Randomized Study of Intravenous Calaspargase Pegol (SC-PEG Asparaginase) and Intravenous Oncaspar in Children and Adolescents With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma
Sponsor: Dana-Farber Cancer Institute

NCT #: NCT01574274 
 
Local Protocol #: 11-001 
 
Title: Randomized Study of Intravenous Calaspargase Pegol (SC-PEG 
asparaginase) and Intravenous Oncaspar in Children and Adolescents with Acute 
Lymphoblastic Leukemia or Lymphoblastic Lymphoma 
 
Protocol Version Date: February 24, 2016 
 

 
 
 
 
STATUS PAGE 
PROTOCOL 11-001 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 06/08/2015 
Reason: Study Accrual Goal Met 
 
 
No new subjects may be enrolled in the study as described above. 
Any questions regarding this closure should be directed to the study’s 
Principal Investigator 

Protocol Version Date: Febmaiy 24, 2016 
NCI Protocol#: NIA
Local Protocol#: 11-001 
FDA IND#: 114,579 
Version Date: 02/24/2016 
Title: Randomized Study of Intravenous Calaspargase Pegol (SC-PEG asparaginase) and 
Intravenous Oncaspar in Children and Adolescents with Acute Lymphoblastic Leukemia 
or Lymphoblastic Lymphoma 
Principal Investigator: Lewis B. Silvennan, MD 
Coordinating Center: Dana-Fai·ber Cancer Institute 
Co-Investigators: 
DFCI/CHCC Collaborating Investigators: 
Participating Sites: 
USA 
•
Columbia University Medical Center, Morgan Stanley Children's Hospital of New
York-Presbyterian, New York, NY (Site PI: Kara Kelly, MD)
•
Hasbro Children's Hospital, Providence, RI (Site PI: Jennifer Welch, MD)
•
Inova Fairfax Hospital, Falls Church, VA (Site PI: Mai·shall Schorin, MD)
•
Montefiore Medical Center, New York, New York (Site PI: Peter Cole, MD)
•
San Jorge Children's Hospital, San Juan, Puerto Rico (Site PI: Luis Clavell, MD)
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

Protocol 11-001 
Version Date: 02/24/2016 
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OVERALL TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Prophase ----- Induction-----Consolidation I -----CNS Therapy-----Consolidation  II------Continuation 
3 days  
 
4 weeks 
 
3 weeks*  
 
3 weeks           
27 weeks 
          ~70 weeks** 
 
Randomization: 
A. IV SC-PEG x 1 dose during induction, then every 3-weeks x 10 doses (30 weeks total) beginning at start of CNS 
Therapy Phase*** 
B. IV Oncaspar  x 1 dose during induction, then every 2-weeks x 15 doses (30 weeks total) beginning at start of 
CNS Therapy Phase*** 
 
 
*~9 weeks for VHR patients 
**Until 104 weeks (24 months) of CCR 
***Post-induction Asparaginase begins during Consolidation I phase in VHR patients   

Protocol 11-001 
Version Date: 02/24/2016 
  
 
 
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TABLE OF CONTENTS 
 
1. 
OBJECTIVES .................................................................................................................................................... 6 
1.1 
Study Design .................................................................................................................................................... 6 
1.2 
Primary Objectives .......................................................................................................................................... 6 
1.3 
Secondary Objectives ...................................................................................................................................... 6 
2. 
BACKGROUND ................................................................................................................................................ 7 
2.1 
Calaspargase Pegol (SC-PEG Asparaginase) ................................................................................................ 7 
2.2 
Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma ............................................................................ 8 
2.3 
Primary Objective: Rationale ......................................................................................................................... 8 
2.4 
Secondary Objectives: Rationale .................................................................................................................. 14 
2.5 
Treatment Regimen: Background .................................................................................................................. 21 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 27 
3.1 
Eligibility Criteria ......................................................................................................................................... 27 
3.2 
Exclusion Criteria ...................................................................................................................................... 28 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 29 
4. 
REGISTRATION AND RANDOMIZATION PROCEDURES .................................................................. 30 
4.1 
General Guidelines ....................................................................................................................................... 30 
4.2 
Registration and Randomization Process............................................................................................. 30 
5. 
RISK GROUP CLASSIFICATION ............................................................................................................... 32 
5.1 
Risk Group Definitions .................................................................................................................................. 32 
5.2 
Determination of Final Risk Group Status for patients with ALL ................................................................. 34 
6. 
TREATMENT PLAN ...................................................................................................................................... 37 
6.1 
STEROID PROPHASE (All patients) ............................................................................................................ 38 
6.2 
Additional Lumbar Punctures for Patients with CNS Leukemia ................................................................... 39 
6.3 
Antibiotic Prophylaxis during Remission Induction Phase ........................................................................... 41 
6.4 
REMISSION INDUCTION PHASE (STANDARD RISK PATIENTS) ........................................................... 42 
6.5 
REMISSION INDUCTION PHASE (HIGH RISK AND VERY HIGH RISK PATIENTS) .............................. 45 
6.6 
Special circumstance: Induction Therapy for Patients with Hyperbilirubinemia on Day 4 .......................... 48 
6.7 
Special circumstance: Induction Therapy for Patients treated without Steroid Prophase ............................ 49 
6.8 
COMPLETION OF REMISSION INDUCTION THERAPY .......................................................................... 50 
6.9 
CONSOLIDATION I PHASE: STANDARD RISK PATIENTS ...................................................................... 54 
6.10 
CONSOLIDATION I PHASE: HIGH RISK PATIENTS ........................................................................... 57 
6.11 
CONSOLIDATION I: VERY HIGH RISK PATIENTS .............................................................................. 60 

