 
Day 29 or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs 
later). Patients must also be in morphologic remission in order to begin Re-Induction. 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 40 
 
 
4.5.1.1 Induction Intensification (ARM A: SR patients classified as MLL-G) 
Modified Induction Intensification is for SR patients (4 weeks/28 days) 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Induction Intensification when ANC > 750/µL and platelets > 75,000/µL and mucositis/diaper area skin ulceration ≥ Grade 3 has 
improved to Grade 2 or less. This Course lasts 28 days and this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High Dose Methotrexate 
(HD MTX) 
IV 
200 mg/m2 over 20 min 
THEN 3800 mg/m2 over 
remainder 24 hrs 
Days 1 & 8* 
4000 mg/m2 total in 24 hrs; see 
Section 4.5.1 for 
administration guidelines 
a. History, physical, ht/wt, 
BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, Cr/ 
AST/ALT/T bili 
d. Serum IgG 
e. CSF cell count, diff, 
cytospin 
f. Local BM eval 
g. OPTIONAL BM for flow 
MRD, molecular MRD 
& resistance 
mechanisms 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Leucovorin (LCV) 
IV/PO 
Start 15 mg/m2/dose q6 hrs 
@ T=42 hr 
Days 2 & 9 
See Section 4.5.1 for 
administration guidelines 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years)   Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 8 
Deliver ITT within 6 hrs of 
beginning IV MTX infusion 
 
Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring 
Ommaya reservoir administration 
Etoposide (ETOP) 
IV over 2 hrs 100 mg/m2/dose 
Days 15-19 
 
Cyclophosphamide 
(CPM) 
IV over 30 
min 
300 mg/m2/dose 
Days 15-19 
 
Mesna 
IV over 30 
min followed 
by CI 
150 mg/m2/dose with 
CPM followed by 
150 mg/m2/dose over 4 hrs 
daily (2 total doses/day) 
Days 15-19 
See Section 4.5.1 for infusion 
details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. on 
Day 20 
Continue until ANC 
> 1500/µL x 2 days post nadir; 
stop at least 48 hrs prior to 
next chemo cycle 
 
Therapy Delivery Map 
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
HD MTX 
__mg __mg 
LCV 
____mg 
ITT 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
ETOP 
____mg 
CPM 
____mg 
MESNA 
____mg ____mg 
G-CSF 
___mcg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
6 
1 
__mg __mg 
 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
 
 
 
a, b, c, d, e, f, g 
 
 
 
2 
 
____mg 
 
 
 
 
 
 
 
 
 
3-7 
 
 
 
 
 
 
 
 
 
 
7 
8* 
(__mg __mg)* 
 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
 
 
 
b, e 
 
 
 
9 
 
____mg 
 
 
 
 
 
 
 
 
 
10-14 
 
 
 
 
 
 
 
 
 
 
8 
15 
 
 
 
______mg 
______mg 
____mg ____mg 
 
b, d 
 
 
 
16 
 
 
 
______mg 
______mg 
____mg ____mg 
 
 
 
 
 
17 
 
 
 
______mg 
______mg 
____mg ____mg 
 
 
 
 
 
18 
 
 
 
______mg 
______mg 
____mg ____mg 
 
 
 
 
 
19 
 
 
 
______mg 
______mg 
____mg ____mg 
 
 
 
 
 
20 
 
 
 
 
 
 
____mcg  
 
 
 
21 
 
 
 
 
 
 
____mcg  
 
 
9 
22-28 
 
 
 
 
 
 
____mcg  
 
 
 
29 
Start next course (Re-Induction, Section 4.5.2) on Day 29 or when blood count parameters are met (whichever 
occurs later). 
 
 
 
 
 
 
 
 
Indicate last G-CSF if past Day 28 _________ 
 
Comments may be documented on a separate page. 
* In order to receive Day 8 HD MTX, mucositis or diaper area skin ulceration ≥ Grade 3 must have improved to Grade 2 or less. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 41 
4.5.2 
Re-Induction: Weeks 10-12 (Arm A) 
To begin Re-Induction, patients must be in morphologic remission. Patient must have ANC > 750/µL and 
platelets > 75,000/µL and have been off G-CSF at least 48 hours 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
0.05 mg/kg on Days 1 & 15 AND 0.03 mg/kg on Day 8 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
Days 1 & 2 
 
Dose is mg/kg/day based on age at diagnosis: 
< 6 months = 1.7 mg/kg/dose 
6 months to 8.99 months = 2.1 mg/kg/dose 
≥ 9 months = 2.6 mg/kg/dose 
 
Cyclophosphamide: IV over 30 minutes 
250 mg/m2/dose q12 hours x 4 total doses on Days 3 & 4 
 
Mesna: IV 
125 mg/m2/dose with each dose of cyclophosphamide over 30 minutes; then 125 mg/m2/dose continuous 
infusion IV over 4 hours following each dose of cyclophosphamide (4 total doses per day). 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 4 
 
Dexamethasone: PO/NG/IV 
10 mg/m2/day divided BID on Days 1-7 & 15-21 
 
Triple Intrathecal Chemotherapy: IT Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Days 1 & 15 ONLY 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 5 and until ANC > 1500/µL x 2 days post nadir. 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 42 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
The therapy delivery map (TDM) for Re-Induction is on the next page. 
 
Following completion of Re-Induction, the next course (Consolidation, Section 4.5.3) starts on Day 22 or 
when counts recover, G-CSF has been discontinued for at least 48 hours and mucositis and/or diaper area 
skin ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 43 
 
 
4.5.2.1 Re-Induction (ARM A: SR patients classified as MLL-G) 
Modified Re-Induction is for SR patients (3 weeks/21 days) 
 
______________________________  _____________________ 
                     Patient name or initials                             DOB 
Begin Re-Induction if patient is in morphologic remission; patient must have ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 
48 hrs. This Course lasts 21 days and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
0.05 mg/kg on Days 1 & 15 
AND 0.03 mg/kg on Day 8@ 
Days 1, 8@, 15 
+ Or infusion via minibag as 
per institutional policy 
@ Dose differs on Day 8 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN 
Cr/AST/ALT/ 
T bili 
d. Serum IgG 
e. CSF cell count, 
cytospin 
f. Local BM eval 
g. Echo or MUGA 
h. OPTIONAL BM 
for flow MRD, 
molecular MRD 
& resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
DAUNOrubicin (DAUN) 
IV over 30 min < 6 mos. = 1.7 mg/kg/dose 
6-8.99 mos.= 2.1 mg/kg/dose 
≥ 9 mos. = 2.6 mg/kg/dose 
Days 1 & 2 
Dosing based on age at 
diagnosis 
Cyclophosphamide (CPM) IV over 30 min 250 mg/m2/dose q12 hrs x 4 
total doses 
Days 3 & 4 
 
Mesna 
IV over 30 min 
followed by CI 
125 mg/m2/dose with CPM 
followed by 125 mg/m2/dose 
over 4 hrs (4 total doses/day) 
Days 3 & 4 
See Section 4.5.2 for infusion 
details 
Pegaspargase (PEG-ASP) 
IM 
2500 International 
units/m2/dose x 1 dose 
Day 4 ONLY 
 
Dexamethasone (DEX) 
PO/NG/IV 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, 
divided BID 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 15 ONLY Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring 
Ommaya reservoir administration 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. on Day 
5; cont. w/o regard 
to VCR or ITs 
Continue until ANC > 1500/µL 
x 2 days post nadir; stop at least 
48 hrs prior to next chemo cycle 
Therapy Delivery Map 
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
D1 &15 
____mg 
D8 ____@ 
DAUN 
____mg 
CPM 
___mg 
___mg 
MESNA 
___mg ___mg 
PEG-
ASP 
___IU 
DEX 
___mg ___mg 
ITT 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
G-CSF 
___mcg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
10 
1 
____mg 
____mg 
 
 
 
___mg ___mg 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
a, b, c, d, e, f, 
g, h 
 
 
 
2 
 
____mg 
 
 
 
___mg ___mg 
 
 
 
 
 
 
3 
 
 
___mg 
___mg 
___mg ___mg 
___mg ___mg 
 
___mg ___mg 
 
 
 
 
 
 
4 
 
 
___mg 
___mg 
___mg ___mg 
___mg ___mg 
___IU 
___mg ___mg 
 
 
 
 
 
 
5 
 
 
 
 
 
___mg ___mg 
 
____mcg 
 
 
 
 
 
6 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
7 
 
 
 
 
 
___mg ___mg 
 
 
 
 
11 
8 
____mg@ 
 
 
 
 
 
 
 
 
 
 
9-14 
 
 
 
 
 
 
 
 
 
 
12 
15 
____mg 
 
 
 
 
___mg ___mg 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
b, e 
 
 
 
16 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
17 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
18 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
19 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
20 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
21 
 
 
 
 
 
___mg ___mg 
 
 
 
 
 
22 
Start next course (Consolidation, Section 4.5.3) on Day 22 or when blood count parameters are met (whichever occurs 
later). 
Comments may be documented on a separate page.  
 
 
Indicate last G-CSF if past Day 21 _______ 
@ Dose differs on Day 8 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE  
Page 1 of 1 


 
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Version Date: 04/05/13                                                                                                                 Page 44 
4.5.3 
Consolidation: Weeks 13-19 (Arm A)  
 To begin Consolidation, patient must have an ANC > 750/µL and platelets > 75,000/µL and have been 
off G-CSF for at least 48 hours. 
 To begin Consolidation, patient must have recovered from mucositis and/or diaper area skin ulceration 
≥ Grade 3. 
 To begin Day 15 ETOP/CPM, patient must have ANC > 500/µL and platelets > 50,000/µL 
 To begin Day 29 HD ARAC, patient must have an ANC > 500/µL and platelets > 50,000/µL and have 
been off G-CSF for at least 48 hours. 
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines. 
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO q6 
hours as long as the T=24 hr methotrexate level is < 150 µM, and will continue at this dose as long as the 
T=42 hr and T=48 hr methotrexate levels are < 1 µM and < 0.4 µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
Triple Intrathecal Chemotherapy: IT Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Day 1 ONLY; deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
 
 
 
HC: 7.5 mg 
 
 
 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
 
 
 
HC: 8 mg 
 
 
 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration. 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19 
 


 
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Version Date: 04/05/13                                                                                                                 Page 45 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19 
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion IV over 4 hours following each dose of cyclophosphamide (2 total doses per day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 20 & Day 31, continuing until ANC > 1500/µL x 2 days post 
nadir. Administer undiluted by subcutaneous injection (preferred).  May also administer diluted in D5W 
by IV infusion over 15-30 minutes or by continuous infusion. 
 
High Dose Cytarabine: IV over 3 hours 
3000 mg/m2/dose q12 hrs x 4 doses total on Days 29 & 30, beginning a min of 48 hrs AFTER G-CSF 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 30 (3 hours after completion of final dose HD ARAC) 
 
The therapy delivery map (TDM) for Consolidation is on the next page. 
 
Following completion of Consolidation, the next course (Continuation I, Section 4.5.4) starts on Day 50 
or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs later). 


 
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Version Date: 04/05/13                                                                                                                 Page 46 
 
 
4.5.3.1 Consolidation (ARM A: SR patients classified as MLL-G) 
Modified Consolidation is for SR patients (7 weeks/49 days) 
 
_______________________________    _________________________ 
                        Patient name or initials                                      DOB 
Begin Consolidation when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs.  Patient must also have recovered from 
mucositis and/or diaper area skin ulceration ≥ Grade 3.  This Course lasts 7 weeks (49 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High Dose Methotrexate 
(HD MTX) 
IV 
200 mg/m2 over 20 min THEN 
3800 mg/m2 over remainder 24 hrs 
Days 1 & 8 4000 mg/m2 total in 24 hrs; see Section 
4.5.3 for admin guidelines 
a. History, 
physical, ht/wt, 
BSA 
b. CBC (diff/plt) 
c. MTX levels* 
d. Electrolytes/ 
BUN/Cr/AST/ 
ALT/T bili 
e. Serum IgG 
f. CSF cell count, 
diff, cytospin 
 
* MTX levels to 
be drawn per 
protocol with each 
dose of HD MTX 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Leucovorin (LCV) 
IV/PO 
Start 15 mg/m2/dose q6 hrs @ 
T=42 hr 
Days 2 & 9 See Section 4.5.3 for administration 
guidelines 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Day 1 
ONLY 
Deliver ITT within 6 hrs of beginning 
IV MTX infusion 
 
Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring Ommaya 
reservoir administration 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Days 15-19 See below for criteria to begin 
ETOP/CPM 
Cyclophosphamide (CPM) 
IV over 30 min 300 mg/m2/dose 
Days 15-19 
Mesna 
IV over 30 min 
followed by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose over 
4 hrs daily (2 total doses/day) 
Days 15-19 
See Section 4.5.3 for infusion details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. 
Days 20 & 
31 
Continue until ANC > 1500/µL x 2 days 
post nadir; stop at least 48 hrs prior to 
next chemo cycle 
High Dose Cytarabine  
(HD ARAC) 
IV over 3 hrs 
3000 mg/m2/dose q12 hrs x 4 
doses; begin min 48 hrs after G-
CSF 
Days 29 & 
30 
See below for criteria to begin HD 
ARAC; see Section 6.4 regarding 
administration of eye drops 
Pegaspargase (PEG-ASP) 
IM 
2500 International units/m2/dose 
Day 30 
Admin 3 hrs after final HDARAC 
Therapy Delivery Map  
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
HD MTX 
_____mg 
LCV 
____mg 
ITT 
____mg (MTX) 
____mg (HC) 
____mg(ARAC) 
ETOP 
____mg 
CPM 
_____mg 
MESNA 
___mg ___mg 
G-CSF 
____mcg 
HD ARAC 
___mg ___mg 
PEG-ASP 
_____IU 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
13 
1 
_____mg 
 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
 
 
 
 
 
a, b, c, d, e, 
f 
 
 
 
2 
 
_____mg 
 
 
 
 
 
 
 
 
 
 
 
3-7 
 
 
 
 
 
 
 
 
 
 
 
 
14 
8 
_____mg 
 
 
 
 
 
 
 
 
c 
 
 
 
9 
 
_____mg 
 
 
 
 
 
 
 
 
 
 
 
10-14 
 
 
 
 
 
 
 
 
 
 
 
 
15 
15** 
 
 
 
____mg 
_____mg 
___mg ___mg 
 
 
 
b, d 
 
 
 
16 
 
 
 
____mg 
_____mg 
___mg ___mg 
 
 
 
 
 
 
 
17 
 
 
 
____mg 
_____mg 
___mg ___mg 
 
 
 
 
 
 
 
18 
 
 
 
____mg 
_____mg 
___mg ___mg 
 
 
 
 
 
 
 
19 
 
 
 
____mg 
_____mg 
___mg ___mg 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
_____mcg 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
16 
22 
 
 
 
 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
17 
29** 
 
 
 
 
 
 
 
___mg ___mg 
 
b 
 
 
 
30 
 
 
 
 
 
 
 
___mg ___mg 
____IU 
 
 
 
 
31-35 
 
 
 
 
 
 
_____mcg 
 
 
 
 
 
18 
36 
 
 
 
 
 
 
 
 
 
 
 
 
37-42 
 
 
 
 
 
 
 
 
 
 
 
19 
43 
 
 
 
 
 
 
 
 
 
 
 
 
44-49 
 
 
 
 
 
 
 
 
 
 
 
 
50 
Start next course (Continuation I, Section 4.5.4) on Day 50 or when blood count parameters are met (whichever occurs later). 
Comments may be documented on a separate page. 
 
Indicate last G-CSF if past Day 49 ________  
 
 
** To begin Day 15 ETOP/CPM and Day 29 HD ARAC therapy, pt must have ANC > 500/µL and plts > 50,000/µL and been off G-CSF for at least 48 hrs 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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Version Date: 04/05/13                                                                                                                 Page 47 
4.5.4 
Continuation I: Weeks 20-41 (Arm A)  
 
To begin Continuation I, patients must have ANC > 750/µL and platelets > 75,000/µL and 
have been off G-CSF for at least 48 hours. 
 
For Weeks 21-23, 25-27, 32-34 & 36-38 IV MTX/MP: Skip week if ANC < 500/µL or 
platelets < 50,000/µL. 
 
For Weeks 24 & 35: Begin regardless of counts 4 weeks after the start of Week 20 or 31. 
 
For Week 31: Begin regardless of counts once off G-CSF for at least 48 hours. 
 
For Weeks 28 & 39: Begin when ANC > 750/µL and platelets > 75,000/µL. 
 
CYCLE #1: 
(Weeks 20-30) 
 
Week 20 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
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. 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir 
administration 
 
Weeks 21-23 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
Week 24 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
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. 


 
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Version Date: 04/05/13                                                                                                                 Page 48 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 
 
Weeks 25-27 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
Week 28 
Etoposide: 100 mg/m2/dose IV over 2 hours Days 1-5 
 
Cyclophosphamide: 300 mg/m2/dose IV over 30 minutes Days 1-5 
Mesna: 150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; 
then 150 mg/m2/dose continuous infusion IV over 4 hours following each dose of 
cyclophosphamide (2 total doses per day) 
 
Filgrastim: 5 mcg/kg/dose SubQ daily beginning Day 6, until ANC > 1500/µL x 2 days 
post nadir. Administer undiluted by subcutaneous injection (preferred).  May also 
administer diluted in D5W by IV infusion over 15-30 minutes or by continuous infusion. 
 
Weeks 29-30 
REST 
 
Continue G-CSF until ANC > 1500/µL x 2 days post nadir 
 
CYCLE #2: 
(Weeks 31-41) Patient must be off G-CSF for at least 48 hours 
 
Weeks 31-41 
Repeat Cycle #1 
 
 
The therapy delivery maps (TDMs) for Continuation I are on the next two (2) pages. 
 
Following completion of Continuation I, the next course (Continuation II, Section 4.5.5) starts the day 
after Week 41/Day 77 or when counts recover and G-CSF has been discontinued for at least 48 hours 
(whichever occurs later). 
 
 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 49 
 
 
4.5.4.1 Continuation I (ARM A: SR patients classified as MLL-G) 
Modified Continuation I is for SR patients (22 weeks/154 days). Continuation I occurs in two cycles. Each 
cycle is 11 weeks [9 weeks therapy & 2 weeks rest/recovery]. Cycle #1 includes the therapy described 
below and is repeated during Cycle #2. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Continuation I when ANC > 750/µL and platelets > 75,000/µL and patient has been off G-CSF for at least 48 hrs. This Course lasts 154 
days; this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
0.05 mg/kg/dose 
Days 1 & 29 
+ Or infusion via minibag 
as per institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN/Cr/ 
AST/ALT/T bili 
d. Serum IgG 
e. CrCl or GFR 
f. CSF cell count, diff, 
cytospin 
g. Local BM eval 
h. OPTIONAL BM for 
flow MRD, molec. 
MRD & resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO/NG/IV 
3 mg/m2/dose BID 
Days 1-5 & 29-33 Total daily dose: 
6 mg/m2/day, divided BID 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 29 
Note age-based dosing 
 
See Section 5.7 regarding 
IT dose reduction for pts 
requiring Ommaya 
reservoir administration 
Methotrexate  
(IV MTX) 
IV push 
20 mg/m2/dose 
Days 8, 15, 22, 
36, 43, 50  
 
Mercaptopurine (MP) 
PO/NG 
75 mg/m2/dose 
See Appendix VI for dosing. 
Days 8-28 & 36-
56 
Should be given on an empty 
stomach 
Etoposide (ETOP) 
IV over 2 hrs 100 mg/m2/dose 
Days 57-61 
 
Cyclophosphamide 
(CPM) 
IV over 30 
min 
300 mg/m2/dose 
Days 57-61 
 
Mesna 
IV over 30 
min followed 
by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose over 
4 hrs daily (2 total doses/day) 
Days 57-61 
See Section 4.5.4 for 
infusion details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. Day 
62 
Continue until ANC > 
1500/µL x 2 days post 
nadir; stop at least 48 hrs 
prior to next chemo cycle 
 
Circle Cycle #: 1 
2 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date Due 
Date Given 
Week 
Day 
VCR 
____mg 
DEX 
___mg ___mg 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
IV MTX 
____mg 
MP 
____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
20/(31)α 1 
____mg 
___mg ___mg 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
 
a*, b, c, d, e*, f, (g, 
h)*  
 
 
 
2 
 
___mg ___mg 
 
 
 
 
 
 
 
3 
 
___mg ___mg 
 
 
 
 
 
 
 
4 
 
___mg ___mg 
 
 
 
 
 
 
 
5 
 
___mg ___mg 
 
 
 
 
 
 
 
6-7 
 
 
 
 
 
 
 
 
(21/32)β 8 
 
 
 
____mg 
____mg 
b 
 
 
 
9-14 
 
 
 
 
 
 
 
(22/33)β 15 
 
 
 
____mg 
b 
 
 
 
16-21 
 
 
 
 
 
 
 
(23/34)β 22 
 
 
 
____mg 
b 
 
 
 
23-28 
 
 
 
 
 
 
 
(24/35)γ 29 
____mg 
___mg ___mg 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
 
b, d, f 
 
 
 
30 
 
___mg ___mg 
 
 
 
 
 
 
 
31 
 
___mg ___mg 
 
 
 
 
 
 
 
32 
 
___mg ___mg 
 
 
 
 
 
 
 
33 
 
___mg ___mg 
 
 
 
 
Comments may be documented on a separate page. 
α  Begin regardless of counts once off G-CSF for at least 48 hours  
β  For IV MTX/MP: skip week if ANC < 500/µL or platelets < 50,000/µL 
γ  Begin regardless of counts 4 weeks after the start of Week 20/31   
* Week 20 (Cycle #1) ONLY
Page 1 of 2 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 50 
 
 
4.5.4.1 Continuation I (ARM A: SR patients classified as MLL-G) 
Modified Continuation I is for SR patients (22 weeks/154 days). Continuation I occurs in 
two cycles. Each cycle is 11 weeks [9 weeks therapy & 2 weeks rest/recovery]. Cycle #1 
includes the therapy described below and is repeated during Cycle #2. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Continuation I when ANC > 750/µL and platelets > 75,000/µL and patient has been off G-CSF for at least 48 hrs. This Course lasts 154 
days; this Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
0.05 mg/kg/dose 
Days 1 & 29 
+ Or infusion via minibag as per 
institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN/ 
Cr/AST/ALT/ 
T bili 
d. Serum IgG 
e. CrCl or GFR 
f. CSF cell count, 
diff, cytospin 
g. Local BM eval 
h. OPTIONAL BM 
for flow MRD, 
molec. MRD & 
resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO/NG/IV 
3 mg/m2/dose BID 
Days 1-5 & 29-
33 
Total daily dose: 6 mg/m2/day, 
divided BID 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 29 
Note age-based dosing 
 
See Section 5.7 regarding IT 
dose reduction for pts requiring 
Ommaya reservoir 
administration 
Methotrexate (IV MTX) 
IV push 
20 mg/m2/dose 
Days 8, 15, 22, 
36, 43, 50  
 
Mercaptopurine (MP) 
PO/NG 
75 mg/m2/dose 
See Appendix VI for dosing. 
Days 8-28 & 
36-56 
Should be given on an empty 
stomach 
Etoposide (ETOP) 
IV over 2 hrs 100 mg/m2/dose 
Days 57-61 
See Section 4.5.4 for criteria to 
begin ETOP/CPM 
Cyclophosphamide (CPM) 
IV over 
30 min 
300 mg/m2/dose 
Days 57-61 
Mesna 
IV over 
30 min 
followed by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose 
over 4 hrs daily (2 total 
doses/day) 
Days 57-61 
See Section 4.5.4 for infusion 
details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. Day 
62 
Continue until ANC > 1500/µL 
x 2 days post nadir; stop at least 
48 hrs prior to next chemo cycle 
 
Circle Cycle #: 
1 
2 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week 
Day 
IV MTX 
____mg 
MP 
_____mg 
ETOP 
____mg 
CPM 
____mg 
MESNA 
___mg ___mg 
G-CSF 
____mcg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
(25/36)α 36 
____mg 
_____mg 
 
 
 
 
b 
 
 
 
37-42 
 
 
 
 
 
 
 
 
(26/37)α 43 
____mg 
 
 
 
 
b 
 
 
 
44-49 
 
 
 
 
 
 
 
 
(27/38)α 50 
____mg 
 
 
 
 
d*, b 
 
 
 
51-56 
 
 
 
 
 
 
 
 
(28/39)β 57 
 
 
____mg 
____mg 
___mg ___mg 
 
b 
 
 
 
58 
 
 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
59 
 
 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
60 
 
 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
61 
 
 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
62 
 
 
 
 
 
____mcg 
 
 
 
 
63 
 
 
 
 
 
____mcg 
 
 
 
29/40 
64-70 
 
 
 
 
 
____mcg 
b 
 
 
30/41 
71-77 
 
 
 
 
 
____mcg 
b 
 
 
 
78 
Start Cycle #2 when patient is off G-CSF for at least 48 hrs. 
 
 
 
Start next course (Continuation II, Section 4.5.5) the day after Week 41/Day 77 or when blood count 
parameters are met (whichever occurs later). 
Comments may be documented on a separate page. 
   Indicate last G-CSF if past Day 78/155 ________ 
 
α  For IV MTX/MP: skip week if ANC < 500/µL or platelets < 50,000/µL 
β  Begin when ANC > 750/µL and plts > 75,000/µL 
* Week 38 (Cycle #2) ONLY 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 2 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 51 
4.5.5 
Continuation II: Weeks 42-104 (Arm A)  
To begin Continuation II, patients must have ANC > 750/µL and platelets > 75,000/µL and have been off 
G-CSF for at least 48 hours.   
 