Protocol 11-001 
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6.12 
CNS PHASE FOR STANDARD RISK PATIENTS .................................................................................... 67 
6.13 
CNS PHASE: HIGH RISK AND VERY HIGH RISK PATIENTS .............................................................. 69 
6.14 
CONSOLIDATION II PHASE .................................................................................................................. 72 
6.15 
CONTINUATION PHASE (for Standard, High Risk and Very High Risk Patients) ................................ 78 
6.16 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 81 
6.17 
Duration of Therapy .................................................................................................................................. 85 
6.18 
Duration of Follow Up ............................................................................................................................. 85 
6.19 
Criteria for Removal from Study .............................................................................................................. 85 
7. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 86 
7.1 
Anticipated Toxicities .................................................................................................................................... 86 
7.2 
Dose Modifications/Delays and Toxicity Management ................................................................................. 96 
A total bilirubin of < 1.4 mg/dL (23.9 micromoles/L) is sufficient to meet the bilirubin criteria for enrollment and 
starting or continuing a cycle during all phases of treatment. ............................................................................... 97 
8. 
DRUG FORMULATION AND ADMINISTRATION ............................................................................... 112 
8.1 
Asparaginase: Calaspargase Pegol ............................................................................................................ 112 
8.2 
Asparaginase: Pegasparagase (PEG-asparaginase, Oncaspar®,) NSC #624239 ..................................... 114 
8.3 
Asparaginase: Erwinia ................................................................................................................................ 115 
8.4 
Cyclophosphamide (Cytoxan) NSC #26271 ................................................................................................ 116 
8.5 
Cytarabine (cytosine arabinoside, Ara-C, Cytosar®) NSC # 63878 ........................................................... 117 
8.6 
Dexamethasone ........................................................................................................................................... 118 
8.7 
Dexrazoxane (Zinecard®), NSC# 169780 ................................................................................................... 119 
8.8 
Doxorubicin (Adriamycin®) NSC #123127 ................................................................................................ 120 
8.9 
Etoposide (VePesid®, Etopophos®, VP-16) NSC #141540 ........................................................................ 121 
8.10 
Hydrocortisone ....................................................................................................................................... 122 
8.11 
Leucovorin Calcium (LCV, Wellcovorin®, citrovorum factor, folinic acid), NSC #003590 .................. 122 
8.12 
Mercaptopurine (6-MP, Purinethol®, 6-mercaptopurine) NSC #000755 .............................................. 123 
8.13 
Methotrexate (MTX, amethopterin, Trexall®) NSC #000740 ................................................................ 125 
8.14 
Prednisone .............................................................................................................................................. 126 
8.15 
Vincristine (Oncovin®, VCR, LCR) NSC #67574 .................................................................................. 127 
9. 
CORRELATIVE/SPECIAL STUDIES ........................................................................................................ 127 
9.1 
Asparaginase Enzyme Activity/Pharmacokinetic (PK) Samples (Required of all participants) .................. 127 
9.2 
Antibody Samples (Required of all participants) ........................................................................................ 129 
9.3 
Minimal Residual Disease (MRD) Samples (Leukemia patients only) ........................................................ 131 
9.4 
Biology Research Samples—Peripheral Blood and Marrow (Optional) .................................................... 132 
9.5 
CSF Research Samples (Optional) .............................................................................................................. 132 
9.6 
Sample Shipment  of MRD, Biology and CSF Research Samples ............................................................... 133 

Protocol 11-001 
Version Date: 02/24/2016 
  
 
 
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10. 
STUDY CALENDAR .................................................................................................................................... 134 
10.1 
Study Assessements: Study Entry and Induction Phase .......................................................................... 134 
10.2 
Study Assessments: Post-Induction Treatment Phases ........................................................................... 137 
10.3 
Assessment Schedule after Completion of Therapy ................................................................................ 138 
11. 
CLINICAL RESPONSE CRITERIA ........................................................................................................... 140 
11.1 
Definition of CNS Status ......................................................................................................................... 140 
11.2 
Definition of Complete Remission .......................................................................................................... 140 
11.3 
Failure to Achieve Remission (Induction Failure) ................................................................................. 140 
11.4 
Criteria for relapse ................................................................................................................................. 141 
12. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................. 142 
12.1 
Definitions .............................................................................................................................................. 142 
12.2 
Serious Adverse Event Reporting Requirements and Criteria ................................................................ 145 
12.3 
Procedures for Adverse Event Recording and Reporting ....................................................................... 147 
12.4 
Reporting to Hospital Risk Management ................................................................................................ 148 
12.5 
Monitoring of Adverse Events and Period of Observation ..................................................................... 148 
13. 
DATA AND SAFETY MONITORING ........................................................................................................ 148 
13.1 
Data Reporting ....................................................................................................................................... 148 
13.2 
Safety Meetings ....................................................................................................................................... 149 
13.3 
Monitoring .............................................................................................................................................. 150 
14. 
REGULATORY CONSIDERATIONS ........................................................................................................ 150 
14.1 
Protocol Review and Amendments ......................................................................................................... 150 
14.2 
Informed Consent ................................................................................................................................... 150 
14.3 
Ethics ...................................................................................................................................................... 150 
14.4 
Study Documentation .............................................................................................................................. 151 
14.5 
Records Retention ................................................................................................................................... 151 
14.6 
Multi-center Guidelines .......................................................................................................................... 151 
15. 
Laboratory Evaluation and Therapy at Outside Affiliate Sites ................................................................. 153 
15.1 
Laboratory Studies ................................................................................................................................. 153 
15.2 
Therapy ................................................................................................................................................... 153 
16. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 155 
16.1 
Primary Objectives: Safety and Feasibility of SC-PEG asparaginase ................................................... 155 
16.2 
Secondary Objectives ............................................................................................................................. 159 
16.3 
Accrual Rate ........................................................................................................................................... 161 
17. 
PUBLICATION PLAN .................................................................................................................................. 161 

Protocol 11-001 
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18. 
REFERENCES ............................................................................................................................................... 162 
19. 
APPENDICES ................................................................................................................................................ 167 
19.1 
Appendix I: Vitamin D and Calcium Supplementation Guidelines ......................................................... 167 
19.2 
Appendix II: Guidelines for the Management of Thrombosis ................................................................. 170 
20. 
DANA-FARBER/HARVARD CANCER CENTER MULTI CENTER DATA AND SAFETY 
MONITORING PLAN ............................................................................................................................................ 174 
20.1 
INTRODUCTION ................................................................................................................................... 174 
20.2 
GENERAL ROLES AND RESPONSIBILITIES ...................................................................................... 175 
20.3 
PROTOCOL DEVELOPMENT .............................................................................................................. 177 
20.4 
PROTOCOL MANAGEMENT ................................................................................................................ 178 
20.5 
REQUISITIONING INVESTIGATIONAL DRUG ................................................................................... 187 
20.6 
SAFETY ASSESSMENTS AND TOXICITY MONITORING ................................................................... 187 
20.7 
PROTOCOL VIOLATIONS AND DEVIATIONS .................................................................................... 189 
20.8 
MONITORING: QUALITY CONTROL .................................................................................................. 191 
20.9 
AUDITING: QUALITY ASSURANCE .................................................................................................... 195 

Protocol 11-001 
 
 
Version Date: 02/24/2016 
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6 
1. OBJECTIVES 
 
1.1 Study Design 
 
A randomized study to determine the safety and feasibility of administering Calaspargase 
Pegol (SC-PEG asparaginase), a new formulation of PEG-asparaginase, compared with 
Oncaspar (the currently available form of PEG-asparaginase), in children and adolescents 
with newly diagnosed acute lymphoblastic leukemia (ALL)and lymphoblastic lymphoma  
treated with a DFCI ALL Consortium therapeutic backbone. 
 
1.2 Primary Objectives 
 
To assess the safety and feasibility associated with the administration of IV Calaspargase 
Pegol 2500 IU/m2 given as a single dose during Remission Induction and every 3-weeks for 
30 weeks during post-induction therapy in children and adolescents with newly diagnosed 
ALL  
1.2.1 To assess the toxicity associated with IV Calaspargase Pegol administration and 
determine if it is significantly different than toxicity associated with IV Oncaspar. 
1.2.2 To determine the serum asparaginase activity (SAA) levels associated with IV 
Calaspargase Pegol administered as a single dose during remission induction and every 
3-weeks for 30 consecutive weeks during post-induction therapy, and to compare them 
to the SAA associated with IV Oncaspar administered as a single dose during 
Remission Induction and every 2-weeks for 30 consecutive weeks during post-
induction therapy. 
 
 
1.3 Secondary Objectives 
 
1.3.1 To assess the frequency of bacteremia, fungemia and invasive fungal infections during 
the remission induction phase in patients receiving antibiotic prophylaxis.    
 
1.3.2 To describe the outcome of children and adolescents with lymphoblastic lymphoma 
treated with a DFCI ALL Consortium treatment regimen. 
 
1.3.3 To explore the impact on outcome of changing therapy for very high risk patients, 
defined as: i)B-precursor ALL patients with high end-induction minimal residual 
disease (MRD); patients withMLL-gene rearrangements or low hypodiploidy; or iii) T-
ALL/lymphoblastic lymphoma patients with ETP phenotype. 
 
 
1.3.4 To assess the feasibility of vitamin D screening and supplementation in children and 
adolescents undergoing treatment for ALL in the context of a multi-institutional trial.  
 
1.3.4.1 To determine the prevalence of vitamin D deficiency in children and 
adolescents with ALL at the following time-points: at diagnosis, at the end of 
remission induction, at the start of continuation, and at the conclusion of therapy. 

Protocol 11-001 
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7
1.3.4.2 To assess the feasibility of correcting vitamin D deficiency with 
supplementation of vitamin D and calcium in patients found to have vitamin D 
deficiency. 
1.3.4.3 To explore the relationship between vitamin D status and skeletal toxicity 
(fracture and osteonecrosis) in children and adolescents undergoing therapy for 
ALL. 
1.3.4.4 To explore risk factors for vitamin D deficiency, including demographic 
variables such as age, sex, and ethnicity, as well as geographic location (geographic 
latitude) and season of measurement. 
 
 
1.3.5 To determine the feasibility of prospective screening for absence of biallelic 
TCRdeletions (ABGD) via qPCR in patients with T-ALL  
1.3.5.1 
To determine the frequency of ABGD in patients with T-cell ALL at 
diagnosis 
1.3.5.2 
To explore the correlation between early T-cell precursor (ETP) phenotype 
and ABGD 
 
1.3.6 To determine the feasibility of prospective screening for abnormalities (eg, mutations, 
deletions, rearrangements) of IKZF1, CRLF2 and JAK1/2 in patients with newly 
diagnosed B-ALL. 
1.3.6.1 
To determine the frequency of these abnormalities in standard-risk and 
high-risk patients 
1.3.6.2 
To explore the correlation between the presence of these abnormalities and 
end-induction MRD levels. 
 