Each cycle of Continuation II lasts 12 weeks and should be repeated until 2 calendar years from 
diagnosis. 
 
Week 42 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
IT Methotrexate: < 1 year: 7.5 mg Day 1 ONLY 
 
 
1 year - < 2 years: 8 mg Day 1 ONLY 
 
 
≥ 2 years: 10 mg Day 1 ONLY 
See Section 5.7 regarding IT dose reduction for pts requiring Ommaya reservoir 
administration 
 
Weeks 43-45 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). See Appendix VI for dosing guidelines. 
 
Week 46 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Weeks 47-49 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). See Appendix VI for dosing guidelines. 
 
Continue repeating 
12 week cycles until 
2 years from diagnosis 
(see below for remaining 
cycle information) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 52 
Week 50 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Weeks 51-53 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). See Appendix VI for dosing guidelines. 
 
The therapy delivery map (TDM) for Continuation II is on the next page. 
Continue repeating 
12 week cycles until 
2 years from diagnosis 
(see above for 
Week 42-49)  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 53 
 
 
4.5.5.1 Continuation II (ARM A: SR patients classified as MLL-G) 
Modified Continuation II is for SR patients (12 week cycles repeated until 2 years from 
diagnosis). Each cycle is 12 weeks in length and includes the therapy described below. 
 
__________________________ 
Patient name or initials 
_________________________ 
DOB 
Begin Continuation II when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course is composed of 12-
week cycles that are repeated until 2 calendar years from diagnosis; this Therapy Delivery Map describes one cycle and is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 1 min+ 
0.05 mg/kg/dose 
Days 1, 29, 57 
+ Or infusion via minibag as per 
institutional policy 
a. History, physical, ht/wt, 
BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN/Cr/AST
/ALT/T bili 
d. Serum IgG 
e. CSF cell count, diff, 
cytospin 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO/NG/IV 3 mg/m2/dose BID 
Days 1-5, 29-33, 
57-61 
Total daily dose: 6 mg/m2/day, 
divided BID 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (years) Dose 
< 1 
7.5 mg 
1 - < 2 
8 mg 
≥ 2 
10 mg 
Day 1 ONLY 
Note age-based dosing 
See Section 5.7 regarding IT dose 
reduction for pts requiring 
Ommaya reservoir administration  
Methotrexate 
(MTX) 
PO/NG 
20 mg/m2/dose 
Days 8, 15, 22, 36, 
43, 50, 64, 71, 78 
Hold with IT MTX 
Mercaptopurine 
(MP) 
PO/NG 
75 mg/m2/dose 
See Appendix VI for dosing. 
Days 8-28, 36-56, 
64-84 
Should be given on an empty 
stomach 
 
Cycle #________ 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
_____mg 
DEX 
___mg ___mg 
IT MTX 
_____mg 
PO MTX 
_____mg 
MP 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
42 
1 
_____mg 
___mg ___mg 
_____mg 
 
 
(a, c, d, e)*, b 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6-7 
 
 
 
 
 
 
 
 
43 
8 
 
 
 
____mg 
_____mg 
 
 
 
 
9-14 
 
 
 
 
 
 
 
44 
15 
 
 
 
____mg 
 
 
 
 
16-21 
 
 
 
 
 
 
 
45 
22 
 
 
 
____mg 
 
 
 
 
23-28 
 
 
 
 
 
 
 
46 
29 
_____mg 
___mg ___mg 
 
 
 
b 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
47 
36 
 
 
 
____mg 
______mg 
 
 
 
 
37-42 
 
 
 
 
 
 
 
48 
43 
 
 
 
____mg 
 
 
 
 
44-49 
 
 
 
 
 
 
 
49 
50 
 
 
 
____mg 
 
 
 
 
51-56 
 
 
 
 
 
 
 
50 
57 
_____mg 
___mg ___mg 
 
 
 
b 
 
 
 
58 
 
 
 
 
 
 
 
 
59 
 
 
 
 
 
 
 
 
60 
 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
 
62-63 
 
 
 
 
 
 
 
 
51 
64 
 
 
 
____mg 
______mg 
 
 
 
 
65-70 
 
 
 
 
 
 
 
52 
71 
 
 
 
____mg 
 
 
 
 
72-77 
 
 
 
 
 
 
 
53 
78 
 
 
 
____mg 
 
 
 
 
79-84 
 
 
 
 
 
 
 
 
End of Therapy 
 
 
 
 
 
 
Comments may be documented on a separate page. 
 
 
 
* Start of each 12-week cycle 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 54 
4.6 
Post-Induction Arm B [Chemotherapy ONLY for IR/HR Patients (MLL-R)] (RETIRED) 
To avoid diaper area skin ulceration, especially at Weeks 6 and 7 of HD MTX, please see Appendix I, 
section on Perineal Irritation.  
 
4.6.1 
Induction Intensification: Weeks 6-9 (Arm B)  
 
Begin Induction Intensification when ANC > 750/µL and platelets > 75,000/µL and mucositis 
and/or diaper area skin ulceration ≥ Grade 3 has improved to Grade 2 or less.  
 
To begin Day 8 HD MTX, mucositis or diaper area skin ulceration ≥ Grade 3 must have 
improved to Grade 2 or less.  
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines.  
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO q6 
hours as long as the T=24 hr methotrexate level is < 150 µM, and will continue at this dose as long as the 
T=42 hr and T=48 hr methotrexate levels are < 1 µM and < 0.4 µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
Triple Intrathecal Chemotherapy: IT  Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
 
Days 1 & 8; deliver the IT therapy within 6 hrs of the beginning of the IV MTX infusion 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 55 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19 
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion (CI) IV over 4 hours following each dose of cyclophosphamide (2 total doses per 
day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 20 and until ANC > 1500/µL x 2 days post nadir. Administer 
undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV infusion over 
15-30 minutes or by continuous infusion. 
 
The therapy delivery map (TDM) for Induction Intensification is on the next page. 
 
Following completion of Induction Intensification, the next course (Re-Induction, Section 4.6.2) starts on 
Day 29 or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs 
later). Patients must also be in morphologic remission in order to begin Re-Induction. 
 


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 57 
4.6.2 
Re-Induction: Weeks 10-12 (Arm B) (RETIRED) 
 
To begin Re-Induction, patients must be in morphologic remission to proceed with therapy. Patient must 
have ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF at least 48 hours. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
0.05 mg/kg on Days 1 & 15 AND 0.03 mg/kg on Day 8 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
Days 1 & 2 
 
Dose is mg/kg/day based on age at diagnosis: 
< 6 months = 1.7 mg/kg/dose 
6 months to 8.99 months = 2.1 mg/kg/dose 
≥ 9 months = 2.6 mg/kg/dose 
 
Cyclophosphamide: IV over 30 minutes 
250 mg/m2/dose q12 hours x 4 doses total on Days 3 & 4  
 
Mesna: IV 
125 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 125 mg/m2/dose 
continuous infusion IV over 4 hours following each dose of cyclophosphamide (4 total doses per day). 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 4 
 
Dexamethasone: PO/NG/IV 
10 mg/m2/day divided BID on Days 1-7 & 15-21 
 
Triple Intrathecal Chemotherapy: IT 
Days 1 & 15 ONLY 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 58 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 5 and until ANC > 1500/µL x 2 days post nadir 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
The therapy delivery map (TDM) for Re-Induction is on the next page. 
 
Following completion of Re-Induction, the next course (Consolidation, Section 4.6.3) starts on Day 22 or 
when counts recover, G-CSF has been discontinued for at least 48 hours and mucositis and/or diaper area 
skin ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 60 
4.6.3 
Consolidation: Weeks 13-19 (Arm B) (RETIRED) 
 
 To begin Consolidation, patient must have an ANC > 750/µL and platelets > 75,000/µL and have been 
off G-CSF for at least 48 hours. 
 To begin Consolidation, patient must have recovered from mucositis and/or diaper area skin ulceration 
≥ Grade 3. 
 To begin Day 15 ETOP/CPM, patient must have ANC > 500/µL and platelets > 50,000/µL 
 To begin Day 29 HD ARAC, patient must have an ANC > 500/µL and platelets > 50,000/µL and have 
been off G-CSF for at least 48 hours. 
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines. 
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO q6 
hours as long as the T=24 hr methotrexate level is < 150 µM, and will continue at this dose as long as the 
T=42 hr and T=48 hr methotrexate levels are < 1 µM and < 0.4 µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
Triple Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Day 1 ONLY; deliver the IT therapy within 6 hrs of the beginning of the IV MTX infusion 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
 
 
 
HC: 7.5 mg 
 
 
 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
 
 
 
HC: 8 mg 
 
 
 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 61 
 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19  
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion IV over 4 hours following each dose of cyclophosphamide (2 total doses per day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 20 & Day 31, continuing until ANC > 1500/µL x 2 days post 
nadir.  
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
High Dose Cytarabine: IV over 3 hours 
3000 mg/m2/dose q12 hrs x 4 doses total on Days 29 and 30, beginning a min of 48 hrs AFTER G-CSF 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 30 (3 hours after completion of final dose HD ARAC) 
 
The therapy delivery map (TDM) for Consolidation is on the next page. 
 
Following completion of Consolidation, the next course (Continuation I, Section 4.6.4) starts on Day 50 
or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs later). 


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 63 
4.6.4 
Continuation I: Weeks 20-49 (Arm B) (RETIRED) 
 
To begin Continuation I, patient must have ANC > 750/µL and platelets > 75,000/µL and 
have been off G-CSF for at least 48 hours. 
 
For Weeks 21-23, 25-26, 34-36, 38-39 & 47-49 IV MTX/MP: Skip week if ANC < 500/µL or 
platelets < 50,000/µL. 
 
For Weeks 24 & 37: Begin regardless of counts 4 weeks after the start of Week 20/33. 
 
For Weeks 27 & 40: Begin when ANC > 750/µL and platelets > 75,000/µL. 
 
For Weeks 30 & 43: Begin when off G-CSF for at least 48 hours and ANC > 750/µL and 
platelets > 75,000/µL. 
 
For Weeks 33 & 46: Begin regardless of counts once off G-CSF for at least 48 hours. 
 
CYCLE #1: 
(Weeks 20-23) 
Week 20 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
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. 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir 
administration 
 
Weeks 21-23 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
CYCLE #2: 
(Weeks 24-32) 
Week 24 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
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 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 64 
liposomal injection, VSLI, Marqibo®). The conventional and liposomal formulations are 
NOT interchangeable. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir 
administration 
 
Weeks 25-26 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
Weeks 27-29 
Etoposide: 100 mg/m2/dose IV over 2 hours Days 1-5 of Week 27 ONLY 
 
Cyclophosphamide: 300 mg/m2/dose IV over 30 minutes Days 1-5 of Week 27 ONLY 
Mesna: 150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; 
then 150 mg/m2/dose continuous infusion IV over 4 hours following each dose of 
cyclophosphamide (2 total doses per day) 
 
Filgrastim: 5 mcg/kg/dose SubQ daily beginning Day 6 of Week 27, until ANC 
> 1500/µL x 2 days post nadir. Administer undiluted by subcutaneous injection 
(preferred). May also administer diluted in D5W by IV infusion over 15-30 minutes or by 
continuous infusion. 
 
Weeks 30-32 
High Dose Cytarabine: 3000 mg/m2/dose IV over 3 hours q12 hours x 4 doses total 
Days 1-2 of Week 30 ONLY 
 
Pegaspargase: 2500 International units/m2/dose IM Day 2 (3 hrs after completion of 
final HD ARAC) of Week 30 ONLY 
 
Filgrastim: 5 mcg/kg/dose SubQ daily beginning Day 3 of Week 30, until ANC 
> 1500/µL x 2 days post nadir. Administer undiluted by subcutaneous injection 
(preferred). May also administer diluted in D5W by IV infusion over 15-30 minutes or by 
continuous infusion. 
 
CYCLE #3: 
(Weeks 33-36) 
Repeat Cycle #1 
 
CYCLE #4: 
(Weeks 37-45) 
Repeat Cycle #2 
 
CYCLE #5: 
(Weeks 46-49) 
Repeat Cycle #1 
 
The therapy delivery maps (TDMs) for Continuation I are on the next three (3) pages. 
 
Following completion of Continuation I, the next course (Continuation II, Section 4.6.5) starts the day 
after Week 49/Day 28 or when counts recover and G-CSF has been discontinued for at least 48 hours 
(whichever occurs later). 
 


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 68 
4.6.5 
Continuation II: Weeks 50-104 (Arm B) (RETIRED) 
To begin Continuation II, patients must have ANC > 750/µL and platelets > 75,000/µL and have been off 
G-CSF for at least 48 hours.   
 
Each cycle of Continuation II lasts 12 weeks and should be repeated until 2 calendar years from 
diagnosis. 
 
Week 50 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
IT Methotrexate: < 1 year: 7.5 mg Day 1 ONLY 
 
 
1 year - < 2 years: 8 mg Day 1 ONLY 
 
 
≥ 2 years: 10 mg Day 1 ONLY 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya 
reservoir administration 
 
Weeks 51-53 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). 
 
Week 54 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2 PO/NG/IV divided BID Days 1-5 
 
Weeks 55-57 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). 
Continue repeating 
12week cycles until 
2 years from diagnosis 
(see below for 
remaining cycle 
information) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 69 
 
Week 58 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Weeks 59-61 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can be 
rounded to half tablet. A liquid formulation is available (see drug 
monograph). 
 
The therapy delivery map (TDM) for Continuation II is on the next page. 
 
Continue repeating 
12 week cycles until 
2 years from diagnosis 
(see above for 
Week 50-57)  


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FHOO


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 71 
4.7 
Post-Induction Arm C [Chemotherapy + Lestaurtinib for IR /HR Patients (MLL-R)] 
 
Note: Post-Induction Arm C therapy is limited to IR/HR patients enrolled at COG sites in the US 
and Canada (see Section 3.1.7). 
 
To avoid diaper area skin ulceration, especially at Weeks 6 and 7 of HD MTX, please see Appendix I, 
section on Perineal Irritation.  
 
4.7.1 
Induction Intensification: Weeks 6-9 (Arm C) 
 
Begin Induction Intensification when ANC > 750/µL and platelets > 75,000/µL and mucositis 
and/or diaper area skin ulceration ≥ Grade 3 has improved to Grade 2 or less. 
 
To begin Day 8 HD MTX, mucositis or diaper area skin ulceration ≥ Grade 3 must have 
improved to Grade 2 or less. 
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines.  
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO q6 
hours as long as the T=24 hr methotrexate level is < 150 µM, and will continue at this dose as long as the 
T=42 hr and T=48 hr methotrexate levels are < 1 µM and < 0.4 µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
Triple Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Days 1 & 8; deliver the IT therapy within 6 hrs of the beginning of the IV MTX infusion 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 72 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19 
 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19 
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion (CI) IV over 4 hours following each dose of cyclophosphamide (2 total doses per 
day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 20 and until ANC > 1500/µL x 2 days post nadir. 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
Lestaurtinib: PO/NG 
Intermediate Risk patients: 5 mg/kg/day (with food) divided BID on Days 20-27 
 
High Risk patients: 4.25 mg/kg/day (with food) divided BID on Days 20-27 
 
Please see Appendices II and III regarding contraindicated medications during lestaurtinib administration. 
 
Lestaurtinib is diluted in juice prior to administration. Dilution instructions are available in the drug 
monograph (Section 6.10) and Appendix IV. 
 
The therapy delivery map (TDM) for Induction Intensification is on the next page. 
 
Following completion of Induction Intensification, the next course (Re-Induction, Section 4.7.2) starts on 
Day 29 or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs 
later). Patients must also be in morphologic remission in order to begin Re-Induction. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 73 
 
 
4.7.1.1 Induction Intensification (ARM C: IR/HR patients classified as MLL-R) 
Modified Induction Intensification + Lestaurtinib is for IR/HR patients (4 weeks/28 days) 
 
_______________________  ___________________ 
      Patient name or initials                   DOB 
Begin Induction Intensification when ANC > 750/µL and platelets > 75,000/µL and mucositis/diaper area skin ulceration ≥ Grade 3 has improved 
to Grade 2 or less. This Course lasts 28 days and this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High Dose Methotrexate 
(HD MTX) 
IV 
200 mg/m2 over 20 min THEN 
3800 mg/m2 over remainder 24 hrs 
Days 1 & 
8* 
4000 mg/m2 total in 24 hrs; 
see Section 4.7.1 for 
administration guidelines 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T bili 
d. Serum IgG 
e. CSF cell count, diff, 
cytospin 
f. Local BM eval 
g. PB for Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
h. OPTIONAL BM for 
flow MRD, 
molecular MRD & 
resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Leucovorin (LCV) 
IV/PO 
Start 15 mg/m2/dose q6 hrs @ 
T=42 hr 
Days 2 & 9 
See Section 4.7.1 for 
administration guidelines 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 8 
Deliver ITT within 6 hrs of 
beginning IV MTX infusion 
 
Note age-based dosing 
 
See Section 5.7 regarding IT 
dose reduction for pts 
requiring Ommaya reservoir 
administration 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Days 15-19  
Cyclophosphamide (CPM) 
IV over 30 min 300 mg/m2/dose 
Days 15-19  
Mesna 
IV over 30 min 
followed by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose over 4 
hrs daily (2 total doses/day) 
Days 15-19 See Section 4.7.1 for infusion 
details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. 
on Day 20 
Continue until ANC 
> 1500/µL x 2 days post nadir; 
stop at least 48 hrs prior to 
next chemo cycle 
Lestaurtinib (LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 20-27 Should be given with food 
Therapy Delivery Map  
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
HD MTX 
__mg __mg 
LCV 
____mg 
ITT 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
ETOP 
____mg 
CPM 
____mg 
MESNA 
___mg ___mg 
G-CSF 
____mcg 
LEST 
____mg ____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
6 
1 
__mg __mg 
 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
 
 
 
 
a, b, c, d, e, f, 
h 
 
 
 
2 
 
____mg 
 
 
 
 
 
 
 
 
 
 
3-7 
 
 
 
 
 
 
 
 
 
 
 
7 
8* 
__mg __mg * 
 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
 
 
 
 
b, e 
 
 
 
9 
 
____mg 
 
 
 
 
 
 
 
 
 
 
10-14 
 
 
 
 
 
 
 
 
 
 
 
8 
15 
 
 
 
____mg ____mg ___mg ___mg 
 
 
b, d 
 
 
 
16 
 
 
 
____mg ____mg ___mg ___mg 
 
 
 
 
 
 
17 
 
 
 
____mg ____mg ___mg ___mg 
 
 
 
 
 
 
18 
 
 
 
____mg ____mg ___mg ___mg 
 
 
 
 
 
 
19 
 
 
 
____mg ____mg ___mg ___mg 
 
 
 
 
 
 
20 
 
 
 
 
 
 
____mcg 
____mg ____mg g 
 
 
 
21 
 
 
 
 
 
 
____mg ____mg  
 
 
9 
22 
 
 
 
 
 
 
____mg ____mg  
 
 
 
23 
 
 
 
 
 
 
____mg ____mg  
 
 
 
24 
 
 
 
 
 
 
____mg ____mg  
 
 
 
25 
 
 
 
 
 
 
____mg ____mg  
 
 
 
26 
 
 
 
 
 
 
____mg ____mg  
 
 
 
27 
 
 
 
 
 
 
____mg ____mg g 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
29 
Start next course (Re-Induction, Section 4.7.2) on Day 29 or when blood count parameters are met (whichever occurs later). 
Comments may be documented on a separate page. 
       Indicate last G-CSF if past Day 28 __________ 
 
* To receive Day 8 HD MTX, mucositis or diaper area skin ulceration ≥ Grade 3 must have improved to Grade 2 or less 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE  
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 74 
4.7.2 
Re-Induction: Weeks 10-12 (Arm C) 
To begin Re-Induction, patients must be in morphologic remission to proceed with therapy. Patient must 
have ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF at least 48 hours. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
0.05 mg/kg on Days 1 & 15 AND 0.03 mg/kg on Day 8 
 
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. 
 