1.3.7 To explore the relationship between mitochondrial BCL-2 family preconditions and 
response to chemotherapy as measured by induction response, end-induction MRD 
level and event-free survival (EFS). 
 
1.3.8 To obtain patient samples for the development of primary xenograft mouse models 
with the goal of identifying novel therapies for high-risk (including those with high 
end-induction MRD, T-ALL with ABGD) and relapsed patients. 
 
2. BACKGROUND 
 
2.1 
Calaspargase Pegol (SC-PEG Asparaginase) 
L-asparaginase, a bacterially-derived enzyme that catalazyes the hydrolysis of L-asparagine, is 
an important and universal component of therapy for childhood ALL.  Lymphoblasts tend to 
have low intracellular levels of asparagine synthetase and so are dependent upon extracellular 
pools of asparagine to support their growth and proliferation.  Treatment with asparaginase 
effectively starves lymphoblasts while normal cells, with higher intracellular levels of asparagine 
synthetase, remain relatively unaffected. 
 

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8
There are three major L-asparaginase preparations available in North America: native E.coli 
asparaginase (Elspar), PEG-asparaginase (Oncaspar), formed by covalently attaching 
polyethylene glycol to the native E. coli enzyme, and Erwinia (Erwinase), derived from Erwinia 
chrysanthemi.  Of the three preparations, PEG asparaginase has the longest half-life and 
Erwinase the shortest.(1)  Studies have suggested that PEG asparaginase may be less 
immunogenic than native E.coli asparaginase.(2, 3) 
 
Calaspargase Pegol (SC-PEG-asparaginase) is a new pegylated asparaginase preparation which 
utilizes a novel linkage between the PEG-moiety and the native E.coli L-asparaginase protein.  
Calaspargase Pegol utilizes the same E.coli L-asparaginase and the same size PEG that is used in 
the currently available form of PEG asparaginase (Oncaspar), but the new linkage utilized in 
Calaspargase Pegol is felt to be more hydrolytically stable.   
2.2 
Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma 
 
ALL is the most common cancer diagnosed in children, representing approximately 25% of 
cancer diagnoses among children younger than 15 years.   There are approximately 2,400 
children and adolescents up to age 20 years diagnosed with ALL each year in the United 
States.(4) ALL most commonly occurs in pre-school aged children (age 2-5 years); the incidence 
of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants 
and is nearly tenfold greater than that for adolescents 16 to 21 years of age.    
 
Several clinical and biologic features have been found to have important prognostic significance 
in childhood ALL, including age, presenting leukocyte count, immunophenotype, recurrent 
chromosomal abnormalities, and response to initial therapy as measured by morphology and 
more sensitive techniques to assess minimal residual disease.(5) These prognostic factors have 
been used to stratify therapy; patients with “high risk” features have received more intensive 
treatments, whereas some of the more morbid components of therapy have been modified or 
eliminated for those children with more favorable presenting features.  With current treatment 
regimens, event-free survival (EFS) rates for childhood acute lymphoblastic leukemia (ALL) 
approach or exceed 80%.(6, 7) (8)         
 
Lymphoblastic lymphoma accounts for approximately 20% of childhood Non-Hodgkin’s 
lymphoma; there are about 150-200 cases diagnosed in the United States each year in children 
and adolescents younger than 20 years.(9)  Although pediatric patients with lymphoblastic 
lymphoma are typically treated with ALL therapeutic regimens, there are relatively few 
published series reporting the outcomes of patients treated in this way.  The BFM has reported 
long-term event-free survival rates of 80-90% for lymphoblastic lymphoma patients treated with 
their ALL regimens.(10, 11)  
 
2.3 
Primary Objective: Rationale 
 
L-asparaginase is an essential component of treatment for ALL, but is associated with multiple 
toxicities.  Because asparaginase preparations are bacterially-derived, they have the potential to 
be highly immunogenic. Hypersensitivity reactions to asparaginase occur in up to 30% of 
patients treated with native E. coli asparaginase.(2)    Clinical allergy is frequently associated 

Protocol 11-001 
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9
with the development of neutralizing antibodies, so that even if symptoms are controlled, there is 
little therapeutic benefit after drug administration.(12)  Other asparaginase-associated toxicities 
include pancreatitis (in 5-10% of patients) and thrombosis (in 2-5% of patients).(13)    
 
Since 1977, the Dana-Farber Cancer Institute (DFCI) ALL Consortium has included 20-30 
consecutive weeks of asparaginase during post-induction consolidation therapy, and has 
demonstrated that this treatment significantly improves long-term event-free survival.(14, 15) 
We also demonstrated that patients who received a truncated course of asparaginase because of 
intolerable side effects had an inferior outcome compared with those who receive all intended 
doses.(2) Thus, it is crucial to determine the optimal dosing and preparation of asparaginase in 
order to reduce a significant source of treatment-related morbidity and potentially improve cure 
rates. 
 