DAUNOrubicin: IV over 30 minutes 
Days 1 & 2 
 
Dose is mg/kg/day based on age at diagnosis: 
< 6 months = 1.7 mg/kg/dose 
6 months to 8.99 months = 2.1 mg/kg/dose 
≥ 9 months = 2.6 mg/kg/dose 
 
Cyclophosphamide: IV over 30 minutes 
250 mg/m2/dose q12 hours x 4 doses total on Days 3 & 4 
 
Mesna: IV 
125 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 125 mg/m2/dose 
continuous infusion IV over 4 hours following each dose of cyclophosphamide (4 total doses per day). 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 4 
 
Dexamethasone: PO/NG/IV 
10 mg/m2/day divided BID on Days 1-7 & 15-21 
 
Triple Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Days 1 & 15 ONLY 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 75 
 
Filgrastim: SubQ/IV 
5 mcg/kg/dose daily beginning on Day 5 and until ANC > 1500/µL x 2 days post nadir 
Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W by IV 
infusion over 15-30 minutes or by continuous infusion. 
 
Lestaurtinib: PO/NG 
Intermediate Risk patients: 5 mg/kg/day (with food) divided BID on Days 5-20 
 
High Risk patients: 4.25 mg/kg/day (with food) divided BID on Days 5-20 
 
Please see Appendices II and III regarding contraindicated medications during lestaurtinib administration. 
 
Lestaurtinib is diluted in juice prior to administration. Dilution instructions are available in the drug 
monograph (Section 6.10) and Appendix IV. 
 
The therapy delivery map (TDM) for Re-Induction is on the next page. 
 
Following completion of Re-Induction, the next course (Consolidation, Section 4.7.3) starts on Day 22 or 
when counts recover, G-CSF has been discontinued for at least 48 hours and mucositis and/or diaper area 
skin ulceration ≥ Grade 3 has improved to Grade 2 or less (whichever occurs later). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 76 
 
 
4.7.2.1 Re-Induction (ARM C: IR/HR patients classified as MLL-R) 
Modified Re-Induction + Lestaurtinib is for IR/HR patients (3 weeks/21 days) 
 
____________________________   _______________________ 
               Patient name or initials                              DOB 
Begin Re-Induction if patient is in morphologic remission; patient must have ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 
48 hrs. This Course lasts 21 days and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
IV push over 
1 minute+ 
0.05 mg/kg on Days 1 & 15 
AND 0.03 mg/kg on Day 8@ 
Days 1, 8@, 15 
+ Or infusion via minibag as per 
institutional policy 
@ Dose differs on Day 8 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T bili 
d. Serum IgG 
e. CSF cell count, 
cytospin 
f. Echo or MUGA 
g. Local BM eval 
h. PB for Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
i. OPTIONAL BM for 
flow MRD, 
molecular MRD & 
resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
DAUNOrubicin (DAUN) 
IV over 30 min 
Age at diagnosis: 
< 6 mos. = 1.7 mg/kg/dose 
6-8.99 mos.= 2.1 mg/kg/dose 
≥ 9 mos. = 2.6 mg/kg/dose 
Days 1 & 2 
Dosing based on age at diagnosis 
Cyclophosphamide 
(CPM) 
IV over 30 min 
250 mg/m2/dose q12 hrs x 4 doses total 
Days 3 & 4 
 
Mesna 
IV over 30 min 
followed by CI 
125 mg/m2/dose with CPM followed by 
125 mg/m2/dose over 4 hrs (4 total 
doses/day) 
Days 3 & 4 
See Section 4.7.2 for infusion 
details 
Pegaspargase 
(PEG-ASP) 
IM 
2500 International units/m2/dose 
Day 4 ONLY 
 
Dexamethasone (DEX) 
PO/NG/IV 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 10 mg/m2/day, 
divided BID 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Days 1 & 15 ONLY 
Note age-based dosing 
 
See Section 5.7 regarding IT 
dose reduction for pts requiring 
Ommaya reservoir 
administration 
Filgrastim  
(G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. Day 5 
Continue until ANC > 1500/µL 
x 2 days post nadir; stop at least 
48 hrs prior to next chemo cycle 
Lestaurtinib  
(LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 5-20 
Should be given with food 
 
Therapy Delivery Map 
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
D1 & 15 
___mg 
 D8 
____@ 
DAUN 
___mg 
CPM 
___mg 
___mg 
MESNA 
___mg ___mg 
PEG-ASP 
___IU 
DEX 
__mg __mg 
ITT 
__mg (MTX) 
__mg (HC) 
__mg (ARAC) 
LEST 
__mg __mg 
G-CSF 
___mcg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
10 
1 
___mg 
___mg 
 
 
 
__mg __mg 
__mg (MTX) 
__mg (HC) 
__mg (ARAC) 
 
 
a, b, c, 
d, e, f, g, 
i 
 
 
 
2 
 
___mg 
 
 
 
__mg __mg 
 
 
 
 
 
 
 
3 
 
 
___mg 
___mg 
___mg ___mg 
___mg ___mg 
 
__mg __mg 
 
 
 
 
 
 
 
4 
 
 
___mg 
___mg 
___mg ___mg 
___mg ___mg 
___IU 
__mg __mg 
 
 
 
 
 
 
 
5-7 
 
 
 
 
 
__mg __mg 
 
__mg __mg 
___mcg  
 
 
11 
8 
___mg@ 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
10-11 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
 
13-14 
 
 
 
 
 
 
 
 
 
 
12 
15 
___mg 
 
 
 
 
__mg __mg 
__mg (MTX) 
__mg (HC) 
__mg (ARAC) 
b, e 
 
 
 
16-18 
 
 
 
 
 
__mg __mg 
 
 
 
 
 
19 
 
 
 
 
 
__mg __mg 
 
h 
 
 
 
20 
 
 
 
 
 
__mg __mg 
 
 
 
 
 
21 
 
 
 
 
 
__mg __mg 
 
 
 
 
 
 
22 
Start next course (Consolidation, Section 4.7.3) on Day 22 or when blood count parameters are met (whichever occurs later). 
Comments may be documented on a separate page.                     @ Dose differs on Day 8 
                     Indicate last G-CSF if past Day 21 ________ 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE  
Page 1 of 1 


 
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Version Date: 04/05/13                                                                                                                 Page 77 
4.7.3 
Consolidation: Weeks 13-19 (Arm C) 
 To begin Consolidation, patient must have an ANC > 750/µL and platelets > 75,000/µL and 
have been off G-CSF for at least 48 hours. 
 To begin Consolidation, patient must have recovered from mucositis and/or diaper area skin 
ulceration ≥ Grade 3. 
 To begin Day 15 ETOP/CPM, patient must have ANC > 500/µL and platelets > 50,000/µL 
 To begin Day 29 HD ARAC, patient must have an ANC > 500/µL and platelets > 50,000/µL 
and have been off G-CSF for at least 48 hours. 
 
High Dose Methotrexate: IV 
200 mg/m2 IV over 20 minutes THEN 3800 mg/m2 IV over remainder of 24 hours [4000 mg/m2 IV in 
24 hours] on Days 1 & 8. See Section 5.8 for IV fluid and dose modification guidelines. 
 
Leucovorin rescue: Leucovorin will begin at T=42 hr at the standard dose of 15 mg/m2/dose IV/PO q6 
hours as long as the T=24 hr methotrexate level is < 150 µM, and will continue at this dose as long as the 
T=42 hr and T=48 hr methotrexate levels are < 1 µM and < 0.4 µM (all timed from the beginning of the 
methotrexate infusion), respectively. If any of the levels is above these thresholds, then the more detailed 
guidelines described in Section 5.8 will be followed. 
 
HD MTX Infusion Guidelines: 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
Triple Intrathecal Chemotherapy: IT 
Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC) 
Day 1 ONLY; deliver the IT therapy within 6 hrs of the beginning of the IV MTX infusion. 
 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir administration 


 
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Version Date: 04/05/13                                                                                                                 Page 78 
 
Etoposide: IV over 2 hours 
100 mg/m2/dose on Days 15-19 
 
Cyclophosphamide: IV over 30 minutes 
300 mg/m2/dose on Days 15-19  
 
Mesna: IV 
150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; then 150 mg/m2/dose 
continuous infusion IV over 4 hours following each dose of cyclophosphamide (2 total doses per day). 
 
Filgrastim: SubQ/IV 
5 mcg/kg daily/dose beginning on Day 20 & Day 31, continuing until ANC > 1500/µL x 2 days post 
nadir. Administer undiluted by subcutaneous injection (preferred). May also administer diluted in D5W 
by IV infusion over 15-30 minutes or by continuous infusion. 
 
High Dose Cytarabine: IV over 3 hours 
3000 mg/m2/dose q12 hrs x 4 doses total on Days 29 & 30, beginning a minimum of 48 hrs AFTER 
G-CSF 
 
Pegaspargase: IM 
2500 International units/m2/dose on Day 30 (3 hrs after completion of final dose HD ARAC) 
 
Lestaurtinib: PO/NG 
Intermediate Risk patients: 5 mg/kg/day (with food) divided BID on Days 20-27 and 31-42 
 
High Risk patients: 4.25 mg/kg/day (with food) divided BID on Days 20-27 and 31-42 
 
Please see Appendices II and III regarding contraindicated medications during lestaurtinib administration. 
 
Lestaurtinib is diluted in juice prior to administration. Dilution instructions are available in the drug 
monograph (Section 6.10) and Appendix IV. 
 
The therapy delivery map (TDM) for Consolidation is on the next page. 
 
Following completion of Consolidation, the next course (Continuation I, Section 4.7.4) starts on Day 50 
or when counts recover and G-CSF has been discontinued for at least 48 hours (whichever occurs later). 
 
 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 79 
 
 
4.7.3.1 Consolidation (ARM C: IR/HR patients classified as MLL-R) 
Modified Consolidation + Lestaurtinib is for IR/HR patients (7 weeks/49 days) 
 
____________________________   _________________________ 
            Patient name or initials                               DOB 
Begin Consolidation when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course lasts 49 days and 
this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High Dose Methotrexate 
(HD MTX) 
IV 
200 mg/m2 over 20 min THEN 
3800 mg/m2 over remainder 24 hrs 
Days 1 & 8 
4000 mg/m2 total in 24 hrs; see 
Section 4.7.3 for administration 
guidelines 
a. History, 
physical, ht/wt, 
BSA 
b. CBC (diff/plt) 
c. MTX levels* 
d. Electrolytes/ 
BUN/Cr/AST/ 
ALT/T bili 
e. Serum IgG 
f. CSF cell count, 
diff, cytospin 
 
* MTX levels to be 
drawn per protocol 
with each dose of 
HD MTX 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Leucovorin (LCV) 
IV/PO 
Start 15 mg/m2/dose q6 hrs @ T=42 
hrs  
Days 2 & 9 
See Section 4.7.3 for 
administration guidelines 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Day 1 ONLY 
Deliver ITT within 6 hrs of 
beginning IV MTX infusion 
 
Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring 
Ommaya reservoir administration 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Days 15-19 
See below for criteria to begin 
ETOP/CPM 
Cyclophosphamide 
(CPM) 
IV over 30 min 300 mg/m2/dose 
Days 15-19 
Mesna 
IV over 30 min 
followed by CI 
150 mg/m2/dose with CPM followed 
by 150 mg/m2/dose over 4 hrs daily 
(2 total doses/day) 
Days 15-19 
See Section 4.7.3 for infusion 
details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. 
Days 20 & 31 
Continue until ANC > 1500/µL x 
2 days post nadir; stop at least 48 
hrs prior to next chemo cycle 
High Dose Cytarabine 
(HD ARAC) 
IV over 3 hrs 
3000 mg/m2/dose q12 hrs x 4 doses 
total; begin min 48 hrs after G-CSF 
Days 29 & 30 See below for criteria to begin HD 
ARAC; see Section 6.4 regarding 
administration of eye drops 
Pegaspargase  
(PEG-ASP) 
IM 
2500 International units/m2/dose 
Day 30 
3 hrs after final HD ARAC 
Lestaurtinib (LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 20-27 & 
31-42 
Should be given with food 
 
Therapy Delivery Map 
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week Day 
HD MTX 
__mg __mg 
LCV 
___mg 
ITT 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
ETOP 
____mg 
CPM 
____mg 
MESNA 
__mg __mg 
G-CSF 
___mcg 
HD ARAC 
__mg __mg 
PEG-
ASP 
___IU 
LEST 
__mg __mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
__mg __mg 
 
___mg (MTX) 
___mg (HC) 
___mg (ARAC) 
 
 
 
 
 
 
 
a, b, c, d, 
e, f 
 
 
 
2 
 
___mg 
 
 
 
 
 
 
 
 
 
 
 
 
3-7 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
8 
__mg __mg 
 
 
 
 
 
 
 
 
 
c 
 
 
 
9 
 
___mg 
 
 
 
 
 
 
 
 
 
 
 
 
10-14 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
15** 
 
 
 
____mg ____mg 
__mg __mg 
 
 
 
 
b, d 
 
 
 
16 
 
 
 
____mg ____mg 
__mg __mg 
 
 
 
 
 
 
 
 
17 
 
 
 
____mg ____mg 
__mg __mg 
 
 
 
 
 
 
 
 
18 
 
 
 
____mg ____mg 
__mg __mg 
 
 
 
 
 
 
 
 
19 
 
 
 
____mg ____mg 
__mg __mg 
 
 
 
 
 
 
 
 
20-21 
 
 
 
 
 
 
___mcg 
 
 
__mg __mg  
 
 
16 
22-27 
 
 
 
 
 
 
___mcg 
 
 
__mg __mg  
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
29** 
 
 
 
 
 
 
 
__mg __mg 
 
 
b 
 
 
 
30 
 
 
 
 
 
 
 
__mg __mg 
___IU 
 
 
 
 
 
31-35 
 
 
 
 
 
 
___mcg 
 
 
__mg __mg  
 
 
18 
36-42 
 
 
 
 
 
 
___mcg 
 
 
__mg __mg  
 
 
19 
43-49 
 
 
 
 
 
 
___mcg 
 
 
 
 
 
 
 
50 
Start next course (Continuation I, Section 4.7.4) on Day 50 or when blood count parameters are met (whichever occurs later). 
Comments may be documented on a separate page.                            Indicate last G-CSF if past Day 49 __________ 
 
 
 
** To begin Day 15 ETOP/CPM & Day 29 HDARAC therapy, pt must have ANC > 500/µL & plts > 50,000/µL and been off G-CSF for at least 48 hrs 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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Version Date: 04/05/13                                                                                                                 Page 80 
4.7.4 
Continuation I: Weeks 20-49 (Arm C) 
 
To begin Continuation I, patients must have ANC > 750/µL and platelets > 75,000/µL and 
have been off G-CSF for at least 48 hours.   
 
For Weeks 21-23, 25-26, 34-36, 38-39 & 47-49 IV MTX/MP: Skip week if ANC < 500/µL or 
platelets < 50,000/µL. 
 
For Weeks 24 & 37: Begin regardless of counts 4 weeks after the start of Week 20/33. 
 
For Weeks 27 & 40: Begin when ANC > 750/µL and platelets > 75,000/µL. 
 
For Weeks 30 & 43: Begin when off G-CSF for at least 48 hours and ANC > 750/µL and 
platelets > 75,000/µL. 
 
For Weeks 33 & 46: Begin regardless of counts once off G-CSF for at least 48 hours. 
 
CYCLE #1: 
(Weeks 20-23) 
Week 20 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir 
administration 
 
Lestaurtinib: for Intermediate Risk patients, 5 mg/kg/day, and for High Risk patients, 
4.25 mg/kg/day (with food) PO/NG divided BID Days 2-6 
 
Weeks 21-23 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
CYCLE #2: 
(Weeks 24-32) 
Week 24 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via minibag as per 
institutional policy Day 1 ONLY 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For 
intravenous use only - Fatal if given by other routes.” 


 
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Version Date: 04/05/13                                                                                                                 Page 81 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
Triple Intrathecal Therapy: Day 1 ONLY [Methotrexate (MTX), Hydrocortisone (HC), 
Cytarabine (ARAC)] 
Age-based dosing: 
Age (years) 
Dose 
< 1 
 
MTX: 7.5 mg 
 
 
HC: 7.5 mg 
 
 
ARAC: 15 mg 
≥ 1 
 
MTX: 8 mg 
 
 
HC: 8 mg 
 
 
ARAC: 16 mg 
See Section 5.7 regarding IT dose reduction for patients requiring Ommaya reservoir 
administration 
 
Lestaurtinib: for Intermediate Risk patients, 5 mg/kg/day, and for High Risk patients, 
4.25 mg/kg/day (with food) PO/NG divided BID Days 2-6 
 
Weeks 25-26 
Methotrexate: 20 mg/m2/dose IV push weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). Administer in 
the evening on an empty stomach (at least 1 hour before or 2 hours after food or drink 
except water). Food or milk delays absorption and decreases the peak concentration. 
Tablets are scored and doses can be rounded to half tablet. A liquid formulation is 
available (see drug monograph). See Appendix VI for dosing guidelines. 
 
Weeks 27-29 
Etoposide: 100 mg/m2/dose IV over 2 hours Days 1-5 of Week 27 ONLY 
 
Cyclophosphamide: 300 mg/m2/dose IV over 30 minutes Days 1-5 of Week 27 ONLY 
Mesna: 150 mg/m2/dose infused with each dose of cyclophosphamide over 30 minutes; 
then 150 mg/m2/dose continuous infusion IV over 4 hours following each dose of 
cyclophosphamide (2 total doses per day). 
 
Filgrastim: 5 mcg/kg/dose SubQ daily beginning Day 6 of Week 27, until ANC 
> 1500/µL x 2 days post nadir. Administer undiluted by subcutaneous injection 
(preferred). May also administer diluted in D5W by IV infusion over 15-30 minutes or by 
continuous infusion. 
 
Lestaurtinib: for Intermediate Risk patients, 5 mg/kg/day, and for High Risk patients, 
4.25 mg/kg/day (with food) PO/NG divided BID Days 27-41 
 
Weeks 30-32 
High Dose Cytarabine: 3000 mg/m2/dose IV over 3 hours q12 hours x 4 doses total 
Days 1-2 of Week 30 ONLY 
 
Pegaspargase: 2500 International units/m2/dose IM Day 2 (3 hrs after completion of 
final HD ARAC) of Week 30 ONLY 
 
Filgrastim: 5 mcg/kg/dose SubQ daily beginning Day 3 of Week 30, until ANC 
> 1500/µL x 2 days post nadir. Administer undiluted by subcutaneous injection 
(preferred). May also administer diluted in D5W by IV infusion over 15-30 minutes or by 
continuous infusion. 
 
Lestaurtinib: for Intermediate Risk patients, 5 mg/kg/day, and for High Risk patients, 
4.25 mg/kg/day (with food) PO/NG divided BID Days 45-56 
 
CYCLE #3: 
(Weeks 33-36) Repeat Cycle #1 
 
CYCLE #4: 
(Weeks 37-45) Repeat Cycle #2 


 
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Version Date: 04/05/13                                                                                                                 Page 82 
 
CYCLE #5: 
(Weeks 46-49) Repeat Cycle #1 
 
Dosing for lestaurtinib: for Intermediate Risk patients, 5 mg/kg/day, and for High Risk patients, 
4.25 mg/kg/day: 
 
Please see Appendices II and III regarding contraindicated medications during lestaurtinib administration. 
 
Lestaurtinib is diluted in juice prior to administration. Dilution instructions are available in the drug 
monograph (Section 6.10) and Appendix IV. 
 
The therapy delivery maps (TDMs) for Continuation I are on the next three (3) pages. 
 