Over the last two decades, we have performed sequential randomized studies to determine the 
optimal dosing and preparation of asparaginase.(2, 16)  Between 1991 and 1995, we conducted a 
randomized clinical trial comparing intramuscular PEG-asparaginase and E.coli L-asparaginase 
in children with newly diagnosed ALL.(2)  We found that PEG-asparaginase was associated with 
decreased frequency of asparaginase-related toxicities, primarily due to a lower incidence of 
allergic reactions, without any significant difference in event-free survival between the two 
preparations.  We subsequently determined that Erwinia asparaginase, when dosed once weekly 
during a 20-week Consolidation phase, was less toxic but also less efficacious than native E.coli 
asparaginase (Protocol 95-01, 1996-2000).(16)   
 
On Protocol 00-01 (2000-5), we compared conventional fixed dosing (25,000 IU/m2/week) of 
E.coli asparaginase with individualized dosing (dosing adjusted based on patient’s pre-dose nadir 
enzyme activity levels, with the goal of maintaining trough levels between 0.1-0.14 IU/mL).   
Nadir serum asparaginase activity (NSAA) was monitored in samples obtained before treatment 
and 7-days after the dose given on weeks 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, and 29, just prior to 
administration of the next dose of asparaginase. 384 patients were randomized, and over 2,500 
samples were collected and assayed in real-time (7-14 day turnaround time) for NSAA over the 
course of that study.  We determined that there was large interpatient variability in NSAA for 
those receiving fixed dose asparaginase, and on the individualized dosing arm, adolescents (10-
18 years of age) required a lower dose of E.coli asparaginase than younger children to maintain 
NSAA within the goal range.  We observed no difference in the frequency of asparaginase-
related toxicities when comparing individualized and fixed dosing.  However, individualized 
dosing of asparaginase was associated with a superior event-free survival (5-yr EFS of 90 ± 2% 
compared with 82 ± 3% for fixed-dose asparaginase, p=0.04).(17) 
 
Between 2005-2010, we conducted a Phase III randomized trial comparing IV Oncaspar with IM 
native E.coli asparaginase in children and adolescents (age 1-18 years) with newly diagnosed 
ALL (DFCI ALL Consortium Protocol 05-001; National Clinical Trial Reference Number 
00400946: Pegasparaginase or Asparaginase and Combination Chemotherapy in Treating Young 
Patients With Newly Diagnosed Acute Lymphoblastic Leukemia).(18)  All patients received IV 
Oncaspar 2500 IU/m2 on Day 7 of multiagent remission induction.  Patients then received 30 
weeks of asparaginase commencing on week 7 of treatment.   Patients were randomized to 
receive either IV Oncaspar 2500 IU/ m2 every 2 weeks x 15 weeks or IM Elspar 25000 IU/ m2 

Protocol 11-001 
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10
every week x 30 weeks.  Serum samples from all patients are collected at several time points for 
analysis of asparaginase enzyme activity.  As of March 1, 2010, 556 eligible subjects were 
enrolled on Protocol 05-001 (accrual rate of 116 patients/year), which met the accrual goal for 
the randomized comparison of IV PEG versus IM E.coli asparaginase. 506 patients (91% of 
enrolled subjects) agreed to participate in the asparaginase randomization.   
 
We analyzed serum asparaginase activity levels weekly during the induction phase beginning 4 
days after the dose of IV Oncaspar was administered.  We observed that 88% of patients had 
serum asparaginase activity > 0.1 IU/mL for 18-days after dosing, but only 7% maintained this 
level of activity after 25 days (Table 2.1), supporting the every 2-week dosing schedule during 
post-induction treatment phases.(18)  The single dose of IV Oncaspar administered during 
induction on Protocol 05-001 was reasonably well-tolerated.  Toxicities included pancreatitis 
(4.5% of patients), thrombotic complications (2%), and hypersensitivity reactions (1.5%).  There 
were no asparaginase-related deaths during the induction phase.     
 
Table 2.1. Serum asparaginase activity (IU/mL) after a single 2,500 IU/m2 dose of PEG-asparaginase 
given as a 1-hour IV infusion in 186 children during Induction phase on DFCI Protocol 05-001. 
 
Days 
 
Serum asparaginase 
Proportion of patients with 
 
after 
No. of  
activity (IU/mL) 
asparaginase activity (IU/mL) 
Inductio
n Day # 
IV 
PEG 
dose 
Patients Median (range)
Mean ± SD 
≥ 0.025 
≥ 0.10 
≥ 0.20 
11 
4 
130 
0.66  
(<0.025, 2.34) 
0.73 ± 0.29 
96 
96 
96 
18 
11 
133 
0.48  
(<0.025, 1.58) 
0.49 ± 0.22 
97 
95 
92 
25 
18 
112 
0.20  
(<0.025, 1.24) 
0.23 ± 0.14 
96 
88 
52 
32 
25 
113 
0.04  
(<0.025, 0.41) 
0.07 ± 0.05 
70 
7 
2 
 
During the post-induction consolidation phase, samples for assessment of nadir serum 
asparaginase activity level were obtained every 6 weeks, just prior to the administration of an 
asparaginase dose (2-weeks after previous Oncaspar dose and 1-week after previous E.coli 
asparaginase dose.  The median nadir serum asparaginase activity (NSAA) levels were higher 
with IV Oncaspar than with IM E.coli (Table 2.2).  Nearly all patients treated with IV Oncaspar 
had NSAA > 0.1 IU/mL (the goal therapeutic level previously associated with serum asparagine 
depletion) throughout the 30-weeks of post-induction asparaginase compared with fewer than 
half of patients treated with IM E.coli asparaginase (Table 2.3,  p<0.01 at each timepoint), and 
significantly more IV Oncaspar-treated patients had NSAA levels exceeding 0.2 and 0.4 IU/mL 
than did IM E.coli asparaginase patients (p<0.01 at each time point).  There was no significant 
difference in asparaginase-related toxicities (allergy, pancreatitis, thrombosis) between the two 
arms (Table 2.4), although there was a trend toward more thrombotic events with E.coli 
asparaginase (p=0.07).    
 