Following completion of Continuation I, the next course (Continuation II, Section 4.7.5) starts the day 
after Week 49/Day 28 or when counts recover and G-CSF has been discontinued for at least 48 hours 
(whichever occurs later). 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 83 
 
 
4.7.4.1 Continuation I (ARM C: IR/HR patients classified as MLL-R) 
Modified Continuation I + Lestaurtinib is for IR/HR patients (30 weeks/210 days). 
Continuation I occurs in five cycles. Cycle #1 lasts 4 weeks, includes the therapy 
described below and is repeated during Cycles #3 and #5. [Cycle #2 lasts 9 weeks, 
includes the therapy described on pages 2-3 and is repeated during Cycle #4] 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Continuation I when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course lasts 
30 weeks (Weeks 20-49) and this Therapy Delivery Map is on three (3) pages. Cycles 1, 3 and 5 are described below. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES OBSERVATIONS 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
0.05 mg/kg/dose 
Day 1 ONLY 
+ Or infusion via 
minibag as per 
institutional policy 
a. History, physical, ht/wt, 
BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN/Cr/AST
/ALT/T bili 
d. Serum IgG 
e. CrCl or GFR 
f. CSF cell count, diff, 
cytospin 
g. Local BM eval 
h. PB for Lestaurtinib 
PK/PIA (see Section 13.1 
for details) 
i. OPTIONAL BM for flow 
MRD, molec. MRD & 
resistance mechanisms. 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO/NG/IV 3 mg/m2/dose BID 
Days 1-5 
Total daily dose: 
6 mg/m2/day, divided 
BID 
Triple Intrathecal 
Therapy (ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Day 1 ONLY 
Note age-based dosing 
 
See Section 5.7 regarding 
IT dose reduction for pts 
requiring Ommaya 
reservoir administration 
Methotrexate (IV MTX) 
IV push 
20 mg/m2/dose 
Days 8, 15, 22  
Mercaptopurine (MP) 
PO/NG 
75 mg/m2/dose 
See Appendix VI for dosing. 
Days 8-28 
Should be given on an 
empty stomach 
Lestaurtinib (LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 2-6 
Should be given with 
food 
 
Circle Cycle #: 
1 
3 
5 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date  
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DEX 
__mg __mg 
ITT 
__mg (MTX) 
__mg (HC) 
__mg (ARAC) 
IV MTX 
____mg 
MP 
____mg 
LEST 
__mg __mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
20/33α/46α 
1 
____mg 
__mg __mg 
__mg (MTX) 
__mg (HC) 
__mg (ARAC) 
 
 
 
a*, b, d, f 
(c, e, g, i)* 
 
 
 
2-5 
 
__mg __mg 
 
 
 
__mg __mg  
 
 
 
6 
 
 
 
 
 
__mg __mg  
 
 
 
7 
 
 
 
 
 
 
 
 
 
(21/34/47)β 8 
 
 
 
____mg 
____mg 
 
b 
 
 
 
9-14 
 
 
 
 
 
 
 
 
(22/35/48)β 15 
 
 
 
____mg 
 
b 
 
 
 
16-21 
 
 
 
 
 
 
 
 
(23/36/49)β 22 
 
 
 
____mg 
 
b 
 
 
 
23-28 
 
 
 
 
 
 
 
 
 
29 
Start next course (Continuation II, Section 4.7.5) the day after Week 49/Day 28 or when blood 
count parameters are met (whichever occurs later). 
Comments may be documented on a separate page. 
α  Begin regardless of counts once off G-CSF for at least 48 hrs 
 
β  For IV MTX/MP: skip week if ANC < 500/µL or plts < 50,000/µL 
* Week 20 (Cycle #1) ONLY 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 3 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 84 
 
 
4.7.4.1 Continuation I (ARM C: IR/HR patients classified as MLL-R) 
Modified Continuation I + Lestaurtinib is for IR/HR patients (30 weeks/210 days). Continuation I occurs in five 
cycles. Cycle #2 lasts 9 weeks, includes the therapy described below and is repeated during Cycle #4. [Cycle #1 lasts 
4 weeks, includes the therapy described previously and is repeated during Cycles #3 and #5]   
 
__________________________ 
Patient name or initials 
__________________________ 
DOB 
Begin Continuation I when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course lasts 30 weeks (Weeks 20-
49) and this Therapy Delivery Map is on three (3) pages. Cycles 2 and 4 are described below. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 
1 minute+ 
0.05 mg/kg/dose 
Day 1 ONLY 
+ Or infusion via minibag as per 
institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/ 
BUN/Cr/AST/ 
ALT/T bili 
d. Serum IgG 
e. CrCl or GFR 
f. CSF cell count, 
diff, cytospin 
g. Local BM eval 
h. PB for 
Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
i. OPTIONAL BM 
for flow MRD, 
molec. MRD & 
resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO/NG/IV 
3 mg/m2/dose BID 
Days 1-5 
Total daily dose: 6 mg/m2/day, divided 
BID 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Day 1 ONLY 
Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring Ommaya 
reservoir administration 
Methotrexate (IV MTX) 
IV push 
20 mg/m2/dose 
Days 8 & 15 
 
Mercaptopurine (MP) 
PO/NG 
75 mg/m2/dose. See Appendix VI. Days 8-21 
Should be given on an empty stomach 
Etoposide (ETOP) 
IV over 2 hrs 100 mg/m2/dose 
Days 22-26 
See page 3 for criteria to receive 
ETOP/CPM 
Cyclophosphamide 
(CPM) 
IV over 30 
min 
300 mg/m2/dose 
Days 22-26 
Mesna 
IV over 30 
min followed 
by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose over 
4 hrs daily (2 total doses/day) 
Days 22-26 
See Section 4.7.4 for infusion details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. 
Days 27 & 45 
Continue until ANC > 1500/µL x 2 
days post nadir; stop at least 48 hrs 
prior to next chemo cycle 
High Dose Cytarabine  
(HD ARAC) 
IV over 3 hrs 3000 mg/m2/dose q12 hrs x 4 
doses total; begin min 48 hrs after 
G-CSF 
Days 43 & 44 See page 3 for criteria to receive HD 
ARAC; see Section 6.4 regarding 
administration of eye drops 
Pegaspargase (PEG-ASP) 
IM 
2500 International units/m2/dose 
Day 44 
3 hrs after final HD ARAC 
Lestaurtinib (LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 2-6, 27-
41 & 45-56 
Should be given with food 
 
Circle Cycle #: 2 
4 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DEX 
___mg ___mg 
ITT 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
IV MTX 
____mg 
MP 
____mg 
LEST 
____mg ____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
(24/37)α 
1 
____mg 
___mg ___mg 
____mg (MTX) 
____mg (HC) 
____mg (ARAC) 
 
 
 
b, d, f 
 
 
 
2 
 
___mg ___mg 
 
 
 
____mg ____mg 
 
 
 
 
3 
 
___mg ___mg 
 
 
 
____mg ____mg 
 
 
 
 
4 
 
___mg ___mg 
 
 
 
____mg ____mg 
 
 
 
 
5 
 
___mg ___mg 
 
 
 
____mg ____mg 
 
 
 
 
6 
 
 
 
 
 
____mg ____mg 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
(25/38)β 
8 
 
 
 
____mg 
____mg 
 
b 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
(26/39)β 
15 
 
 
 
____mg 
 
b 
 
 
 
16 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
c, d 
Comments may be documented on a separate page. 
α  Begin regardless of counts 4 weeks after start of Week 20/33  
β  For IV MTX/MP: skip week if ANC < 500/µL or platelets < 50,000/µL
Page 2 of 3 


 
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Version Date: 04/05/13                                                                                                                 Page 85 
 
 
4.7.4.1 Continuation I (ARM C: IR/HR patients classified as MLL-R) 
Modified Continuation I + Lestaurtinib is for IR/HR patients (30 weeks/210 days). Continuation I occurs in five 
cycles. Cycle #2 lasts 9 weeks, includes the therapy described below and is repeated during Cycle #4. [Cycle #1 
lasts 4 weeks, includes the therapy described previously and is repeated during Cycles #3 and #5] 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Continuation I when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course lasts 30 weeks 
(Weeks 20-49) and this Therapy Delivery Map is on three (3) pages. Cycles 2 and 4 are described below. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 
minute+ 
0.05 mg/kg/dose 
Day 1 ONLY 
+ Or infusion via minibag as 
per institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN, 
Cr/AST/ALT/T 
bili 
d. Serum IgG 
e. CrCl or GFR 
f. CSF cell count, 
diff, cytospin 
g. Local BM eval 
h. PB for 
Lestaurtinib 
PK/PIA (see 
Section 13.1 for 
details) 
i. OPTIONAL BM 
for flow MRD, 
molec. MRD & 
resistance 
mechanisms. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO/NG/IV 
3 mg/m2/dose BID 
Days 1-5 
Total daily dose: 6 mg/m2/day, 
divided BID 
Triple Intrathecal Therapy 
(ITT): 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age (years) 
Dose 
< 1 
MTX: 7.5mg 
 
HC: 7.5 mg 
 
ARAC: 15 mg 
≥ 1 
MTX: 8 mg 
 
HC: 8 mg 
 
ARAC: 16 mg 
Day 1 ONLY 
Note age-based dosing 
 
See Section 5.7 regarding IT 
dose reduction for pts 
requiring Ommaya reservoir 
administration 
Methotrexate (IV MTX) 
IV push 
20 mg/m2/dose 
Days 8 & 15 
 
Mercaptopurine (MP) 
PO/NG 
75 mg/m2/dose 
See Appendix VI for dosing. 
Days 8-21 
Should be given on an empty 
stomach 
Etoposide (ETOP) 
IV over 2 hrs 
100 mg/m2/dose 
Days 22-26 
See below for criteria to 
receive ETOP/CPM 
Cyclophosphamide (CPM) 
IV over 30 min 300 mg/m2/dose 
Days 22-26 
Mesna 
IV over 30 min 
followed by CI 
150 mg/m2/dose with CPM 
followed by 150 mg/m2/dose over 4 
hrs daily (2 total doses/day) 
Days 22-26 
See Section 4.7.4 for infusion 
details 
Filgrastim (G-CSF) 
SubQ/IV 
5 mcg/kg/dose 
Daily beg. 
Days 27 & 45 
Continue until ANC 
> 1500/µL x 2 days post nadir; 
stop at least 48 hrs prior to 
next chemo cycle 
High Dose Cytarabine  
(HD ARAC) 
IV over 3 hrs 
3000 mg/m2/dose q12 hrs x 4 doses 
total; begin min 48 hrs after G-CSF 
Days 43 & 44 See below for criteria to 
receive HD ARAC; see 
Section 6.4 regarding 
administration of eye drops 
Pegaspargase 
(PEG-ASP) 
IM 
2500 International units/m2/dose 
Day 44 
3 hrs after final HD ARAC 
Lestaurtinib (LEST) 
PO/NG 
IR: 5 mg/kg/day divided BID 
HR: 4.25 mg/kg/day divided BID 
Days 2-6, 27-
41, 45-56 
Should be given with food 
 
Circle Cycle #: 
2 
4 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week 
Day 
ETOP 
____mg 
CPM 
____mg 
MESNA 
___mg ___mg 
G-CSF 
____mcg 
HD ARAC 
__mg __mg 
PEG-ASP 
___IU 
LEST 
___mg ___mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
(27/40)α 22 
____mg 
____mg 
___mg ___mg 
 
 
 
 
b 
 
 
 
23 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
 
 
 
24 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
 
 
 
25 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
 
 
 
26 
____mg 
____mg 
___mg ___mg 
 
 
 
 
 
 
 
 
27 
 
 
 
____mcg 
 
 
___mg ___mg 
 
 
 
 
28 
 
 
 
 
 
___mg ___mg 
 
 
 
28/41 
29-35 
 
 
 
 
 
___mg ___mg 
b 
 
 
29/42 
36-39 
 
 
 
 
 
___mg ___mg 
b 
 
 
 
40-41 
 
 
 
 
 
___mg ___mg 
h 
 
 
 
42 
 
 
 
 
 
 
 
 
 
 
(30/43)β 43 
 
 
 
 
__mg __mg 
 
 
b, d 
 
 
 
44 
 
 
 
 
__mg __mg 
___IU 
 
 
 
 
 
45 
 
 
 
____mcg 
 
 
___mg ___mg 
 
 
 
 
46-49 
 
 
 
 
 
___mg ___mg 
 
 
 
31/44 
50-56 
 
 
 
 
 
___mg ___mg 
b 
 
 
32/45 
57-63 
 
 
 
 
 
 
b 
 
 
 
 
         Indicate last G-CSF if past Day 63 _________ 
Comments may be documented on a separate page. 
α  Begin when ANC > 750/µL & plts > 75,000/µL 
 
β  Begin when off G-CSF for at least 48 hrs and ANC > 750/µL & plts > 75,000/µL 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS.  SEE APPENDIX I FOR SUPPORTIVE CARE. 
Page 3 of 3 


 
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Version Date: 04/05/13                                                                                        Page 86 
4.7.5 
Continuation II: Weeks 50-104 (Arm C) 
 
Arm C Continuation II Update as of Amendment #5: 
Lestaurtinib will no longer be administered with Continuation II therapy as of 
Amendment #5. All newly enrolled patients and patients that have not yet reached 
Continuation II will cease lestaurtinib treatment following Continuation I. Patients 
currently receiving Continuation II as of Amendment #5 will cease Lestaurtinib as of the 
activation of the amendment. 
 
To begin Continuation II, patients must have ANC > 750/µL and platelets > 75,000/µL 
and have been off G-CSF for at least 48 hours. 
 
Each cycle of Continuation II lasts 12 weeks and should be repeated until 2 calendar 
years from diagnosis. 
 
Week 50 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
IT Methotrexate: < 1 year: 7.5 mg Day 1 ONLY 
 
 
1 year - < 2 years: 8 mg Day 1 ONLY 
 
 
≥ 2 years: 10 mg Day 1 ONLY 
See Section 5.7 regarding IT dose reduction for patients requiring 
Ommaya reservoir administration 
 
 
Weeks 51-53 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each 
week). Administer in the evening on an empty stomach (at least 1 hour 
before or 2 hours after food or drink except water). Food or milk delays 
absorption and decreases the peak concentration. Tablets are scored and 
doses can be rounded to half tablet. A liquid formulation is available 
(see drug monograph). See Appendix VI for dosing guidelines. 
 
Week 54 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
Continue repeating 
12 week cycles until 
2 years from diagnosis 
(see below for 
remaining cycle 
information).


 
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Version Date: 04/05/13                                                                                        Page 87 
 
 
Weeks 55-57 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week) 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can 
be rounded to half tablet. A liquid formulation is available (see drug 
monograph). See Appendix VI for dosing guidelines. 
 
Week 58 
VinCRIStine: 0.05 mg/kg/dose IV push over 1 minute or infusion via 
minibag as per institutional policy Day 1 ONLY 
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. 
 
Dexamethasone: 6 mg/m2/day PO/NG/IV divided BID Days 1-5 
 
Weeks 59-61 
Methotrexate: 20 mg/m2/dose PO/NG weekly (Day 1 of each week) 
 
Mercaptopurine: 75 mg/m2/dose PO/NG daily (Days 1-7 of each week). 
Administer in the evening on an empty stomach (at least 1 hour before or 
2 hours after food or drink except water). Food or milk delays absorption 
and decreases the peak concentration. Tablets are scored and doses can 
be rounded to half tablet. A liquid formulation is available (see drug 
monograph). See Appendix VI for dosing guidelines. 
 
The therapy delivery map (TDM) for Continuation II is on the next page. 
Continue repeating 
12 week cycles until 
2 years from diagnosis 
(see above for weeks 
50-54). 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 88 
 
 
4.7.5.1 Continuation II (ARM C: IR/HR patients classified as MLL-R) 
Modified Continuation II is for IR/HR patients. (12 week cycles repeated until 2 years from 
diagnosis). Each cycle is 12 weeks in length and includes the therapy described below. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin Continuation II when ANC > 750/µL and platelets > 75,000/µL and have been off G-CSF for at least 48 hrs. This Course is composed of 
12-week cycles that are repeated until 2 calendar years from diagnosis; this Therapy Delivery Map describes one cycle and is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
IV push over 1 min+ 0.05 mg/kg/dose 
Days 1, 29 & 57 
+ Or infusion via minibag as per 
institutional policy 
a. History, physical, 
ht/wt, BSA 
b. CBC (diff/plt) 
c. Electrolytes/BUN/C
r/AST/ALT/ 
T bili 
d. Serum IgG 
e. CSF cell count, diff, 
cytospin 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO/NG/IV 
3 mg/m2/dose BID 
Days 1-5, 29-33 & 
57-61 
Total daily dose: 6 mg/m2/day, 
divided BID 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (years) Dose 
< 1 
7.5 mg 
1 - < 2 
8 mg 
≥ 2 
10 mg 
Day 1 ONLY 
Note age-based dosing 
 
See Section 5.7 regarding IT dose 
reduction for pts requiring Ommaya 
reservoir administration  
Methotrexate  
(MTX) 
PO/NG 
20 mg/m2/dose 
Days 8, 15, 22, 36, 
43, 50, 64, 71 & 78 
Hold with IT MTX 
Mercaptopurine  
(MP) 
PO/NG 
 
75 mg/m2/dose 
See Appendix VI for 
dosing. 
Days 8-28, 36-56 & 
64-84 
Should be given on an empty 
stomach 
 
Cycle # _______ 
 
 
 
Ht_____cm 
        Wt________kg 
 
         BSA________m2 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DEX 
___mg ___mg 
IT MTX 
____mg 
PO MTX 
_____mg 
MP 
____mg 
 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
50 
1 
____mg 
____mg ____mg 
____mg 
 
 
(a, c, d, e)*, b 
 
 
 
2 
 
____mg ____mg 
 
 
 
 
 
 
 
3 
 
____mg ____mg 
 
 
 
 
 
 
 
4 
 
____mg ____mg 
 
 
 
 
 
 
 
5 
 
____mg ____mg 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
51 
8 
 
 
 
_____mg 
____mg 
 
 
 
 
9-14 
 
 
 
 
 
 
 
52 
15 
 
 
 
_____mg 
 
 
 
 
16-21 
 
 
 
 
 
 
 
53 
22 
 
 
 
_____mg 
 
 
 
 
23-28 
 
 
 
 
 
 
 
54 
29 
____mg 
____mg ____mg 
 
 
 
b 
 
 
 
30-33 
 
____mg ____mg 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
 
 
 
55 
36 
 
 
 
_____mg 
____mg 
 
 
 
 
37-42 
 
 
 
 
 
 
 
56 
43 
 
 
 
_____mg 
 
 
 
 
44-49 
 
 
 
 
 
 
 
57 
50 
 
 
 
_____mg 
 
 
 
 
51-56 
 
 
 
 
 
 
 
58 
57 
____mg 
____mg ____mg 
 
 
 
b 
 
 
 
58-61 
 
____mg ____mg 
 
 
 
 
 
 
 
62 
 
 
 
 
 
 
 
 
 
63 
 
 
 
 
 
 
 
 
59 
64 
 
 
 
_____mg 
____mg 
 
 
 
 
65-70 
 
 
 
 
 
 
 
60 
71 
 
 
 
_____mg 
 
 
 
 
72-77 
 
 
 
 
 
 
 
61 
78 
 
 
 
_____mg 
 
 
 
 
79-84 
 
 
 
 
 
 
 
 
End of Therapy 
 
 
 
Comments may be documented on a separate page. 
 
 
 
* Start of each 12-week cycle 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND APPENDIX I FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 89 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
Notify a Study Co-Chair at the time of removing a patient from protocol therapy for toxicity. The drugs are 
listed in alphabetical order. 
 
5.1 
Asparaginase [E. coli, Pegaspargase (PEG-Asparaginase) or Erwinia] 
Allergy 
Because of toxicity concerns with the use of pegaspargase during Induction, patients developing 
allergic reactions to E. coli asparaginase during Induction will receive Erwinia asparaginase for 
each remaining dose of E. coli asparaginase. Also, in cases where E. coli asparaginase is not 
available, Erwinia asparaginase should be substituted. If Erwinia asparaginase is not available, then 
the remaining doses of E. coli asparaginase during Induction should be omitted. If the patient 
develops a severe allergic reaction to Erwinia during Induction, then the remaining doses during 
Induction should be omitted. Upon completion of Induction, patients should resume therapy with 
pegaspargase. If allergy subsequently develops to pegaspargase, patients should then receive 
Erwinia asparaginase for any remaining pegaspargase doses. If the patient previously experienced 
severe allergic reaction to Erwinia during Induction, the decision to administer any asparaginase 
product in the post-Induction period should be carefully weighed by the treating physician.  
 
Local Allergic Reactions (inflammation at injection site, swelling): 
Continue administration in the presence of Grade 1 allergy as defined by CTCAE v4.0 (transient flushing 
or rash; drug fever < 38ºC).  
 
Systemic Allergic Reactions: Discontinuation may be considered for severe Grade 2 or higher allergic 
reactions as defined by CTCAE v4.0. 
 
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 severe systemic or recurrent local allergic reaction, 
Erwinia asparaginase should be substituted. 
 
Anaphylaxis: Discontinue pegaspargase or E. coli asparaginase 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.44,45 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.46 
Current COG trials have adopted pegaspargase as the preparation of choice, based on the results of CCG 
1962.47 COG AALL07P2 showed that Erwinia asparaginase was well tolerated and achieved nadir serum 
asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with 
pegaspargase. Based on these and other data, the FDA approved Erwinia asparaginase for use following 
allergy to pegaspargase, with a dose of Erwinia 25,000 IU/m2 x 6 doses IM on a 
Monday/Wednesday/Friday schedule substituted for a single dose of pegaspargase. 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 90 
The dose modification guidelines for ALL trials recommend the substitution of Erwinia asparaginase for 
either native or pegaspargase utilizing the following schedule: 
 
 
 
Phase(s) of Treatment1 
Drug(s) 
Replacement Schedule for Erwinia 
asparaginase 
Induction therapy 
(≥ 6 months at diagnosis) 
One or more doses of E. coli 
asp (7,500 IU/m2) 
30,000 IU/m2/dose IM for each 
remaining dose of E. coli asparaginase 
Induction therapy 
(≥ 7 days - < 6 months of age at diagnosis) 
One or more doses of E. coli 
asp (6,675 IU/m2) 
27, 000 IU/m2/dose IM for each 
remaining dose of E. coli asparaginase 
Induction therapy 
(< 7 days of age at diagnosis) 
One or more doses of E. coli 
asp (5,000 IU/m2) 
20,000 IU/m2/dose IM for each 
remaining dose of E. coli asparaginase 
Post-Induction therapy 
One or more doses of 
pegaspargase (2,500 IU/m2) 
25,000 IU/m2/dose IM 
M/W/F x 6 doses 
1 Patients developing allergy to E. coli asparaginase during Induction should receive Erwinia asparaginase for each remaining E. coli 
asparaginase during Induction as indicated in the table. These patients should resume therapy with pegaspargase post-Induction. If 
subsequent allergy develops to pegaspargase, they should receive Erwininia asparaginase as outlined in the table. 
 
 
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. There are no specific guidelines available. 
 
Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically indicated. 
 
Hyperlipidemia: Do not modify dose. 
 
Ketoacidosis: Hold asparaginase until blood glucose can be regulated with insulin. 
 
Pancreatitis (Grade 3-4): Discontinue asparaginase in the presence of hemorrhagic pancreatitis or severe 
pancreatitis. In the case of mild pancreatitis, asparaginase should be held until symptoms and signs 
subside, and amylase levels return to normal and then resumed. Severe pancreatitis is a contraindication 
to additional asparaginase administration. 
 
Thrombosis: Withhold asparaginase until resolved, and treat with appropriate anti-thrombotic therapy, as 
indicated. Upon resolution of symptoms consider resuming asparaginase, while continuing LMWH or anti-
thrombotic therapy. Do not withhold dose for abnormal laboratory findings without clinical correlate. 
 
CNS Events (bleed, thrombosis or infarction): Discontinue asparaginase. Treat as appropriate. 
 
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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Version Date: 04/05/13                                                                                                                 Page 91 
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) 
ARAC Syndrome: Do not withhold ARAC for fever if it is likely to have been caused by the ARAC. 
Obtain blood cultures if a central line is present. For rash or conjunctivitis, withhold for Grade 3-4 
toxicity until resolved. Make up missed doses and consider concurrent treatment with hydrocortisone or 
dexamethasone, and/or with dexamethasone ophthalmic drops for conjunctivitis. Once the cycle with HD 
ARAC (Induction 3, Intensification 2) has started do not interrupt for uncomplicated myelosuppression; 
do hold for ANC < 500/L and severe infection. Do make up missed doses. 
 
Adequate renal function (as defined as creatinine within normal range) is required for the administration 
of high dose ARAC. Creatinine Clearance should be measured for patients with elevated creatinine or 
suspected renal insufficiency. For CrCl < 60 mL/min/1.73 m2, hold pending recovery and omit if recovery 
requires > 3 weeks. 
 
5.4 
Daunorubicin  
Cardiac Toxicity: Discontinue for clinical or echocardiographic evidence of cardiomyopathy (SF < 27% 
or EF < 50%) or Grade 3-4 LVSD per CTCAE version 4.0. 
 
Note: use the following term to report decreases in the EF or SF: Cardiac disorders – other.  
 
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. 
 
Hyperbilirubinemia:  
Direct bilirubin < 1.2 mg/dL 
- Full dose 
Direct bilirubin 1.2-3.0 mg/dL - 50% dosage decrease. 
Direct bilirubin 3.1-5.0 mg/dL - 75% dosage decrease. 
Direct bilirubin > 5 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/extravasationguidelines.pdf for COG 
guidelines. 
 