 

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11
 
 
 
Table 2.2 Median and mean nadir Serum asparaginase activity (IU/mL) during the Post-
Induction Consolidation Phase on Protocol 05-001  
 
 
 
IV Oncaspar 
 
IM E.coli 
Sample 
Time 
 
Nadir serum asparaginase activity 
(IU/mL) 
 
Nadir serum asparaginase activity 
(IU/mL) 
(weeks) 
N 
Median (range) 
Mean ± SD 
N 
Median (range) 
Mean ± SD 
5 
84 
0.67 
(<0.025, 1.99) 
0.67 ± 0.32 
92 
0.094 
(<0.025, 1.71) 
0.15 ± 0.22 
11 
70 
0.71  
(<0.025, 1.30) 
0.70 ± 0.26 
74 
0.094  
(<0.025, 1.69) 
0.15 ± 0.24 
17 
73 
0.76  
(<0.025, 2.53) 
0.76 ± 0.32 
86 
0.092  
(<0.025, 1.33) 
0.15 ± 0.19 
23 
60 
0.70  
(0.21, 1.46) 
0.72 ± 0.23 
76 
0.094  
(<0.025, 1.72) 
0.17 ± 0.26 
29 
68 
0.70  
(0.11, 2.42) 
0.74 ± 0.31 
63 
0.095  
(<0.025, 1.28) 
0.13 ± 0.18 
Mean 
per 
Patient 
114 
0.70 
(0.22, 1.38) 
0.72 ± 0.21 
136 
0.10 
(<0.025, 1.17) 
0.15 ± 0.19 
 
 
Table 2.3  Proportion of patients with NSAA at or exceeding 0.025, 0.10, 0.20 and 0.40 
IU/mL during the Post-Induction Consolidation Phase on Protocol 05-001 (lower limit of 
detection of assay: 0.025 IU/mL) 
 
 
 
IV Oncaspar 
 
IM E.coli 
Sample  
time 
 
Proportion of patients with 
asparaginase activity (IU/mL) 
 
Proportion of patients with 
asparaginase activity (IU/mL) 
(weeks) 
N 
≥ 0.025 
≥ 0.10 
≥ 0.20 
≥ 0.40 
N 
≥ 0.025 
≥ 0.10 
≥ 0.20 
≥ 0.40 
5 
84 
98 
95 
94 
85 
92 
87 
48 
18 
8 
11 
70 
99 
97 
97 
91 
74 
88 
47 
18 
7 
17 
73 
99 
97 
95 
90 
86 
90 
47 
21 
5 
23 
60 
100 
100 
100 
93 
76 
92 
46 
16 
8 
29 
68 
100 
100 
99 
91 
63 
92 
44 
14 
5 
 
 
 
 
 
 
 

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Thus, all patients treated with 2500 IU/ m2 Calaspargase Pegol maintained serum asparaginase 
activity levels > 0.1 IU/mL for 4 weeks after a single dose.  The COG study was subsequently 
amended so that patients randomized to Calaspargase Pegol received a dose of 2100 IU/m2, 
which was felt to be more comparable pharmacokinetically to Oncaspar 2500 IU/m2.  However, 
the COG study was suspended on December 22, 2010 based on a higher rate of Day 29 end-
induction MRD-positivity for patients treated with Calaspargase Pegol 2100 IU/m²/dose 
compared with Calaspargase Pegol 2500 IU/m²/dose or Oncaspar 2500 IU/m²/dose.  The 
difference in frequency of MRD-positivity was statistically significant and crossed pre-defined 
safety monitoring boundaries.  Subsequent analyses indicated that their was an imbalance in the 
randomization, with a greater proportion of higher risk patients randomized to Calaspargase 
Pegol 2100 IU/m2 arm than to Oncospar 2500 IU/m2: there were more patients on the 
Calaspargase Pegol 2100 IU/m2 arm who were older than 16 years at diagnosis, and more 
patients who were older than 10 years with presenting WBC counts > 50K.  This imbalance 
likely contributed to the differing rates in end-induction MRD rates between the two arms. 
 
Data from the COG protocol suggests that a single dose of IV Calaspargase Pegol 2500 IU/m² is 
tolerable and likely to lead to asparagine depletion for up to 4 weeks after a single dose.  
Additionally, at this dose, there was no difference in end-induction MRD rates compared with 
Oncasspar 2500 IU/m2. It still remains to be determined how best to dose Calaspargase Pegol 
during post-induction therapy.  On COG Protocol AALL07P4, asparaginase is administered 
intermittently during the post-induction treatment phases (Days 15 and 43 of Consolidation, 
Days 2 and 22 of Interim Maintenance #1, Days 4 and 43 of Delayed Intensification #1, Days 2 
and 22 of Interim Maintenance #1 and Days 4 and 43 of Delayed Intensification #2).  On DFCI 
ALL Consortium protocols, asparaginase is given at regular intervals during the post-induction 
consolidation phase with the goal of maintaining therapeutically effective serum enzyme activity 
for 30 consecutive weeks.   Additionally, the induction phase on DFCI ALL Consortium 
protocols is similar but not identical to COG high-risk ALL protocols, and so both the 
pharmacokinetics and toxicity of Calaspargase Pegol may be different during this phase as well.  
Thus, the toxicity and PK data derived from COG Protocol AALL07P4 may not fully inform 
how best to dose Calaspargase Pegol within the context of a DFCI ALL Consortium treatment 
regimen.  The main objective of Protocol 11-001 is to determine the safety and feasibility of 
administering Calaspargase Pegol within the DFCI ALL Consortium regimen in anticipation of 
this formulation soon becoming the only available commercial PEG-asparaginase preparation.   
 
Based on the initial data from the COG AALL07P4 protocol, we will plan on administering IV 
Calaspargase Pegol at a dose of 2500 IU/m2.  We will administer this dose once during the 
Remission Induction phase and then every 3 weeks for 30 weeks during post-induction treatment 
phases.  The 3-week dosing interval has been chosen based on the results from COG AALL07P4 
indicating that Calaspargase Pegol has a longer half-life than Oncaspar, with nearly all patients 
demonstrating levels > 0.1 IU/mL 3-4 weeks after a single dose.   Given that chemotherapy 
during post-induction therapy on DFCI ALL Consortium protocols is given in 3-week cycles, 
administration of PEG-asparaginase every 3-week is likely to be more convenient (requiring 
fewer clinic visits) for patients and families than every 2-week dosing (the Oncaspar dosing 
schedule on Protocol 05-001). 
 

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We will conduct this trial in a randomized fashion.  Patients will be randomized to receive either 
Calaspargase Pegol (dosed as described above) or IV Oncaspar, dosed as on Protocol 05-001 (a 
single dose during induction and then every 2-weeks for 30 weeks during post-induction 
treatment phases).  We will prospectively collect information regarding toxicity, and will assess 
enzyme activity weekly during the induction phase and prior to every post-induction 
asparaginase dose.  Serum samples will also be collected to screen for anti-asparaginase 
antibodies.  We will also closely monitor the frequency of high end-induction MRD (defined as 
> 0.001 by PCR assay).   The randomized design will allow us to directly compare serum 
asparaginase activity levels between the two preparations, and also ensure that asparaginase-
related toxicities are not significantly different on either arm compared with those observed with 
IV Oncaspar on Protocol 05-001.   
 
The administration of IV Calaspargase Pegol at 2500 IU/ m2 as a single dose during induction 
and every 3 weeks for 30 weeks will be considered feasible if we determine that, when compared 
to every 2–week dosing of IV Oncaspar (from data collected both on this study and historic data 
from Protocol 05-001), it is no more toxic, is associated with NSAA > 0.1 IU/mL in a similarly 
high proportion of patients during post-induction treatment phases, and is not associated with a 
higher frequency of high end-induction MRD in patients with ALL. 
 
We will also monitor NSAA in real-time to identify any patients with extremely low 
asparaginase enzyme activity levels (<0.025 IU/mL). Results from DFCI ALL Consortium 
Protocol 00-01 indicate that sequential measurements of NSAA during the 30-week 
consolidation phase are feasible and identify patients maintaining inadequate serum enzyme 
activity levels.  Moreover, individualized dose adjustment of native E.coli asparaginase on that 
trial (which included switching asparaginase preparations for patients with extremely low NSAA 
for presumed “silent” inactivation) was associated with superior EFS compared with standard 
dosing based on body surface area.   In this pilot trial, patients on either arm (Oncaspar or 
Calaspargase Pegol) found to have non-detectable NSAA (<0.025 IU/mL) on two consecutive 
measurements will be switched to twice-weekly Erwinia asparaginase.  
 
2.4 
Secondary Objectives: Rationale 
 
2.4.1 Antibiotic Prophylaxis during Remission Induction 
Despite improvement in supportive care over the last several decades, infectious complications 
are a major cause of treatment-related morbidity and mortality, especially during the initial, more 
intensive treatment phases. On Protocol 05-001, approximately 25% of patients had at least one 
documented episode of infection during the induction phase, and 2% of patients died during this 
phase due to treatment complications (primarily infectious).  The majority of these infectious 
episodes are bacteremias, with invasive fungal disease representing only a small fraction of 
cases.  Episodes of bacteremia during remission induction frequently lead to prolonged 
hospitalization, as well as delays and/or dose reductions in chemotherapy, raising the question of 
whether antibacterial prophylaxis might be beneficial during this treatment phase.   
 
The role of antibiotic prophylaxis in neutropenic cancer patients has been controversial for many 
years.(19) Meta-analyses of clinical trials have suggested that prophylaxis with fluoroquinolones 
or sulfamethoxazole may reduce gram negative bacteremias in neutropenic adult cancer 

Protocol 11-001 
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15
patients.(20, 21) However, these results have not been considered definitive because most of the 
analyzed trials included a limited number of patients, many of whom were of different risk 
categories, and only a few trials were randomized, placebo-controlled.  In addition the recent 
emergence of fluoroquinolone-resistant bacterial strains is of increasing concern.(22, 23)  
 
In 2005, the results of two large double-blind, placebo-controlled trials using levofloxacin as 
antibiotic prophylaxis in adult cancer patients with neutropenia were published.(24, 25)  In one 
study, 760 adult cancer patients in whom chemotherapy-induced neutropenia was expected to 
occur for more than seven days were randomized to receive either oral levofloxacin or placebo 
from the start of chemotherapy until the resolution of neutropenia.(24) Patients randomized to 
prophylactic levofloxacin had fewer episodes of fever and a significantly lower rate of 
microbiologically documented infections. The effects of prophylaxis were also similar in patients 
with acute leukemia (who had more sustained and profound neutropenia) and those with solid 
tumors or lymphoma.  In the second study, 1565 adult patients with lymphoma or solid tumors 
were randomized to receive oral levofloxacin or placebo during periods of chemotherapy-
induced neutropenia, and, as in the first study, the incidence of fever and clinically documented 
infections was significantly lower in the group of patients receiving levofloxacin 
prophylaxis.(25)   In 2008, based on these studies, the National Comprehensive Cancer Network 
(NCCN) recommended the use of fluoroquinolone prophylaxis in high risk cancer patients, 
including leukemia patients receiving induction chemotherapy.(26) 
  
The role of antibiotic prophylaxis has not been as extensively studied in pediatric cancer patients. 
Studies evaluating the efficacy of trimethoprim-sulfamethoxazole (SMX-TMP) in preventing 
bacterial infections in ALL patients have had conflicting results,(27-30) although most of the 
published series suggest that SMX-TMP prophylaxis reduces the frequency of bacteremias.   
However, in randomized studies, the use of SMX-TMP has also been associated with a longer 
duration of neutropenia,(27) which potentially could lead to chemotherapy dose reductions or 
delays.  In a non-randomized, retrospective study of 78 pediatric AML patients treated at St. 
Jude’s Children’s Hospital, antibiotic prophylaxis with either cefepime or vancomycin with 
ciprofloxacin (or a cephalosporin) were associated with lower rates of bacteremia (including 
lower rates of Strep viridans) compared with the use of an oral cephalosporin or no 
prophylaxis.(31) No change in the rate or type of fungal infections was observed based on the 
type of antibiotic prophylaxis. 
 