Perineal Irritation: 
See Appendix I. 
 
5.5 
Etoposide (VP-16) 
Allergic Reaction: Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose is 
50 mg). If symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use premedication before 
etoposide in future. Also consider substituting an equimolar amount of etoposide phosphate, in the face of 
significant allergy and/or hypotension. Etoposide phosphate is a water soluble prodrug that does not 
contain polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that may induce 
allergic reactions and hypotension. 
 
Hypotension: If hypotension develops during infusion, hold infusion and manage blood pressure. When 
blood pressure is stable, consider resuming infusion at 25%-50% reduction in rate. 
 


 
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Renal Insufficiency: If renal function decreases, adjust etoposide as follows: CrCl 10-50 mL/min/1.73 m2, 
decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 50%. 
 
Hyperbilirubinemia: If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct bilirubin is 
> 5 mg/dL, hold etoposide. 
 
5.6 
Lestaurtinib  
While a patient is receiving scheduled doses of lestaurtinib, either of the following adverse events 
necessitates cessation of lestaurtinib: 
 
 
Any Grade 3 or greater non-hematologic toxicity that is at least possibly attributable to 
lestaurtinib and is of at least 48 hours duration, with the specific exception of: febrile neutropenia, 
infection, constitutional symptoms (see Section 4.2), mucositis and diaper area skin ulceration. 
 
 
Any life-threatening toxicity regardless of attribution and of any duration 
 
Missed doses will not be made up. Lestaurtinib therapy may not resume until the toxicity has resolved to 
≤ Grade 2. If the toxicity that caused the cessation is NOT a DLT (as defined in Section 4.2.3), then 
lestaurtinib therapy may resume without dose modification with the next scheduled dose. If the toxicity 
that caused the cessation is a DLT, and is the patient’s first DLT, then lestaurtinib therapy may resume 
with a 25% dose reduction with the next scheduled dose. Patients that experience a second DLT after a 
dose reduction will be required to discontinue lestaurtinib therapy. Dose modification or withholding of 
doses other than as described in this section is not permitted. 
 
NOTE: A study co-chair should be notified for all lestaurtinib dose modifications. 
 
5.7 
Intrathecal Methotrexate/Triple Intrathecal Therapy 
Do not withhold dose given on Day 1 of Induction.   
 
Systemic toxicity: The dosage for IT chemotherapy will not be reduced for systemic toxicity 
(myelosuppression, mucositis, etc). Instead, leucovorin may be used at a dose of 5mg/m2/dose every 12 hours 
x 2 doses, beginning 48 hours after the IT therapy has been delivered. IT MTX does have a systemic effect 
and is cleared by the kidney. Consider omitting MTX in the face of renal failure or severe dysfunction. 
 
Dose modifications following an episode of acute neurotoxicity: 
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.48-53 It is clear however, that CNS prophylaxis is a mandatory 
component of curative therapy for children with ALL. Effective prophylaxis generally takes two 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, Ara-C and hydrocortisone). For 
infants, the latter approach is generally used due to high risk of radiation-induced neurotoxicity.   
 
Guidelines are offered for consideration following an acute event. 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 
with appropriate laboratory and radiological evaluation.   
 
Many acute events like seizures or episodes of transient hemiparesis, are temporally related to the 
administration of intrathecal therapy, commonly 9 to 11 days after the IT administration.54 For patients 
who return to their “pre-event” status, without residual deficits on physical or neurologic exam, there are 
few data to support or guide therapeutic interventions. It is reasonable to hold the next dose of IT therapy, 


 
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or, substitute IT ARAC for one 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. In the face of 
multiple 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.   
 
Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal chemotherapy 
via lumbar puncture:  
Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal therapy delivered 
by LP. Intraventricular chemotherapy should be given according to the same schedule, but at 50% of the 
corresponding age-based doses that would be given by LP. NOTE: Obstruction to CSF flow may be a 
contraindication to intrathecal and/or intraventricular therapy. 
 
Viral, bacterial, or fungal meningitis:  Omit until resolved. 
 
5.8 
High-Dose Methotrexate (HD MTX) and Leucovorin Rescue 
[Please note that HD MTX refers to IV MTX 4 or 5g/m2 given over 24 hrs] 
Methotrexate levels at 24 hours following HD MTX range from 30-70 µM. The treating physician should 
be notified of all MTX levels. Levels at 24 hours which exceed 90 µM should lead the physician to 
carefully monitor subsequent levels and renal function. 
 
HD MTX Infusion Guidelines 
See Appendix V for a flowchart of the HD MTX/LCV guidelines. 
 
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of 
the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX bolus). 
 
Hold TMP-SMX 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, as well as nonsteroidal anti-inflammatory agents, 
proton pump inhibitors, aspirin-containing drugs and penicillins. 
 
Infants receiving therapeutic doses of amphotericin should have that drug withheld on the day HD MTX 
is administered and for the following 24 hours due to the risk of delayed MTX excretion, renal 
dysfunction and resultant toxicity. 
 
See Appendix I for supportive care guidelines aimed at reducing the risk of perineal irritation associated 
with HD MTX administration. 
 
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. Adjust fluid volume and sodium bicarbonate to 
maintain urine specific gravity and pH at above parameters. A bicarbonate bolus (25 mEq/m2 over 15 
min) may be given to raise the urine pH relatively quickly, a normal saline bolus may also be helpful in 
facilitating hydration. Continue hydration and alkalinization throughout HD MTX infusion, and for a 
minimum of 48 hours after its completion. In patients with delayed MTX clearance, continue hydration 
until the plasma MTX concentration is below 0.1 µM. 
 
Hour 0: MTX 200 mg/m2 IV mixed in 40 mL/m2 D5 ¼ NS with 30 mEq NaHCO3/L and infused over 
20 minutes. This is followed, immediately, by MTX 3800 mg/m2 mixed in 2960 mL/m2 D5 ¼ NS with 
30 mEq NaHCO3/L given by continuous IV infusion over the remainder of 24 hours at 125 mL/m2/hr. Be 
certain that the HD MTX 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 MTX level and serum creatinine; NOTE: 36 hour level is only drawn if 
needed (see below) 
 
 
For MTX levels that exceed these expected values modify the rescue regimen as noted below 
and increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value ≥ 7 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 MTX 
contamination is possible. While waiting for the result and if the value is “real” refer to the 
changes in hydration, etc. described above and repeat the level with a serum Cr at hour 36. Then 
refer to the table below. 
 
 
If the 42 and 48 hour levels are ≤ 1 and 0.4 M, respectively, give leucovorin at 15 mg/m2 
IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No additional levels are 
needed, nor is additional leucovorin. 
(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 and 
monitor urine output to determine if volume is > 80% of the fluid intake, measured every 4 hours. If urine output fails 
to continue at 80% of the fluid intake, consider furosemide. Regardless of urine output, also consider glucarpidase if 
36 hour MTX level exceeds 10 M (see below). 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of ≤ 1 
and/or ≤ 0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine output 
remains satisfactory.  
 
Nephrotoxicity: Postpone course if pre-treatment (MTX) serum creatinine is > 1.5 x baseline or GFR 
creatinine clearance < 65 mL/minute/1.73m2. If renal function does not recover, omit MTX. Do not give 
HD MTX to a patient with this degree of renal impairment, assuming that prolonged excretion can be 
managed with glucarpidase.   
 
NOTE: For patients who have markedly delayed MTX clearance secondary to renal dysfunction, strongly 
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 


 
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availability through ASD Healthcare, Cardinal, and McKesson. Canadian sites should contact McKesson 
at (877) 384-7425 for further information. Sites in Australia and New Zealand should contact Hospira at 
1300-046-774 (local) or medicalinformationAUS@hospira.com.Patients requiring glucarpidase rescue will 
remain on study.  
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to 
a course of intravenous MTX. Blood samples for ALT should not be drawn following the start of MTX 
infusions as MTX causes significant short term elevation in ALT levels. 
 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 consecutive 
cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses 
at point of interruption. 
Do not skip doses. 
> 20 X ULN 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses 
at point of interruption.   
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, 
total protein, and hepatitis A, B, C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy given.   
*Alternative prophylaxis with dapsone, aerosolized pentamidine, or atovaquone (30 mg/kg/day if 1-3 mo. or 
> 2 years, 45 mg/kg/day if between 3 mo. & 2 years) should be considered. 
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
Mucositis: For Grade 3-4 mucositis, withhold IV MTX until resolved. Decrease subsequent IV MTX dose by 
20%. If subsequent cycle is not associated with Grade 3-4 mucositis, attempt to increase to full dose MTX for 
next cycle. Considering culturing lesions for herpes simplex if mucositis persists or recurs. 
 
Myelosuppression: If prolonged neutropenia (ANC < 750/µL for more than 7 days) despite 
discontinuation of TMP/SMX or prolonged thrombocytopenia (platelets < 75,000/µL for > 7 days) then 
hold IV MTX until recovery and then administer IV MTX at full dose. If prolonged myelosuppression 
recurs then reduce methotrexate dose by 20%.  
 
5.9 
Weekly IV or PO/NG Methotrexate (MTX) and 6-Mercaptopurine (6-MP) 
Continuation I (ARM A: Weeks 21-23, 25-27, 32-34, 36-38; ARMS B/C: Weeks 21-23, 25-26, 34-36, 38-
39, 47-49) 
Check counts weekly prior to IV MTX/MP dosing. If ANC < 500/µL or platelets < 50,000/µL, skip that 
week’s therapy (one IV MTX dose and seven daily doses of 6-MP). Do not make up missed weeks. For 
first episode of a skipped week of IV MTX/MP, resume IV MTX/MP at 100% dosing. For each 
subsequent episode of a skipped week of IV MTX/MP, resume IV MTX/MP with a 25% reduction in 
dose. Consider discontinuing TMP/SMZ and starting alternative PCP prophylaxis as per supportive care 
guidelines in Appendix I. Perform thiopurine pharmacology testing as described below. 
 
*ADDITIONAL NOTES for Continuation I: 
1) Do not escalate IV MTX/MP above 100% dosing during Continuation I. 
2) ARM A:  


 
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 
For Weeks 24 & 35 VCR/DEX/ITT: Begin regardless of counts 4 weeks after the start of Week 
20/31. 
 
For Week 31 VCR/DEX/ITT: Begin regardless of counts once off GCSF for 48 hours. 
3) ARMS B/C:  
 
For Weeks 24 & 37 VCR/DEX/ITT (+/-Lestaurtinib): Begin regardless of counts 4 weeks after 
the start of Week 20/33.  
 
For Weeks 33 & 46 VCR/DEX/ITT: Begin regardless of counts once off GCSF for 48 hours. 
 
Continuation II: 
Check counts every 4 weeks. If neutrophil count falls below 500/L or if platelet count falls below 
50,000/L during Continuation II, only MP and MTX will be held until recovery above these levels. For 
the first drop in ANC or platelets, resume chemotherapy at 100% after ANC is ≥ 750/µL and platelets are 
≥ 75,000/µL. If neutrophil count falls below 500/L or if platelet count falls below 50,000/L for a 
second time, discontinue doses until ANC is ≥ 750/µL and platelets are ≥ 75,000/µL. Restart 
mercaptopurine and/or MTX at 50% of the original dose on the same day the counts recover. Increase to 
75% and then 100% of the original dose at 2-4 week intervals provided ANC remains ≥ 750/µL and 
platelets remain ≥ 75,000/µL. Consider discontinuing TMP/SMZ and starting alternative PCP prophylaxis 
as per supportive care guidelines in Appendix I. If neutrophil count falls below 500/µL or if platelet count 
falls below 50,000/µL on ≥ 2 occasions during Continuation, 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 Continuation II: 
For ANC ≥ 1500/L on 3 CBC(s) done over 6 weeks or 2 successive monthly CBC(s) alternately increase 
doses of MTX or MP by 25%. If both MTX and MP are increased once without a fall in ANC, consider 
noncompliance as a possibility. Noncompliance can be assessed by obtaining sample for RBC thioguanine 
nucleotides (TGNs). Consider observing the administration of an oral dose of MTX and checking plasma 
MTX 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: 
MTX should be reduced to 50% if Grade 3 toxicity develops; withhold in the presence of Grade 4 toxicity 
until there is a resolution, then resume at 50% of original dose with gradual dose escalation. If mucositis 
persists or recurs, consider culturing for herpes simplex. 
 
Liver Dysfunction: 
For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN consistent with 
Grade 3 toxicity, obtain total bilirubin. Monitor SGPT/ALT or SGOT/AST and total bilirubin every 2 weeks 
during Consolidation and every 4 weeks during Maintenance as long as transaminases remain over 5x ULN. 
 
Continue full dose therapy unless either of the following occurs: 
1) Direct bilirubin > 2.0 mg/dL  
2) SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) on 2 determinations at 
least 1 week apart. 
 
If either of these occurs, hold MTX and monitor labs as above, weekly. Restart at full dose therapy when the 
transaminase is less than 5x ULN, if bilirubin is normal. If liver dysfunction persists, consider a trial period 
with MTX but without 6MP, especially if red cell meTIMP is elevated. If liver function improves in the 
absence of MP, consider resuming MP dose at 50% and escalating every 2 weeks as tolerated.  Also consider 
liver biopsy. 
 


 
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Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT or SGOT/AST 
above 5x ULN. 
 
Thiopurine Pharmacology Testing and Dosage Adjustments: 
MP and TG are methylated directly by thiopurine methyltransferase (TPMT) to an inactive metabolite.  
TPMT activity varies tremendously among patients, because of a common inherited genetic defect in 
TPMT. One in 300 patients is completely deficient (homozygous defective) and 10% of the population are 
moderately deficient in TPMT activity because they have inherited 1 variant (non-functional) TPMT allele 
(i.e., heterozygotes).57-60 Patients with low TPMT form higher concentrations of the thioguanine nucleotides 
(TGNs) and are more susceptible to acute thiopurine toxicity (primarily myelosuppression, involving 
neutropenia, thrombocytopenia, and anemia). Patients with the complete deficiency of TPMT tolerate less 
than 10% of protocol doses of MP (10 to 30 mg/m2/day 3 days per week). About 35% of heterozygotes 
require a lower dose of MP to avoid dose-limiting myelosuppression.61  
 
There are now CLIA certified tests for TPMT genotype and phenotype, and for meTIMP and TGN 
measurements.  
 
Recommendations for Thiopurine Monitoring and Dosage Adjustments: 
When myelosuppression has led to significant delays in therapy (> 2 weeks) or is disproportionate to the 
therapy, thiopurine testing should be performed: 
-  
For patients who have received full dose thiopurine therapy during the 2 weeks immediately 
preceding the test, RBC thiopurine metabolites will likely predict TPMT status and actual 
thiopurine exposure. 
-  
In the absence of RBC transfusions for 3 months prior, TPMT activity will accurately reflect 
TPMT status 
-  
TPMT genotyping will be informative in all patients, if at least 1 mutant allele is identified. If 
not, and myelosuppression continues, send samples for TPMT activity and/or metabolites 
since TPMT genotyping will miss 5%-10% of mutants. NOTE: Genotyping can be done 
despite recent transfusions. 
 
Suggested Dose adjustments in patients with unacceptable myelosuppression: 
-  
If the patient is homozygous deficient for TPMT, the thiopurine dose should be reduced to 10-
20 mg/m2/day 3 days per week. If the patient is heterozygous for TPMT and has experienced 
significant myelosuppression, the thiopurine dose should be reduced by 30%-50%. Do not 
increase the dose in response to a high ANC for 4 weeks to allow for achievement of steady 
state. All other myelosuppressive medications should be delivered at full dose, and the 
thiopurine dose should be titrated based on blood counts. Further thiopurine pharmacologic 
measures are not often necessary. 
-  
If the patient is homozygous wild-type (high activity) for TPMT, then discontinue TMP/SMZ 
and use pentamidine or dapsone. For modifications of the oral MP and MTX, see the beginning 
of this section (5.9). 
 
At the time of clinic visit the treating physician needs to follow-up with the caregiver to ascertain that the 
patient has been receiving the oral medication per protocol and this information needs to be documented in 
the patient record. 
 
5.10 
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. 


 
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Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase. Discontinue steroids, 
except for stress doses, in the presence of hemorrhagic pancreatitis or severe pancreatitis (abdominal pain 
> 72 hours and ≥ Grade 3 amylase elevation (> 2.0 x ULN).   
 
Osteonecrosis: Do not modify corticosteroid therapy for osteonecrosis (also referred to as avascular necrosis) 
prior to Continuation. Consider omitting Continuation steroid for osteonecrosis Grade 1 (clinically 
asymptomatic, radiographic finding only). Omit Continuation steroid for osteonecrosis Grade 2 or greater, 
and notify Study Chair. Consider resuming Continuation steroid after 6 months if joint symptoms have 
resolved and if MRI findings have significant improved or normalized. 
 
Varicella: Steroids should be held during active infection except during Induction. Do not hold during 
incubation period following exposure. 
 
Inability to use oral doses: For prednisone, substitute IV methylprednisolone at 80% of the oral prednisone 
dose. Note that if substituting prednisolone for prednisone, the doses are the same; prednisone is converted in 
the liver to prednisolone. For dexamethasone, substitute the IV preparation mg for mg.   
 
Severe infection: Do not hold or discontinue steroids during Induction without serious consideration, as this is 
a critical period in the treatment of ALL. Later in therapy, one may consider holding steroid until patient 
achieves cardiovascular stability, except for “stress doses.” 
 
Severe psychosis: Steroid dose may be decreased by 50% for severe psychosis. 
 
5.11 
Vincristine 
 
** PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See 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. Severe peripheral neuropathies, with or without a positive family 
history might suggest the need for a molecular diagnostic evaluation to rule out hereditary neuropathy 
syndromes.   
 
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. Physical therapy may be beneficial   
 
Jaw pain: Treat with analgesics; do not modify vincristine dose. 
 
Hyperbilirubinemia:62,63  
 
Direct bilirubin  
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 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. 


 
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Extravasation: In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to institutional guidelines. 
Also see https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for 
COG guidelines.  
 
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 (such as grasp, rake or reach) or gross motor skills (such 
as head control, sit, ambulate) without abrogating ability to perform these tasks. 
• Grade 3: Unable to perform fine motor tasks (such as grasp, rake or reach) or gross motor skills (such as 
head control, sit, 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 (such as grasp, rake or reach) or gross motor 
skills (such as head control, sit, ambulate), without abrogating ability to perform these tasks. 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function (gross 
and 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. 
 
5.12 
Drug Interactions 
Lestaurtinib is metabolized by the cytochrome P450 isoform CYP3A4/5. Potent inhibitors of CYP3A4/5 
are likely to inhibit lestaurtinib metabolism and increase systemic exposure. Therefore, concomitant 
treatment with lestaurtinib and cyclosporine, HIV (human immunodeficiency virus) protease inhibitors, 
and nefazodone (see Appendices II and III for additional details) and the agents listed in the table below 
should be avoided. It is also likely that inducers of CYP3A4/5, such as dexamethasone and St. John’s 
Wort will reduce the plasma exposure to lestaurtinib. Concomitant administration of these drugs is also 
discouraged, except for dexamethasone as prescribed in the treatment regimen (see Appendix II for 
additional details). 
 
In addition, 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.64 Neither gabapentin nor levetiracetam induce hepatic drug metabolizing enzymes and may be 
suitable alternative anticonvulsant. Azole antifungals (e.g., fluconazole, itraconazole, voriconazole, 
posaconazole, and ketoconazole) and the macrolide group of antibiotics (e.g., erythromycin, 
clarithromycin, and azithromycin) may have potent inhibitory effects on drug-metabolizing enzymes, and 
the doses of some antileukemic drugs (e.g., vincristine, anthracyclines, etoposide) may need to be reduced 
in some patients on chronic azole antifungals or antibiotics (see table below). 


 
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DRUGS 
POTENTIAL INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug metabolizing 
enzymes 
Lowered EFS 
AVOID phenytoin, phenobarbital, 
carbamazepine 
Consider gabapentin or levetiracetam 
(Keppra) as alternative 
Rifampin 
Induction of drug metabolizing 
enzymes  
DO NOT USE 
Azole Antifungals 
(fluconazole, itraconazole*, 
voriconazole, ketoconazole) 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS. 
May need dose reductions of 
vincristine*, anthracyclines, 
etoposide, steroids 
Macrolide Antibiotics 
(erythromycin, clarithromycin, 
azithromycin, troleandomycin) 
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.65,66 
 
For more complete list of CYP3A4/5 Inhibitors and Inducers see Appendix II. Please note: patients 
assigned to receive lestaurtinib should avoid concomitant treatment with CYP3A4/5 Inhibitors or 
Inducers (see Sections 4.1.2.2 and 4.1.2.3). 
 
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: 
When IT therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy 
within 6 hours of the beginning of the IV methotrexate infusion (hour -6 to +6, with 0 being the start of 
the methotrexate bolus). 
 
Hold 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 0.4 M. In the presence of 
delayed clearance, continue to hold TMP/SMX until 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 0.4 M. In the presence of delayed clearance continue 
to hold these medications until methotrexate level is less than 0.1 M. 


 
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6.0 
DRUG INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 104 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 106 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 107 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 108 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   


 
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Version Date: 04/05/13                                                                                                                 Page 109 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


 
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Version Date: 04/05/13                                                                                                                 Page 110 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 112 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 


 
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Version Date: 04/05/13                                                                                                                 Page 113 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 114 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 115 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 116 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 117 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 119 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
. 
 


 
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Version Date: 04/05/13                                                                                                                 Page 120 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
. 


 
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Version Date: 04/05/13                                                                                                                 Page 121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 122 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 123 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
t 
to 
 
 
 
 
  
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 124 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 125 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 126 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 


 
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Version Date: 04/05/13                                                                                                                 Page 127 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 128 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version Date: 04/05/13                                                                                                                 Page 129 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
(X = start of phase) 
STUDIES TO BE OBTAINED 
Pre-treatment/ 
Induction 
Induction 
Intensification 
Re-
Induction 
Consolidation 
Continuation I 
Continuation 
II 
Off 
Therapy  
Relapse, 
Progression 
REQUIRED 
Hx/PE/Ht/Wt/BSA 
X 
X 
X 
X 
X 
Every 12 wks 
X 
X 
CBC/diff/plt 
Weekly 
Days 1, 8, 15 Days 1, 15 Days 1, 15, 29 
Weekly 
Every 4 wks 
X 
X 
Electrolytes/BUN/Cr/AST/ALT/T bili 
Days 1, 15 & 29 
X 
X 
Days 1, 15 
Arm A: Wks 20, 31 
Arms B/C: Wks 20, 26, 39 Every 12 wks 
X 
X 
Serum IgG† 
Days 1, 15 & 29 
Days 1, 15 
X 
X 
See below1 
Every 12 wks 
X 
X 
Echo or MUGA 
X 
 
X 
 
 
 
X 
 
CrCl or GFR (may be estimated using 
Schwartz method) 
X 
 
 
 
X 
 
X 
 
CSF cell count/diff/cytospin 
With IT 
With IT 
With IT 
With IT 
With IT 
With IT 
X 
X 
Local bone marrow evaluation@ 
X@ 
X 
X 
 
X 
 
 
X 
Bone marrow for AALL08B1 (Columbus)$ 
X$ 
 
 
 
 
 
 
X 
Blood for lestaurtinib PK/PIA (Hopkins) 
X# 
X& 
X& 
 
X& 
 
 
 
Supportive care measures† 
Induction 
 
 
 
 
 
 
 
OPTIONAL 
Bone marrow for flow MRD, molecular 
MRD and resistance mechanisms (Hopkins)^ 
X^ 
Week 6 
Week 10 
 
Week 20 
 
 
X 
@ Pre-treatment local bone marrow evaluation MUST include MLL FISH and standard cytogenetics performed at a COG-certified institutional or commercial laboratory.  MLL FISH results 
must be entered into RDE no later than Day 10.  In cases where bone marrow aspirate cannot be performed for medical reasons, or adequate material cannot be obtained, it is permissible to 
establish the diagnosis using peripheral blood IF there are at least 2500 circulating blasts/µL (i.e., WBC of 10,000 with 25% blasts or WBC of 5000 with 50% blasts). 
$ 
5 mL in EDTA or heparin.  For patients undergoing leukopheresis or manual exchange transfusion, shipment of entire pheresis bag or anticoagulated manually exchanged blood to Columbus 
is highly encouraged, and may be substituted for bone marrow.  IF there are at least 2500 circulating blasts (i.e., WBC of 10,000 with 25% blasts or WBC of 5000 with 50% blasts), 
peripheral blood (at least 5 mL in EDTA or heparin) may be submitted in addition to bone marrow (highly encouraged) or as a substitute for bone marrow (permissible in cases where bone 
marrow aspirate cannot be performed for medical reasons, or adequate material cannot be obtained).  
#  All patients must have pre-treatment blood sample (3 mL in heparin) sent to Johns Hopkins for baseline measurements.   
& 3 mL in heparin.  Applies ONLY to MLL-R patients receiving lestaurtinib.  See Sections 4.7.1, 4.7.2, 4.7.4 and 13.1 for detailed blood collection schedule.  
^ 
5 mL in heparin. For patients undergoing leukopheresis or manual exchange transfusion, a portion (at least 5 mL in heparin or other anticoagulant) of the pheresate/exchanged blood may be 
substituted for bone marrow (in these cases, the pheresis bag/remainder of exchanged blood should be shipped to Columbus).  IF there are at least 2,500 circulating blasts/µL (i.e., WBC of 
10,000 with 25% blasts or WBC of 5,000 with 50% blasts), peripheral blood (at least 5 mL in heparin) may be submitted in addition to bone marrow (highly encouraged) or as a substitute for 
bone marrow (permissible in cases where bone marrow aspirate cannot be performed for medical reasons, or adequate material cannot be obtained). 
† Data regarding serum IgG levels, anti-fungal treatment & hospitalization should be submitted via the eRDES on the Induction Reporting Period CRF (see Appendix I for full details). 
1 
Arm A: Weeks 20, 24, 31, 35, 38; Arms B/C: Weeks 20, 24, 26, 30, 33, 37, 39, 43, 46 (see Sections 4.5.4.1, 4.6.4.1, and 4.7.4.1 for details). 
See Section 13.0 for specimen handling/shipping instructions. 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and 
family logistical, or facility,  procedure and/or anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol).  


 
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7.2 
Recommended Follow-up  
 
Year One:  
-Hx/PE/HT/WT/FOC/CBC diff plt - q month 
-MUGA or ECHO/ EKG 
-LFT/RFT/UA 
-Neuropsychological testing 
-Serum IgG q 4 weeks until normal 
-Continue TMP/SMZ off therapy for 6 months. 
-BM/CSF exams as indicated 
 
Year Two:  
-Hx/PE/HT/WT/FOC/CBC diff plt - q 2 months 
-MUGA or ECHO/ EKG (if normal, repeat every 2 years for a minimum of 10 years. If 
abnormal, consider cardiology consultation and more frequent screening) 
-LFT/RFT/UA 
-Neuropsychological testing 
-BM/CSF exams as indicated 
 
Year Three:  
-Hx/PE/HT/WT/FOC/CBC diff plt - q 3 months 
-LFT/RFT/UA 
-Neuropsychological testing 
-BM/CSF exams as indicated 
 
Year Four:  
-Hx/PE/HT/WT/FOC/CBC diff plt - q 6 months 
-LFT/RFT/UA 
-Neuropsychological testing 
-BM/CSF exams as indicated. 
 
Beginning  
-Hx/PE/HT/WT/FOC/CBC diff plt - q 12 months 
Year Five 
-LFT/RFT/UA as indicated 
-Neuropsychological testing as indicated 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Failure to achieve remission (defined as M1 marrow; see Section 4.1.1) by end-Induction 
Intensification (i.e., the beginning of Week 10) 
b) 
Relapse of any site following remission 
c) 
Toxicity or other complications 
d) 
Refusal of further protocol therapy by patient/parent/guardian 
e) 
Completion of planned therapy 
f) 
Physician determines it is in patient’s best interest 
g) 
Development of a second malignancy 
h) 
MLL status is indeterminate 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below).  
Follow-up data will be required unless consent was withdrawn. 
 


 
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8.2 
Off Study Criteria 
 
a) 
Death 
b) 
Lost to follow-up 
c) 
Enrollment onto another COG study with tumor therapeutic intent (e.g., at recurrence) 
d) 
Withdrawal of consent for any further data submission 
e) 
Tenth anniversary of study entry 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design 
Patients will be stratified at the end of Week 5 of Induction, by MLL status and age at diagnosis as 
defined below:  
Standard Risk (SR): MLL-germline (MLL-G) 
Intermediate Risk (IR): ≥ 90 days at diagnosis, MLL-rearranged (MLL-R) 
High Risk (HR): < 90 days at diagnosis, MLL-R 
 
SR patients will be non-randomly assigned to receive a less intensive chemotherapy regimen without 
lestaurtinib. A safety/activity phase was conducted separately for the IR and HR patients to identify a 
safe, tolerable, and biologically active dose of lestaurtinib combined with P9407-based chemotherapy 
backbone. A tolerable/active dose of lestaurtinib has been identified for IR patients, and the efficacy 
phase opened to IR patients as of 01/28/11, where they were randomized (1:1) to P9407-based 
chemotherapy backbone ± lestaurtinib. A tolerable/active dose of lestaurtinib was identified for HR 
patients, and they proceeded to the randomized efficacy phase on 02/03/12. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Original Design: The safety phase will accrue 20 evaluable MLL-R patients (10 IR and 10 HR). The 
accrual duration for the safety phase is expected to be around 3 months for IR patients (annual accrual 
rate: 40/year) and 1 year for HR infants (annual accrual rate: 10/year). Thus, it is likely that the IR stratum 
will proceed to the efficacy phase before the HR stratum. If a tolerable/active dose cannot be identified 
for the IR stratum, the study will close, since we would be unable to answer the lestaurtinib efficacy 
question in a reasonable period of time with the small number of patients in the HR stratum. If a 
tolerable/active dose is identified for the IR stratum but cannot be identified for the HR stratum, the study 
would remain active until accrual goals are met (n = 162 evaluable MLL-R infants) as described below. 
 
A total of 202 patients will contribute to the efficacy questions for the MLL-R and MLL-G patients. Of 
these, about 162 are projected to be MLL-R and 40 will be MLL-G (SR).  Assuming that both IR and HR 
strata successfully proceed to the efficacy phase, around 80% of the MLL-R infants (n = 130) will be ≥ 90 
days old (IR) and the rest (n = 32) will be < 90 days old at diagnosis (HR).  
 
Hence a total of 222 patients (MLL-G: 40; MLL-R: safety phase – 20, efficacy phase – 162) will be 
accrued on this study. Accounting for a 10% loss due to early deaths, withdrawal/refusal of protocol 
therapy, and refusal of the post-Induction randomization, a total of 244 patients will be enrolled during 
the safety and efficacy phases. Accrual duration for these patients will be around 4.73 to 5 years 
(adjusting for an initial slow accrual allowing institutions to get IRB approvals for the study), with 
minimum follow-up of 2 years for all patients. MLL-R patients from ‘participating’ institutions only will 
be included in the safety phase. MLL-R patients enrolled from ‘nonparticipating’ institutions (during the 
Safety Phase only) will not be eligible to receive Lestaurtinib and will be assigned to the standard 
chemotherapy arm without Lestaurtinib, after Induction therapy. In addition, while DLT assessments are 
being made (see Section 9.3.1 for details) for IR/HR patients at the dose level being studied, the study 


 
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will continue to accrue patients and during this time MLL-R patients will be assigned to the standard 
chemotherapy arm without Lestaurtinib, for post Induction therapy. Thus, the total number of patients 
accrued on this study will likely be greater than the projected 244. However, it is not possible to get a 
good estimate of the number of additional patients (as described above) that are likely to be enrolled. 
Hence all statistical analyses to be conducted are based on the initial projection of 222 (244 with a 10% 
adjustment for losses due to various reasons described above) enrollments on study. 
 
Amended Accrual (Amendment #4):  
Tolerable and biologically active doses of lestaurtinib for both the IR and HR arms have been identified. 
The efficacy phase opened to the IR patients on 01/28/2011 and to the HR patients on 02/03/2012. IR 
patients are now being randomized (1:1) post-Induction to chemotherapy ± lestaurtinib at 5 mg/kg/day 
and HR patients at 4.25 mg/kg/day. 
 
A total of 52 MLL-R patients (19 HR; 33 IR) were accrued to the safety phase, since HR and IR patients 
continued to enroll to the non-lestaurtinib arm during DLT assessments and since patients enrolled at non-
Phase 1(+) institutions were not eligible to receive lestaurtinib during the safety phase. The overall target 
accrual has been increased to account for ineligibles, inevaluables, and the higher than expected number 
of patients enrolled during the safety phase.  
 
Hence, the modified total accrual for this study is 286 patients (safety phase: 60; efficacy phase: 
162 (MLL-R only); MLL-G: 64). Accounting for a 10% loss due to early deaths, withdrawal/refusal of 
protocol therapy, and refusal of the post-Induction randomization, a total of 315 patients will be enrolled 
during the safety and efficacy phases.  
 
Patients accrued during the safety phase will not contribute to the efficacy questions. Thus, the increased 
accrual will not impact the efficacy analyses, and the number of patients required (i.e., 
162 eligible/evaluable MLL-R) to answer the efficacy questions will not change. 
 
Amended Accrual (Amendment #5):  
The primary objective of AALL0631 has been revised to estimate the 3-year EFS for infants with MLL-R 
treated with chemotherapy plus the FLT3 inhibitor lestaurtinib (Arm C) at DL2. This will include 
10 evaluable patients from the safety phase assigned to DL2, 30 patients randomized to Arm C during the 
efficacy phase (pre-Amendment #5), and 40 patients non-randomly assigned to lestaurtinib post-
Amendment #5. A total of 80 MLL-R patients will be treated on Arm C (chemotherapy + lestaurtinib) to 
answer the revised primary objective on AALL0631.  
 
Secondary objectives include comparison of the 3-year EFS of infants with MLL-R ALL treated with 
chemotherapy plus the FLT3 inhibitor lestaurtinib (Arm C) at DL2 to all MLL-R patients treated with 
chemotherapy alone (Arm B). This will include a total of 55 patients treated on Arm B: 25 from the safety 
phase and 30 randomized to Arm B during the efficacy phase pre-Amendment #5. 
 
A total of 80 and 55 MLL-R patients will be enrolled on Arm C and Arm B, respectively, to answer the 
revised primary and secondary objectives on AALL0631. MLL-G patients will continue to enroll on the 
study at an expected rate of 13 patients per year. Hence, the modified total accrual on this study is 
220 patients (safety phase: 60; post-safety phase (MLL-R only): 100; MLL-G: 60). To account for a 10% 
loss due to ineligibles, early deaths, withdrawals, and refusal of post-Induction therapy, a total of 
242 patients will be enrolled on AALL0631 prior to June 2014, anticipated closure date to enrollment due 
to limited supply of lestaurtinib.  
 
 


 
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9.3 
Statistical Analysis Methods 
 
9.3.1 
Safety / Activity Phase 
The dose finding (lestaurtinib) part of the study was restricted to the first 2 courses of post-Induction 
therapy (Induction Intensification and Re-Induction) for the MLL-R patients. The MLL-R patients were 
stratified according to age at diagnosis (< 90 days old versus ≥ 90 days old). Dose finding was conducted 
separately for each of the strata. The schema describing the design is detailed in Section 4.2.1 with the 
toxicities targeted in the safety phase, detailed in Section 4.2.3. 
 
9.3.2 
Efficacy Phase  
 
Design Prior to Amendment #5  
The primary objective of this study is to compare 3-year EFS of MLL-R infants randomized to a modified 
P9407 backbone +/- lestaurtinib. All randomized patients will be included in the intent-to-treat efficacy 
analyses. Event-free survival time will be calculated from the time of randomization, which is just prior to 
beginning Induction Intensification (see Section 3.1.6). Only if the lestaurtinib arm results in a significant 
improvement in EFS will it be considered as the superior regimen. Hence 1-sided tests will be used to 
compare EFS between the 2 arms. The baseline 3-year EFS for these patients on the P9407 backbone is 
around 50%.  Power calculations are based on a 1-sided log rank test (alpha = 0.15) with 5 planned 
analyses of the data for interim monitoring purposes.  The efficacy stopping boundaries are based on the 
alpha  (time)2 spending function. The study will also be monitored for futility. The lower boundaries are 
based on repeated testing the alternative hypothesis at the 0.005 level.67  This monitoring rule can be 
applied to any interim analysis schedule and maintains the overall significance level of 0.05 
approximately. The comparative analyses of regimen outcome will occur at approximately 20%, 40%, 
60%, 80%, and 100% of the projected combined EFS event horizon for the overall randomized group.   
 
For the purpose of sample size and power calculations a significant difference is assumed to be an 
improvement in outcome from 50% EFS at 3 years to 65% EFS. This represents a relative EFS event 
reduction of approximately 38% for the better regimen (HR = 1.6). An event horizon of 69 EFS events 
was calculated using the previous EFS outcome assumptions. The cumulative power to detect a difference 
by the last (fifth) interim analysis is 80.3%. Should a difference of that relative hazard size exist, there is a 
22% chance of stopping at the second interim analysis, and 65% chance of stopping at the fourth interim 
analysis. The monitoring boundaries (for efficacy and futility) are given in the table below. 
 
Looks # of events Information  Upper Boundary (Z value) Lower Boundary (Z value) 
1 
14 
20% 
2.5121 
-1.6856 
2 
28 
40% 
2.0358 
-1.3172 
3 
41 
60% 
1.7022 
-1.0529 
4 
55 
80% 
1.4179 
-0.8122 
5 
69 
100% 
1.1573 
1.1573 
 
Revised Design as of Amendment #5 
The primary objective of AALL0631 is to estimate the 3-year EFS of those patients treated on Arm C 
(chemo + lestaurtinib) at DL2 from both the safety and the efficacy phases. A total of 80 patients on 
Arm C would allow estimation of EFS with a maximum standard error of 5.6%. A one-sided 95% 
confidence interval for EFS will be constructed. If the 3-year EFS is 50%, the lower limit of the 95% 
confidence interval will be 40.8%. If the true 3-year EFS is 65%, the lower limit of the confidence 
interval will be 56.2%. 
 


 
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The secondary objective is to assess the effect of lestaurtinib by comparing patients on Arm C (chemo + 
lestaurtinib) to those assigned to Arm B (chemo only). Using a one-sided log rank test with 135 patients 
(55 on Arm B; 80 on Arm C), alpha=15%, and minimum follow-up of 3 years, there is 82% power to 
detect an improvement in 3-year EFS from 50% to 65% (HR=0.62). 
 
9.3.3 
Toxicity Monitoring  
The study will be closely monitored for toxicities and adverse events due to the addition of lestaurtinib to 
the P9407 based chemotherapy backbone. Specific criteria for dose adjustments of lestaurtinib are 
described in the dose modifications section of the protocol. All toxicities related to lestaurtinib, dose 
adjustments of lestaurtinib and delays in subsequent therapy due to lestaurtinib will be required to be 
reported immediately via the RDE. We will also require reporting of the number of prescribed lestaurtinib 
doses each patient receives during each reporting period. These data will be used to calculate the 
percentage of patients that are not able to receive at least 75% of the prescribed doses of lestaurtinib 
during each reporting period. If a specific course is associated with a high percentage of patients unable to 
receive 75% of the prescribed doses, this may indicate a problem with the tolerability of lestaurtinib in the 
context of that specific course. The Study Chairs will closely monitor patterns of lestaurtinib toxicity 
during each reporting period, and amend the study appropriately if toxicity appears to be excessive for 
one or more of them.  Section 4.2.3 describes the DLTs applicable to the safety/activity phase. 
 
Pre-Amendment #5:  
Analysis of toxicities associated with lestaurtinib will include all patients who receive at least one dose of 
drug. Incidence of Grade 3/4 non-hematologic toxicities (infection and AST/ALT) will be compared 
between the two randomized arms (starting from Induction Intensification therapy Week 6), at the time of 
each interim monitoring analysis for efficacy. Baseline incidence of infections for the standard arm 
(P9407 chemotherapy backbone) is expected to be around 30% (data from P9407). A total of 162 patients 
(81 on each arm), would give 80% power to detect a difference in infection rates between the two arms 
(30% Std vs. 50% Std + lestaurtinib) using a one-sided Z-test of proportion, alpha = 5%. The study will 
be monitored for excessive infections on the lestaurtinib arm compared to the standard backbone therapy. 
The timepoints for sequential monitoring will coincide with the times of the reporting to the COG Data 
and Safety Monitoring Committee. Interim monitoring looks will occur every six months for the first 2 
years of accrual to the efficacy phase, followed by yearly looks. The monitoring boundaries for the 
projected 5 looks using an alpha x (time)2 spending function are given below. 
 
Look 
Time point 
Monitoring Boundary 
P-value  
1 
6 months 
2.8782 
0.002 
2 
12 months 
2.4702 
0.008 
3 
18 months 
2.2009 
0.018 
4 
24 months 
1.9818 
0.032 
5 
36 months 
1.7902 
0.050 
 
The baseline incidence rate of Grade 3/4 AST/ALT on P9407 on Re-Induction or later part of therapy is 
around 9%. The incidence of AST/ALT will be compared between the standard and standard plus 
lestaurtinib arms. A total sample size of 162 gives 80% power to detect a difference in AST/ALT rates 
(9% Std. vs. 24% Std. + lestaurtinib) using a one-sided Z-test of proportions, with an alpha of 5%. 
Sequential monitoring plan will be the same as that detailed above for infections. 
 
Toxic death rates on P9407 on Re-Induction or later part of therapy was around 3%. The toxic death rate 
will be compared between the standard and standard plus lestaurtinib arms. A total sample size of 162 
gives 80% power to detect a difference in toxic death rates (3% Std. vs. 14% Std. + lestaurtinib) using a 
one-sided Z-test of proportions, with an alpha of 5%. Sequential monitoring plan will be the same as that 
detailed above for infections. 


 
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Amendment #5:  
Grade 3/4 non-hematologic toxicities (infection and AST/ALT) will continue to be monitored closely and 
reported (by stratum) biannually to the COG Data and Safety Monitoring Committee during the time of 
the study reports. 
 
9.3.4 
Toxic Death Monitoring 
Toxic deaths on the amended Induction therapy will be closely monitored. Deaths will be counted afresh 
after the modified Induction therapy goes into effect. At the time of this amendment, a total of 26 patients 
have enrolled onstudy (Less than 30 days old at diagnosis: 2; Greater than or equal to 30 days old at 
diagnosis: 24). Of the remaining planned accrual of 218 patients, it is projected (based on the age 
distribution in P9407 Cohort 3) that 6 patients will be less than 30 days old and 212 will be ≥ 30 days old 
at diagnosis.  
 
Less than 30 days old at diagnosis: 
Approximately 6 patients in this age group will be enrolled on the modified induction regimen. On 9407 
Cohort 3, there was one death among 5 patients in this age group. Due to the small sample size, it is not 
possible to have formal statistical rules for monitoring deaths. If 2 deaths occur (on the modified 
Induction therapy), the study accrual to patients < 30 days old at diagnosis will be temporarily suspended; 
the data will be closely reviewed before a decision is made on whether to permanently close accrual to 
this age group.  
 
Greater than or equal to 30 days old at diagnosis: 
The 212 patients expected to be enrolled in this age group on the modified Induction therapy, will be 
included in the continuous monitoring plan detailed below. The study will be temporarily closed for 
detailed review if: 
 
# cumulative toxic deaths 
# of Patients on Study 
> 4 
1-50 
> 8 
51-100 
 
The modified Induction regimen will be deemed too toxic if there are 15 or more toxic deaths at any time 
among the 212 patients. The probability of declaring the Induction regimen too toxic is 97%, 83%, 50%, 
16%, and 1.2% when the true toxic death rate is 10%, 8%, 6%, 4%, and 2%, respectively. 
 
9.3.5 
Supportive Care for Fungal Infections 
Data will be collected (in eRDE on the reporting period CRF) during Induction on the prophylactic 
treatment given for prevention of fungal infections. Details will also be collected on empiric treatment 
given for patients with possible fungal infections. These will be summarized using descriptive statistics. 
Proportion of infants who received prophylactic treatment, empiric treatment and IVIG will be 
determined. Mean serum IgG levels (Days 1 and 15 of Induction) will be calculated. Mean number of 
days hospitalized during Induction until count recovery will also be computed. 


 
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9.3.6 
Outcome for Standard Risk Patients 
The outcome for SR patients (MLL-G) will be described. A sample of 60 patients will allow estimation of 
3-year EFS with a maximum standard error of 6.5%. The outcome for these patients will be informally 
compared with that of MLL-G patients on P9407.  
 
9.3.7 
Correlative Biology Studies 
The correlative biology studies listed in the secondary objectives are described in Sections 14.1 – 14.5. 
Analyses to be performed are detailed in each of these sections. As detailed in Section 14.4, MRD will be 
measured in patients at Weeks 6, 10 and 20 of chemotherapy and at the time of relapse. These are 
optional studies and, hence, it is difficult to estimate how many patients will have MRD measured at each 
of these timepoints. Hence, correlation between MRD and outcome will be described in this population. 
Cox regression will be utilized to correlate MRD values with 3 year EFS as defined in Section 9.3.2. 
 
 
9.4 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
16 
25 
41 
Not Hispanic or Latino 
87 
114 
201 
Ethnic Category: Total of all subjects 
103 
139 
242 
Racial Category 
 
American Indian or Alaskan Native 
2 
4 
6 
Asian 
4 
9 
13 
Black or African American 
4 
11 
15 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
93 
115 
208 
Racial Category: Total of all subjects 
103 
139 
242 
 
 
 
 
 
This distribution was derived from P9407. 
 
 
10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting beginning April 1, 2011. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0 and a copy can be downloaded 
from the CTEP web site (http://ctep.cancer.gov).  
 
10.2 
Response Criteria 
See definitions in Section 4.1.1. 
 


 
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Certain adverse events must be reported in an expedited manner to allow for timelier 
monitoring of patient safety and care. The following sections provide information about expedited 
reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event.  
An investigational agent is a protocol drug administered under an Investigational New Drug Application 
(IND). In some instances, the investigational agent may be available commercially, but is actually being 
tested for indications not included in the approved package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
 
Concurrent administration: When an investigational agent is used in combination with a 
commercial agent, the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a period of 
time prior to starting the investigational agent, expedited reporting of adverse events which 
occur prior to starting the investigational agent would follow the guidelines for commercial 
agents.  Once therapy with the investigational agent is initiated, all expedited reporting of 
adverse events follow the investigational agent reporting guidelines. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment with 
investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial neoplasm is not 
considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via AdEERS. Three 
options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy   
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
11.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria (CTCAE) [use version 4, 
beginning 04/01/11]. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). All appropriate treatment 
locations should have access to a copy of the CTCAE. 


 
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Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine the attribution of adverse event in relation to the protocol therapy. Attribution 
categories are: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event.   
For investigational agents that are not commercially available and are being studied under a 
company’s IND or an investigator held IND, expected AEs are usually based on the 
Investigator’s Brochure.   
 
Guidance on expectedness of the agent is provided in the Drug Information Section of this 
protocol. 
 
Step 5: Review Tables A and/or B in this section to determine if: 
 
 
there are any protocol-specific requirements for expedited reporting of specific adverse 
events that require special monitoring; and/or 
 
there are any protocol-specific exceptions to the reporting requirements. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included an investigational 
agent, a commercial agent, or a combination of investigational and commercial agents.  
 
Note: If the patient received at least one dose of investigational agent, follow the guidelines in Table A. If 
no investigational agent was administered, follow the guidelines in Table B. 
 
11.4 
Reporting methods 
 
 
The reporting methods described below are specific for clinical trials evaluating agents for 
which the IND is held by COG, an investigator, or a pharmaceutical company. It is 
important to note that these procedures differ slightly from those used for reporting AEs for 
clinical trials for which CTEP holds the IND. 
 
 
Use the NCI’s Adverse Event Expedited Reporting System (AdEERS). The NCI’s 
guidelines for AdEERS can be found at http://ctep.cancer.gov. 
 
 
An AdEERS report must be submitted by the following method: 
 
- 
Electronically submit the report via the AdEERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm 
 
 
Fax or email supporting documentation for AEs related to investigational agents to the 
Children’s Oncology Group (fax # 626-303-1768; email: 
COGAdEERS@childrensoncologygroup.org; Attention: COG AdEERS Coordinator).  
 
 
DO NOT send the supporting documentation for AEs related to commercial agents to 
the NCI. Fax this material to COG (fax # 626-303-1768; attention: COG AdEERS 
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. 


 
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11.5 
When to report an event in an expedited manner 
 
 
Some adverse events require notification within 24 hours (refer to Table A) via e-mail to the 
COG AdEERS Coordinator.  
 
 
Submit the report within 5 calendar days of learning of the event. 
 
11.6 
Other recipients of adverse event reports 
 
COG will forward reports and supporting documentation to the Study Chair, to the drug company (for 
industry sponsored trials) and to the FDA (when COG holds the IND). 
 
Adverse events determined to be reportable must also be reported according to the local policy and 
procedures to the Institutional Review Board responsible for oversight of the patient. 
 
11.7 
Reporting of Adverse Events for investigational agents  
 
Reporting requirements are provided in Table A. The investigational agent used in this study is 
Lestaurtinib (CEP-701; IND#76431); COG is the IND holder. 
 
Table A 
Phase 2 and 3 Trials and COG Group-wide Pilot Studies utilizing an Agent under a CTEP IND or a 
Non-CTEP IND:  AdEERS Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the Last Dose of the Investigational Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
43 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
5 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as 
follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for: 
 Grade 4 and Grade 5 unexpected events  
 
AdEERS 5 calendar day report: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions 
below 
 Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a 
full report is required as outlined in the table. 
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
Note: All deaths on study require timely reporting to COG via RDE regardless of causality. Attribution to 
treatment or other cause must be provided.   
 


 
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 
Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE via e-
mail to COG AE Coordinator within 24 hours of learning of the event followed by 
a complete AdEERS report within 5 calendar days of the initial 24-hour report. 
 
“5 calendar days” - A complete AdEERS report on the AE must be submitted 
within 5 calendar days of the investigator learning of the event.  
 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
 
 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS if the event occurs following 
treatment. 
 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
 
Protocol specific reporting of AEs, in addition to the AdEERS requirements, are to be 
entered in the COG remote data entry system.   
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2 
and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND: 
 
 Any death that occurs more than 30 days after the last dose of treatment with an 
investigational agent which can be attributed (possibly, probably, or definitely) to the agent 
and is not due to cancer recurrence/progression must be reported via AdEERS per the 
timelines outlined in the table above. 
 
 Grades 1-4 myelosuppression do not require expedited reporting. 
 
 
11.8 
Reporting of Adverse Events for commercial agents – AdEERS 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 AdEERS report to be submitted within 5 calendar days of learning of the event. 


 
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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. 
 
AdEERS 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 
 
 
AdEERS 
Possible, Probable, 
Definite 
AdEERS 
 
AdEERS 
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 which can be 
attributed (possibly, probably, or definitely) to the agent and is not due to cancer 
recurrence must be reported via AdEERS. 
 
11.9 
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 AdEERS reporting. 
 
The NCI defines both routine and expedited AE reporting. Use CTCAE version 4.0 beginning 04/01/11. 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database. For this study, routine reporting will include: 
 
Grades 3 and higher non-hematologic adverse events; 
 
Grades 3 and higher hematologic adverse events that result in a delay in therapy greater than one 
(1) week; 
 
All adverse events that meet the requirements for filing an AdEERS report as per Section 11. 
 
 
 
12.0 
RECORDS AND REPORTING 
 
12.1 
Categories of Research Records 
Computerized Information Electronically Submitted: all computerized data will be entered in the COG 
Remote Data Entry System with the aid of schedules and worksheets (essentially paper copies of the RDE 
screens) provided in the data form packet. 
 
See separate Data Form Packet posted on the COG web site, which includes a submission schedule. 
 
12.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will 
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and 
October 31. This is not a responsibility of institutions participating in this trial. 
 


 
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13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
13.1 
Blood for Lestaurtinib PK/PIA (required) 
IMPORTANT NOTE: Submission of a pre-treatment blood sample is required for all patients as part 
of the baseline evaluations. All additional samples are required ONLY for MLL-R patients receiving 
lestaurtinib. 
 
Collection Schedule (Part 1) 
Treatment 
Block 
Induction* 
Induction Intensification 
Re-Induction 
Continuation I 
(Cycle 2 only) 
Total Vol. of 
Blood (mL) 
Preferred 
Day 
1 
20 
(baseline) 
24 
27 
5 
(baseline) 
9 
12 
19 
40 
27 
Acceptable 
Days 
Prior to  
Day 1 
18, 19 
23, 25 26, 28 
3, 4 
7, 8 
11, 13 
18, 20 
39, 41 
* Pre-treatment sample is required for ALL patients 
 
Collection Schedule (Part 2) 
Treatment Block 
Induction* 
Induction Intensification 
Re-Induction 
Continuation I 
(Cycle 2 only) 
Total Vol. of 
Blood (mL) 
Preferred Day 
1 
20 
(baseline) 
27 
19 
40 
15 
Acceptable Days 
Prior to Day 1 
18, 19 
26, 28 
18, 20 
39, 41 
* Pre-treatment sample is required for ALL patients 
 
At each time point, 3 mL of blood must be drawn into green-top (heparin) Vacutainer(s). Each blood 
collection tube must be labeled as “Block ____, Day: ____ PK/PIA sample” with patient initials, COG 
registration number, sample date and collection time recorded to the nearest minute using a 24-hour clock. A 
completed AALL0631 Specimen Transmittal Form must accompany the sample(s) when shipped. Any 
missing samples, and samples not drawn, must be noted on the Specimen Transmittal Form. Samples should 
be maintained at room temperature (no refrigeration or icing of samples is necessary) and shipped via 
overnight courier service to: 
 
Dr. Patrick Brown 
Johns Hopkins Oncology 
Cancer Research Building I, Room 276 
1650 Orleans Street 
Baltimore, MD 21231 
Laboratory phone:  410-955-8688 
Pager no:  410-434-0732 
E-mail:  pbrown2@jhmi.edu 
 
Samples can be shipped 7 days a week. Saturday deliveries are permissible. If a Saturday delivery is required, 
please notify Dr. Brown of the planned shipment via pager (410-434-0732) PRIOR to the time of shipment 
and clearly mark the package “For Saturday Delivery”. 
 
If parent/guardian consents, the discarded cell pellet will be used for correlative biology studies as detailed in 
Section 14.0. 
 
13.2 
Bone Marrow for AALL08B1 (required) 
For a patient to be eligible for this study, they must have been enrolled on either AALL08B1, and bone 
marrow (or a suitable substitute, as described below) must be submitted to the COG ALL Reference 


 
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Laboratory in Columbus prior to initiation of treatment and at the time of relapse or disease progression.  
Please refer to the classification study protocol for comprehensive sample requirements and instructions.   
 
13.3 
Bone Marrow for Flow MRD, Molecular MRD and Resistance Mechanisms (optional) 
Bone marrow aspiration must be performed on all patients prior to initiation of treatment, and at other times 
as noted in Section 7.1 for local evaluation. If parent/guardian consents, bone marrow should also be 
submitted for MRD and resistance mechanism studies. At least 5 mL of marrow should be transferred to 
green-top (heparin) Vacutainer(s). All of the studies will be performed on the same bone marrow sample. 
 
IF there are at least 2500 circulating blasts/µL (i.e., WBC of 10,000 with 25% blasts or WBC of 5000 
with 50% blasts), peripheral blood (at least 5 mL in green top (heparin) Vacutainer(s)) may be submitted 
as a substitute for the pre-treatment or relapse/progression bone marrow samples (permissible in cases 
where bone marrow aspirate cannot be performed for medical reasons, or adequate material cannot be 
obtained). 
 
For patients undergoing leukopheresis, the submission of a portion (at least 5 mL) of the anticoagulated 
pheresate is acceptable and may be substituted for the pre-treatment or relapse/progression bone marrow 
samples. In these cases, the pheresis bag should be submitted to Columbus for AALL08B1 (see 
Section 13.2). 
 
For patients undergoing manual exchange transfusion, a portion (at least 5 mL) of the manually exchanged 
anticoagulated blood is acceptable and may be submitted for any of the pre-treatment or relapse/progression 
bone marrow samples. The remainder of the exchanged blood volume should be submitted to Columbus for 
AALL08B1 (see Section 13.2). 
 
Each specimen must be labeled with time point in therapy, patient initials, COG registration number, and 
sample date and collection time recorded to the nearest minute using a 24-hour clock. A completed 
AALL0631 Specimen Transmittal Form must accompany the sample(s) when shipped. Samples should be 
maintained at room temperature (no refrigeration or icing of sample is necessary) and shipped via overnight 
courier service to: 
 
Dr. Patrick Brown 
Johns Hopkins Oncology 
Cancer Research Building I, Room 276 
1650 Orleans Street 
Baltimore, MD 21231 
Laboratory phone:  410-955-8688 
Pager no:  410-434-0732 
E-mail:  pbrown2@jhmi.edu 
 
Samples can be shipped 7 days a week. Saturday deliveries are permissible. If a Saturday delivery is required, 
please notify Dr. Brown of the planned shipment via pager (410-434-0732) PRIOR to the time of shipment 
and clearly mark the package “For Saturday Delivery”. 
 
 
14.0 
DESCRIPTION OF CORRELATIVE LABORATORY ASSAYS 
 
14.1 
Lestaurtinib Pharmacokinetic (PK)/Plasma Inhibitory Activity (PIA) Assay 
Plasma will be separated by centrifugation from 3 mL blood samples collected during lestaurtinib 
administration and cryopreserved. Aliquots of 4 x 106 TF1/ITD cells (human AML cell line transfected 
with FLT3/ITD construct) will then be incubated for 1 hour with 0.5 mL of plasma from each timepoint. 


 
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The cells will then be washed, lysed and analyzed for FLT3 phosphorylation by FLT3 
immunoprecipitation and sequential immunoblotting with 4G10 anti-phosphotyrosine antibody and anti-
FLT3 antibody. Densitometric analysis will be used to calculate the PIA (the percent inhibition of FLT3 
phosphorylation of each timepoint relative to the pre-treatment sample).  These results will be used to 
determine whether a given dose of lestaurtinib is biologically active. Another 0.1 mL of plasma from the 
same timepoints will be used to measure the levels of plasma AGP and albumin using standardized radial 
immunodiffusion kits from Kent Laboratories (will give quantitative levels in mg/dL plasma). We will 
plot PIA vs. PK level for each data point. If a consistent relationship is seen, future studies could use PK 
as a simpler surrogate for biologic activity. Measurement of albumin and AGP levels, in conjunction with 
review of clinical data from the trial, will allow other variables to be incorporated, so that an attempt can 
be made to develop a predictive model of PIA using these readily available inputs in future studies.  If 
these efforts fail to establish a reliable model of PIA, then future trials would need to continue using the 
measurement of PIA as described here as the best means of assessing FLT3 inhibition. 
 
14.2 
Correlating Clinical Responses with PIA and In Vitro Lestaurtinib Sensitivity 
The PIA (expressed as percent inhibition of FLT3 phosphorylation relative to the pretreatment sample) at 
trough timepoints will be determined for each patient as described in Section 14.1. For each patient, if a 
majority of available trough plasma samples demonstrate a PIA of ≥ 90%, then, for the purpose of our 
analysis, “adequate” PIA will have been achieved. 
 
For each patient, an “expected response” will be determined based on presence or absence of the criteria 
for lestaurtinib sensitivity and adequate PIA (see table). The clinical responses to be considered will be 
(1) remission status at end of Induction and end of Induction Intensification, (2) presence or absence of 
MRD at end of Induction and end of Induction Intensification, and (3) 3-year EFS. 
 
 
 
 
 
 
 
 
14.3 
Determining Mechanisms of Resistance to Lestaurtinib 
We have already discussed obtaining bone marrow from patients at study entry and using the MTT 
cytotoxicity assay to define each patient’s pre-treatment in vitro lestaurtinib sensitivity (Section 14.2). 
Mononuclear cells will also be isolated from bone marrow samples obtained at other timepoints during 
therapy, at the time of progressive disease in patients who do not respond, and at the time of relapse in 
patients who initially respond. We will perform MTT cytotoxicity assays and define these post-treatment 
samples as “sensitive” or “resistant” to lestaurtinib using the same criteria as described in Section 14.2. 
 
We will investigate mechanisms of primary resistance to lestaurtinib using samples that were 
determined in Section 14.2 to be resistant (or sensitive, for comparison) at the time of study entry. One 
potential mechanism of resistance is (1) lack of FLT3 protein expression or constitutive activation. We 
will isolate total RNA from each sample and perform quantitative PCR (qPCR) analysis of FLT3 
expression relative to the housekeeping gene GAPDH. We will also examine FLT3 expression and 
constitutive (ligand-independent) phosphorylation/activation at the protein level by performing 
immunoprecipitation (IP) on clarified whole cell lysate (WCL) with anti-FLT3 antibody, followed by 
acrylamide gel electrophoresis and sequential immunoblotting (IB) with 4G10 anti-phosphotyrosine (anti-
pY) antibody (to assess receptor activation) and anti-FLT3 antibody (to ensure equal loading). Another 
potential mechanism is (2) primary (i.e., pre-existing) resistance of the activated FLT3 receptor to 
inhibition by lestaurtinib. While none of the samples we have tested to date with either of the 2 major 
-
+
-
+
Adequate
PIA
N
+
Y
+
N
-
N
-
Expected 
response?
In vitro
sensitivity
-
+
-
+
Adequate
PIA
N
+
Y
+
N
-
N
-
Expected 
response?
In vitro
sensitivity
Table 2


 
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types of FLT3 mutations (ITD and PM) have demonstrated this type of primary resistance, it is possible 
that we may find novel variants which do.  We will extract WCL from cells before and after 1 hour of 
exposure to lestaurtinib (50 nM, which is sufficient to inhibit FLT3 phosphorylation), then perform anti-
FLT3 IP and sequential 4G10 anti-pY and anti-FLT3 IB. If we find a sample where FLT3 
phosphorylation is not inhibited under these conditions, we will reverse transcribe total RNA to cDNA, 
and use a series of 5 PCR primer sets to amplify the coding region of FLT3.  We will then directly 
sequence these PCR products to look for novel mutations that may mediate primary resistance to 
lestaurtinib. A third possible mechanism is (3) FLT3-independent activation of downstream signaling 
pathways. We have seen persistent activation of MAPK and STAT5 in lestaurtinib-resistant pediatric and 
adult AML samples with FLT3 activating mutations despite potent inhibition of FLT3 
phosphorylation.14,38 We will extract WCL from cells before and after 1 hour of exposure to lestaurtinib, 
which will be electrophoresed on acrylamide gel and then immunoblotted sequentially with anti-phospho 
STAT5, MAPK and AKT followed by anti-total STAT5, MAPK and AKT (loading controls).  If 
persistent activation in 1 or more of these is seen, this could signal the presence of mutations in upstream 
signaling proteins involved in these pathways. We will reverse transcribe total RNA to cDNA for these 
samples, and then interrogate them for known mutations of upstream oncogenes (e.g., mutations in RAS, 
PTEN or JAK2 as a cause of persistent activation of MAPK, AKT or STAT5, respectively, using 
screening methods appropriate for each particular mutation). Any mutations discovered will be confirmed 
by sequencing using the original RNA and genomic DNA. 
 
Patients whose leukemia cells develop in vitro resistance after demonstrating in vitro sensitivity at study 
entry will be examined for potential mechanisms of acquired resistance to lestaurtinib, including: (1) 
Loss of expression of activated FLT3, which we will examine using PCR screens for FLT3/ITD and 
FLT3/PM mutations, in addition to qPCR and IP/IB assays of FLT3 RNA expression and FLT3 protein 
expression and activation. An inherently FLT3-resistant subclone that accounted for a small percentage of 
leukemia cells at study entry emerges as the dominant clone under the selective pressure of FLT3 
inhibition (clonal evolution). We may see, for example, that leukemia cells that develop in vitro resistance 
express significantly lower levels of FLT3 RNA by qPCR, and/or activated FLT3 protein by IP/IB, and/or 
mutant FLT3 RNA vs. wild-type RNA by PCR (including loss of expression of the FLT3 mutation 
entirely). These types of changes in expression have been seen in published studies of paired diagnostic 
and relapse FLT3/ITD+ adult AML samples, even without the selective pressure of FLT3 inhibitor 
therapy.68 (2) Development of resistance of the activated FLT3 receptor to inhibition by lestaurtinib, due 
to acquisition of a mutation in the kinase domain of FLT3 that decreases the affinity of binding of the 
FLT3 inhibitor to the ATP-binding pocket of the receptor. Similar mutations were discovered in a 
majority of patients with CML in blast crisis who initially responded to imatinib, then relapsed.69 
Mutations in the ATP-binding domain FLT3 have also been discovered in cell lines that developed 
resistance to FLT3 inhibitors under the pressure of exposure to FLT3 inhibitors in culture.70,71 We will 
directly sequence the ATP-binding domain of FLT3 in samples that develop in vitro resistance to detect 
the acquisition of a mutation. If a mutation is discovered, we will first confirm that it has indeed been 
acquired during therapy by sequencing the relevant portion of FLT3 in the same patient’s pre-treatment 
sample. Finally, FLT3 IP/IB before and after treatment of the cells with lestaurtinib will be done to 
determine whether the acquired mutations result in increased resistance to inhibition of FLT3 
phosphorylation, compared to the same studies performed on the patient’s leukemia cells obtained at 
study entry. (3) Development of FLT3-independent activation of downstream signaling pathways, due to 
mutations in upstream signaling proteins. We will use IB of WCL from cells before and after exposure to 
lestaurtinib to detect whether the development of persistent activation of downstream targets including 
MAPK, STAT5 and AKT may be responsible for the acquired resistance.  Follow-up directed mutational 
analysis will be performed if such a case is discovered. 
 
It is possible that the leukemia cells from a patient that initially demonstrates a clinical response to the 
combination of lestaurtinib and chemotherapy, but then progresses or relapses, will retain in vitro 


 
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sensitivity to lestaurtinib at the time of progression or relapse. By analyzing the results of the 
pharmacokinetic (PK), FLT3 PIA, and plasma protein binding assays (AGP, albumin) described in 
Section 14.1, we may be able to gain insight into such cases. If these data show, for example, inadequate 
PIA and low PK levels, this may suggest non-compliance with the prescribed lestaurtinib therapy, 
decreased intestinal lestaurtinib absorption, or increased lestaurtinib clearance (due to Induction of 
hepatic CYP3A4, which is primarily responsible for metabolism of lestaurtinib, for example). If the data 
show inadequate PIA but relatively high PK levels, then increased plasma binding protein levels may be 
responsible, a possibility that is assessable via examination of the measured AGP and albumin levels. 
 
14.4 
Minimal Residual Disease (MRD) Testing 
MRD assessments by multiparameter flow cytometry and by quantitative RT-PCR are included as 
optional evaluations at Week 6, Week 10, Week 20 (MLL-G/MLL-R), and off therapy.    
 
14.5 
Gene Expression Analysis 
These studies will utilize samples submitted to the COG ALL Reference Laboratory in Columbus as part 
of AALL08B1 (see Section 13.2). Gene expression arrays will be using RNA isolated from sterile, viable 
cryopreserved leukemic cell suspensions prepared from aspirated bone marrow and peripheral blood 
samples that had been stored at -135oC. RNA will be amplified with the Affymetrix One Round labeling 
kit. Data will be analyzed using various statistical and computational methods, in collaboration between 
the UNM High Performance Computing Center and the COG Statistical Core. Dr. Cheryl Willman at the 
University of New Mexico has grant funding for these studies (NCI U01CA114762; Strategic 
Partnerships to Evaluate Cancer Signatures: Leukemia Signatures for Risk Classification and Targeting). 
The results of gene expression profiling will be correlated with the functional biochemical assays of 
sensitivity or resistance to lestaurtinib described in Section 14.3 in an attempt to develop gene expression 
profiles predictive of sensitivity or resistance to this new agent. The results will also be used in an attempt 
to extend and validate the novel molecular classification scheme we have developed for infant leukemia, as 
described in Section 2.7.5. 
 


 
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APPENDIX I:  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. 
General guidance may also be found in: Supportive Care of Children with Cancer: Current Therapy and 
Guidelines from the Children's Oncology Group, 2004 ed., Arnold J. Altman, M.D. 
 
Hydration/Allopurinol/Rasburicase (recombinant urate oxidase) 
All infants should be placed on allopurinol (250mg/m2/day or 10 mg/kg/day divided into 3 divided doses 
orally or intravenously) or Rasburicase (recombinant urate oxidase) when the diagnosis of leukemia is 
made or strongly suspected. Prior to instituting Induction therapy, all patients should be well hydrated. 
Evidence of severe tumor lysis syndrome should be stabilized prior to the institution of therapy. In 
patients with extremely elevated WBC (> 300,000), 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 (preferably double lumen) placed. A 
central line (broviac catheter) is preferable to a portacath. 
 
Blood Components 
 
Blood products should be irradiated following the current FDA guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.htm  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components 
CAN/CSA-Z902-04 issued in March 2004 and available at http://www.shopcsa.ca. 
 
Red blood cells (RBCs) 
Transfusion with RBCs is indicated to correct severe or symptomatic anemia or acute blood loss.  
 
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. 
 
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 / NG feeding in patients with difficult early courses or 
extensive mucositis/diaper area skin ulceration. NEC 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. 


 
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Fever and Neutropenia 
uction/Intensification or 
when the patient is neutropenic with an ANC ≤ 1000. The risk of life threatening infection is particularly 
high during the first 4-
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. 
 
The specific choice of antibiotics to be used in empiric treatment of febrile neutropenia is dependent on 
your institution’s experience regarding the type of infecting organisms, and antibiotic sensitivity. 
Adequate coverage for gram positive organisms including viridans streptococci in addition to double 
gram negative coverage should be strongly considered for patients admitted with fever and neutropenia. 
 
In the absence of response after 3-5 days, institution of antifungal therapy should be strongly considered. 
Patients that require amphotericin should receive a lipid formulation to decrease amphotericin associated 
toxicity. These infants are also at high risk for life-threatening viral infections, particularly RSV (see RSV 
Prophylaxis and Treatment sections below), during respiratory season. 
 
Infection Prophylaxis and Treatment 
Bacterial and fungal infections have been prevalent and often severe during Induction on AALL0631. As 
shown in Table 1, there have been 4 fatal infections in the first 26 patients. The following tables 
summarize the Grade 3 or greater infectious toxicities that have been reported during the Induction phase 
of therapy on AALL0631. Of the 4 gram negative bacteremias, it is noteworthy that 2 were breakthrough 
infections, occurring 5 and 7 days after starting broad spectrum antibiotics. 
 
All Infections 
 
Organism Type 
AE’s 
Fatal AE’s % of AE’s 
# Patients 
% of Patients 
Bacteria 
19 
2 
76% 
15 
58% 
Fungi 
4 
2 
16% 
4 
15% 
Viral 
2 
0 
8% 
2 
8% 
Totals 
25 
4 
100% 
18* 
69%* 
* these are not simple sums, since some patients had multiple AE’s 
 
Bacterial Infections 
 
Site/type of bacterial infection 
AE’s 
Fatal AE’s % of AE’s 
# Patients 
% of patients 
Bloodstream 
16 
2 
64% 
13 
50% 
               Gram positive 
12 
1 
48% 
12 
46% 
               Gram negative 
4 
1 
16% 
4 
15% 
Urine 
3 
0 
12% 
2 
8% 
               Gram positive 
1 
0 
4% 
1 
4% 
               Gram negative 
2 
0 
8% 
2 
8% 


 
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Bacterial Blood Isolates 
 
Organism Name 
N 
Gram Positive 
12 
  Bacillus NOS 
2 (1*) 
  Enterococcus faecalis 
1 
  Staphylococcus NOS 
1 
  Staphylococcus epidermidis 
1 
  Streptococcus pneumoniae 
1 
  Streptococcus mitis 
3 
  Viridans group Streptococcus 
3 
Gram Negative 
4 
  Enterobacter cloacae 
1 
  Escherichia coli 
2 
  Pseudomomas aeruginosa 
1* 
* fatal infections 
 
Fungal Infections 
 
Isolate 
Site 
Fatal? 
Comments 
Candida albicans 
Blood 
N 
 
Candida tropicalis 
Blood 
Y 
 
Aspergillus fumigatus 
Nasal sinsuses/ 
brain 
Y 
 
Aspergillus fumigatus 
Lung 
N 
Found incidentally at autopsy in patient 
that died of Pseudomonal sepsis 
 
Based on these data, we will emphasize our strong recommendation that patients should be 
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 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 Prophylaxis 
Infection related mortality continues to be high during Induction/Intensification. There are insufficient 
data to support specific recommendations regarding the use of antibiotic prophylaxis. 
 
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. 


 
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1. The drug of choice is trimethoprim-sulfamethoxazole at a dosage of 150/750 mg/m2/day in 2 
divided doses on 3 consecutive days per week in infants > 2 months 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: 
a. Dapsone 2 mg/kg/day in infants > 1 month of age, or 
b. Aerosolized pentamidine for all age infants. 
 
Fungal Prophylaxis 
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. 
 
Azole antifungals may also increase the levels of lestaurtinib if taken concurrently. For those patients 
receiving lestaurtinib, azole antifungals are discouraged beginning Week 8 of therapy. Fungal prophylaxis 
with azoles is permissible in Consolidation and Continuation EXCEPT during the weeks where 
lestaurtinib is given. A 4-day azole “washout” period prior to beginning lestaurtinib is recommended to 
minimize the risks of drug interactions. 
 
The incidence of fungal infections is relatively high during Induction treatment (4/26 patients; 15%). 
Although the confidence interval around the 15% point estimate is wide (6 to 34%), at this level it is 
reasonable to consider antifungal prophylaxis and/or structured empirical antinfungal therapy. An 
alternative strategy is to use empirical antifungal therapy in neutropenic patients on or after 3-5 days of 
persistent fever or recurrent fever receiving broad spectrum antibiotics. Amphotericin B, liposomal 
amphotericin B, and caspofungin are licensed for this indication. The strategy for empricial antifungal 
therapy is to provide early treatment for clinically occult mycoses and prophylaxis in high risk 
neutropenic patients. Micafungin is licensed for prophylaxis during neutropenic phase in adult HSCT 
patients. Although not licensed for use in pediatric patients, micafungin has been extensively studied in 
the neonatal population. Pharmacokinetic and bridging pharmacodynamic studies have defined dosages of 
micafungin that would be active in treatment of invasive candidiasis, as well as for prophylaxis in this 
population. 
 
There are downsides to all agents for fungal prophylaxis in this age range. Only two agents are approved 
and have dosing data and extensive experience with use in infants of all ages: fluconazole and 
amphotericin. There are empiric data that fluconazole is an effective prophylactic treatment strategy for 
adults undergoing SCT, and perhaps for adults with acute leukemia in Induction therapy.72 There are no 
clear data on the efficacy of fluconazole for prophylaxis of fungal infections in pediatric patients with 
leukemia. It is well-tolerated in infants, but there are significant theoretical concerns about how this agent 
might affect the metabolism of chemotherapy agents in infants, particularly vincristine. If it is used, 
careful attention should be paid to vincristine toxicity. There are no empiric data to establish that 
amphotericin is a good agent for prophylactic use, and there are significant concerns about renal toxicity 
with amphotericin in this patient population. Caspofungin is approved for use in infants 3 months of age 
and older and there are some dosing data in younger infants. However, there are, at this time, no empiric 
data that caspofungin is an effective strategy for anti-fungal prophylaxis during leukemia Induction 
therapy. There are significant limitations for all the other agents, including lack of dosing information 
(most of the agents) and potential hepatic toxicity (voriconazole and posaconazole). It is also important to 
note that the concerns regarding inhibition of the metabolism of chemotherapy agents (particularly 
vincristine) are greater for voriconazole and posaconazole than they are for fluconazole. In addition, 
micafungin has recently received a pediatric warning label because of the occurrence of liver tumors in 
rats. The clinical significance of these findings for micafungin and other members of this class is 


 
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uncertain. However, given this data micafungin should only be considered if other antifungals are not 
appropriate. Local centers should consider all of these data carefully when making clinical decisions 
regarding fungal prophylaxis in patients enrolled on this study. There are pluses and minuses with each 
prophylactic choice, for example coverage of specific organisms and tissue penetration (such as CNS). If 
prophylaxis is utilized, consultation with Infectious Disease is strongly recommended. 
 
RSV Prophylaxis 
Palivizumab 15 mg/kg IM every month should be initiated just before the onset 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. Ribavirin 6 grams diluted in 300 mL 
preservative-free sterile water (20 mg/mL) over 12-18 hours by aerosol through a SPAG-2 unit should be 
administered every day for a minimum of 3-7 days. Alternatively, in the non-ventilated patient, ribavirin 
2 grams may be administered over 2 hours 3 times per day for a minimum of 3-7 days. The 6 grams of 
ribavirin delivered in the 3 times per day dosing should be diluted in 100 mL of preservative-free sterile 
water to a final concentration of 60 mg/mL. 
1. Additionally, palivizumab 15 mg/kg IM should be administered, if not already given as 
prophylaxis.   
  
Influenza Immunization 
Infants > 6 months of age should receive the influenza immunization with the trivalent inactivated 
influenza vaccine (TIV). Household contacts and out-of-home caregivers should also receive the 
influenza immunization with TIV. 
 
Varicella Infection and Prophylaxis 
Varicella infection occurred in 7 of the 115 patients enrolled on CCG 1953. Of these 4 (57%) had at least 
1 recurrence. Patients should be treated promptly with intravenous acyclovir, and monitored closely for 
the development of invasive systemic disease. The use of oral acyclovir for prophylaxis is recommended 
after completion of treatment for varicella. 
 
Empiric Management of Pulmonary Infiltrates 
Pulmonary infiltrates should be evaluated in the context of the patient’s clinical and laboratory profile. 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 patient is neutropenic, more aggressive 
diagnostic measures should be undertaken. Empiric coverage should consider gram-negative and positive 
bacteria, fungi, RSV, influenza, CMV, Pneumocystis, and Legionella. Begin empiric treatment with 
amphotericin B given the high likelihood of fungal disease during Induction and after the use of steroids. 
It is advisable to seek an infectious disease consult under these circumstances. 
 
Stress Steroid Support 
If serious illness (particularly a potentially life-threatening infection) should occur in close proximity to 
the completion of the Induction or Re-Induction, consider additional "stress steroid" support. 


 
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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 
lestaurtinib. DO NOT PROCEED WITH FURTHER HD MTX/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 has 
dramatically reduced this diaper area skin ulceration. Use of a strong barrier technique is also 
recommended, such as Critiq-aid. 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 
Antiemetics should be given as needed. The routine use of steroids is discouraged. Administer lestaurtinib 
with food to decrease treatment associated nausea and vomiting, and consider administering a 5-HT3 
antagonist with lestaurtinib doses to prevent nausea and vomiting. 
 
Expanded Supportive Care Data Collection 
Given the risks of serious infections that have prompted the changes to Induction chemotherapy, centers 
are required to report via eRDE detailed information regarding infections and supportive care measures so 
that we can carefully assess the impact of the protocol changes. The Induction reporting period case 
report form has been modified to gather information regarding use of antifungal prophylaxis and empiric 
treatment, IgG levels and use of IVIG, and duration of hospitalization during Induction. 
 


 
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 APPENDIX II: CYP3A4/5 INHIBITORS AND INDUCERS 
 
 
Note: Anticonvulsants should definitely be avoided. The use of the other agents listed below should 
be limited due to concerns of drug interactions.  
 
Adapted from Cytochrome P-450 Enzymes and Drug Metabolism. In: Lacy CF, Armstrong LL, Goldman 
MP, Lance LL eds. Drug Information Handbook 8th edition. Hudson, OH; LexiComp Inc. 2000: 1364-
1371. 
 
CYP3A4/5 Inhibitors: 
CYP3A4/5 Inducers: 
Amiodarone  
Anastrozole  
Azithromycin  
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delaviridine 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Posaconazole 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Roxithromycin 
Saquinavir 
Sertindole 
Sertraline 
Telithromycin 
Troleandomycin 
Valproic acid (weak) 
Voriconazole 
Verapamil 
Zafirlukast 
Zileuton 
 
 
 
 
 
 
 
 
 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids (except as 
prescribed in treatment 
regimen) 
Griseofulvin 
Modafinil 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifapentine 
Rifampin 
Rofecoxib (mild) 
St. John’s Wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
This list may not be comprehensive due to new agents coming to market. Below is a link to a list of drugs 
that are metabolized by cytochrome P450 isoform. Drug names are hyperlinks to specific literature 
references, most of which include a link to the abstract of the article in the NLM's PubMed database.  
 
http://medicine.iupui.edu/flockhart/ 


 
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APPENDIX III: P-GLYCOPROTEIN SUBSTRATES/INDUCERS (OVER TIME)/INHIBITORS 
 
P-GLYCOPROTEIN 
SUBSTRATES 
P-GLYCOPROTEIN 
INHIBITORS 
P-GLYCOPROTEIN 
INDUCERS 
amiodarone 
amprenavir  
(also indinavir, fosamprenavir, 
ritonavir, saquinavir, nelfinavir) 
atorvastatin, lovastatin 
celiprolol 
cetrizine 
cimetidine 
ciprofloxacin 
colchicines 
cyclosporine 
daunorubicin  
(also doxorubicin, idarubicin) 
desloratidine, loratadine 
dexamethasone 
digitoxin, digoxin 
diltiazem 
docetaxel 
erythromycin 
estradiol 
etoposide, teniposide 
fexofenadine 
hydrocortisone 
imatinib 
irinotecan 
ivermectin 
lidocaine 
loperamide 
methotrexate 
mitomycin 
nadolol 
nicardipine 
ondansetron 
paclitaxel 
pravastatin 
quinidine 
ranitidine 
rifampin 
sirolimus 
tacrolimus 
verapamil 
vinblastine, vincristine 
amiodarone 
amitriptyline  
(also desipramine, imipramine, trimipramine) 
atorvastatin (also lovastatin, simvastatin) 
azelastine 
carvedilol, propranolol 
chlorpromazine, prochlorperazine 
cimetidine, ranitidine 
clarithromycin, erythromycin 
cyclosporine 
dexrazoxane 
diltiazem, felodipine  
(also nicardipine, nifedipine, nitredipine, 
verapamil) 
dipyridamole, 
disulfiram 
doxepin 
esomeprazole (also lansoprazole, omperazole) 
fluphenazine 
grapefruit juice 
haloperidol 
hydrocortisone 
hydroxyzine 
imatinib 
itraconazole, ketoconazole 
ivermectin 
lidocaine 
maprotiline 
mefloquine 
midazolam 
mifepristone 
mitomycin 
nefazodone 
nelfinavir  
(also ritonavir, saquinavir) 
ofloxacin 
probenicid 
progesterone 
propafenone 
quinidine, quinine 
reserpine 
rifampin 
tracrolimus 
tamoxifen 
testosterone 
vinblastine 
aspirin 
dexamethasone 
doxorubicin 
nefazodone 
prazosin 
rifampin 
St. John’s Wort 
trazodone 
vinblastine 
Table adapted from Lexi-Comp’s Drug Interaction Handbook 2nd edition 2004 
Note: Predictions of drug interactions due to an effect on PGP transport is limited by the fact that drugs may be metabolized by 
multiple pathways, offering an alternative elimination route; the sum of the multiple drug effects on PGP is unknown; and PGP 
activity is influenced by non-drug entities such as: inflammation, irradiation, etc.)


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 156 
APPENDIX IV: Instructions to Patient/Caregiver for Administering Lestaurtinib (CEP-701) at a 
5 mg/mL dilution 
This document has instructions for patients/caregivers on the preparation, administration and storage of 
Lestaurtinib solution.  Below are instructions on how to prepare a mixture of Lestaurtinib and juice, how 
to give your child the Lestaurtinib/juice mixture, and how to store the drug and supplies.  You should read 
and learn the information on these pages before you prepare and give your child the Lestaurtinib/juice 
solution.  Please read these instructions carefully and ask you doctor or pharmacist any questions 
you may have. 
 
The following are instructions for storing Lestaurtinib: 
1. The Lestaurtinib solution should be stored in its bottle at room temperature of 20 to 25°C (68–77°F) 
in the box it came in.  (NOTE: for centers outside the US, solutions of Lestaurtinib in juice should be 
stored below 25ºC (77°F)) 
2. The Lestaurtinib solution should not be exposed to light.  Keep used and unused bottles in the original 
boxes they came in. 
3. Lestaurtinib must be kept out of reach of children. 
4. Any used and unused bottles of Lestaurtinib should be returned in the boxes they came in to the 
investigator at each study visit. 
 
The following are general instructions on giving Lestaurtinib to your child: 
1. Lestaurtinib is to be given orally (by mouth) only. 
2. Give your child the Lestaurtinib/juice mixture approximately every 12 hours (there must be at least 
8 hours between doses). 
3. Lestaurtinib can be given with food to reduce the amount of nausea and vomiting the drug may cause. 
4. If your child’s study doctor prescribed medicine to prevent nausea or vomiting with Lestaurtinib, you 
should give your child this medicine 30-60 minutes before you give the Lestaurtinib/juice mixture. 
5. If your child vomits after you’ve given a dose of the Lestaurtinib/juice mixture, do not repeat this 
dose.  Give your child the next dose at the next scheduled time. 
6. Juices approved for use in mixing with Lestaurtinib are apple, grape, pineapple, V8® 100% vegetable 
juice, cranberry and orange juice. 
 
Instructions for preparing the Lestaurtinib/juice solution (mixture) 
You will need the following items to prepare the Lestaurtinib/juice solution: 
 100 mL Bottle of Lestaurtinib drug and the box it came in. 
 Push-in bottle adapter. 
 One 5 mL oral syringe. 
 Two 10 mL oral syringes (or one 10 mL and one 5 mL oral syringe depending on your child’s 
dose). 
 Apple juice or any type of juice approved for mixing with Lestaurtinib (see above). 
 Medicine cup or other container for mixing the drug and juice. 
 
1. Remove the child-resistant cap from the 100 mL bottle of Lestaurtinib. 
 
2. Insert the push-in adapter into the top of the 100 mL bottle of Lestaurtinib (if not already done). 
 
3. Remove the cap from the 5 mL oral syringe and insert the tip into the push-in adapter. 
 
4. Flip the 100 mL bottle of Lestaurtinib with the connected 5 mL oral syringe so that the bottle is 
upside down and the tip of the syringe is facing upwards. 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 157 
5. Gently pull down on the plunger of the syringe and pull 2 mL of the Lestaurtinib liquid into the 
syringe. There should be liquid visible in the top portion of the syringe up to the ‘2’ mark on the 
syringe (see the diagram below). 
 
 
 
6. Pull the syringe (now filled with the 2 mL of Lestuartinib liquid) out of the push-in adapter.  Leave 
the push-in adapter in the bottle, replace the child-resistant cap and twist it to lock the cap onto the 
bottle.  (If the cap doesn’t lock, remove it and repeat this step.  Make sure the cap and bottle are clean 
of any Lestaurtinib solution.) 
 
7. Take the 10 mL oral syringe and withdraw 8 mL of apple juice, or any other approved juice, into this 
syringe (see diagram below). 
 
 
 
8. Slowly empty the juice from the syringe into the medicine cup or mixing container by pushing 
forward on the syringe. 
 
9. Take the syringe with the 2 mL of Lestaurtinib liquid you withdrew in step #5 and slowly empty the 
liquid into the same container with the juice. 
 
10. Using a plastic spoon, gently mix or stir the Lestaurtinib liquid and the juice for at least one minute, 
or until they are well mixed. 
 
11. You now have a solution with a 5mg/mL concentration of Lestaurtinib.  Your doctor will tell you 
how much of this solution you should be giving your child.  Take the second (unused) 10 mL or 
5 mL oral syringe and withdraw the amount of the Lestaurtinib/juice mixture your doctor instructed 
you to from the mixing container.  Give your child this dose of the Lestaurtinib/juice mixture.  If you 
are administering this solution by nasogastric (NG) tube, then after giving your child the 
Lestaurtinb/juice mixture, give him/her a 2nd syringe of juice only (no medication) followed by a flush 
of the NG tube with 10 – 20 mL of juice or water to make sure your child got all of the medicine. 
 
12. Give your child the diluted solution immediately after mixing.  (If the solution of Lestaurtinib in juice 
must be stored, it may be kept one hour at room temperature or up to 8 hours refrigerated.  It should 
be protected from light during the time it is stored.) 
 
13. After you have given your child the Lestaurtinib/juice mixture, pull the plungers out of all the 
syringes and rinse the syringes, plungers and medicine cups with warm water for 30 seconds.  Place 
the plungers back into their syringes and store them and the mixing cups in the original boxes they 
came in for the next time. 
1
3
2
4 
5
2
6
4
8 
10


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0631 
Version Date: 04/05/13                                                                                                                 Page 159 
APPENDIX VI: MERCAPTOPURINE DOSING GUIDELINES 
 
MERCAPTOPURINE 75 mg/m2  
 
Body Surface 
Area (m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly 
Dose 
0.36 - 0.40 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.41 - 0.45 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.46 - 0.49 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.50 - 0.54 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.55 - 0.59 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.60 - 0.64 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.65 - 0.69 
1 tab / day 
350 mg/wk 
0.70 - 0.73 
1 tab / d x 6; 1½ tab / d x 1 
375 mg/wk 
0.74 - 0.78 
1 tab / d x 5; 1½ tab / d x 2 
400 mg/wk 
0.79 - 0.83 
1 tab / d x 4; 1½ tab / d x 3 
425 mg/wk 
0.84 - 0.88 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
0.89 - 0.92 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
0.93 - 0.97 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
0.98 - 1.00 
1½ tab / day 
525 mg/wk 
*Patients exceeding a BSA of 1.00 m2 should have their MP doses calculated 
on actual BSA with no maximum dose. 
 


 
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AALL0631 
Version Date: 04/05/13                                                                                                                 Page 160 
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Version Date: 04/05/13                                                                                                                 Page 163 
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