Based on the high rate of bacteremia in patients during the induction phase of DFCI ALL 
Consortium studies, we will study the use of antibiotic prophylaxis during this phase during 
Protocol 11-001.  All patients will receive a fluoroquinolone (either levofloxacin or 
moxifloxacin), or an alternative agent if unable to receive a fluoroquinolone, during the 
induction phase as a prophylaxis; antibiotic coverage will be extended for those who develop 
fever or documented infection.  Rates of bacteremia will be compared to historic controls (25% 
incidence of bacteremia during the induction phase on Protocols 00-01 and 05-001).   
Fluoroquinolones offer several advantages over other antibiotics used as prophylaxis: broad 
antimicrobial spectrum, systemic bactericidal activity, good tolerability and lack of systemic 
myelosuppression.(32) The choice of a fluoroquinolone in our study is in accord with NCCN 
guidelines for leukemia patients during induction therapy.   
 

Protocol 11-001 
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16
2.4.2 Intensifying Therapy for B-precursor Patients with High End-Induction MRD 
Multiple studies have demonstrated that end-induction MRD is an important, independent 
predictor of outcome in children with ALL. Patients with higher levels of end-induction MRD 
have a poorer prognosis than those with lower or undetectable levels. MRD at end-induction is 
used by almost all childhood ALL consortia as a factor to determine the intensity of post-
induction treatment, with patients found to have higher levels allocated to more intensive 
therapies regardless of other presenting features.  
 
We have assessed minimal residual disease levels (MRD) in all patients since 1996 by a 
polymerase chain reaction (PCR) technique targeting lymphoblast-specific immunoglobulin gene 
rearrangements.  Using this technique, we demonstrated that MRD levels at the end of the 
remission induction phase significantly predicted subsequent risk of relapse for B-precursor 
patients treated between 1996-2000.(33) On Protocol 05-001, end-induction MRD was used to 
risk-stratify B-precursor patients, with those found to have levels >0.001 considered to be very 
high risk. We will continue to use this value as a VHR criterion on Protocol 11-001.  Therefore, 
obtaining MRD levels at end of induction (Day 32) will be mandatory for all patients enrolled on 
this protocol.  On Protocol 05-001, approximately 10% of enrolled subjects were classified as 
VHR and were treated with a more intensified post-induction regimen, consisting of two 
additional Consolidation I cycles and a high-risk Consolidation II backbone.  Additionally, all 
VHR patients received cranial radiation.  Treatment of VHR patients will be identical on 
Protocol 11-001.   In this way, we will able to expand the cohort of patients  treated with the 
VHR  regimen first tested on Protocol 05-001 to explore how this intensified regimen impacts 
patient outcome. 
 
MRD levels at later time points (e.g., day 78 after initiation of therapy) also have been shown to 
predict long-term outcome.(34-36) The BFM group uses MRD levels assessed at both end-
induction and week 12 of treatment to risk-stratify patients.(36) They have demonstrated that, for 
patients with high MRD levels at week 4 (end-induction), those with persistently high MRD at 
week 12 have significantly worse outcomes than those whose MRD levels are low at this later 
timepoint.(36)  Based on this finding, we will assess marrow MRD at the start of the CNS phase 
(week 13 of treatment, after completion of Consolidation IB and IC) in all patients with high 
end-induction MRD on Protocol 11-001.  In addition, we will assess peripheral blood MRD prior 
to the start of Consolidation IB and IC.  These results will be used to determine whether MRD at 
this timepoint has prognostic significance within the context of our VHR regimen, but will not be 
used to determine therapy for patients treated on Protocol 11-001. 
 
Other groups utilize MRD values obtained from earlier timepoints (during remission induction) 
to determine final risk group.  In addition to end-induction MRD, the Children’s Oncology 
Group (COG) considers Day 8 MRD (as assessed in the peripheral blood) and the St. Jude 
Children’s Research Hospital utilizes marrow MRD assessments from Day 19 when risk-
stratifying patients.(34, 35)  On Protocol 05-001, we collected MRD specimens at Day 18 of 
induction therapy from patients who consented to an additional, optional marrow specimen at 
that timepoint and will continue to do so on Protocol 11-001.   
 
For patients with T-ALL, MRD assessed at later timepoint may be prognostically significant.  In 
the AIEOP-BFM ALL 2000 trial, MRD status at day 78 (week 12) was the most important 

Protocol 11-001 
Version Date: 02/24/2016 
 
 
 
17
predictor for relapse in patients with T-cell ALL.(37) A high MRD level at day 78 was 
associated with a significantly higher risk of relapse. Importantly, patients with detectable MRD 
at end-induction who had negative MRD by day 78 did just as well as patients who achieved 
MRD-negativity at the earlier end-induction time point.  On DFCI ALL Consortium protocols, 
MRD has not been assessed at timepoints beyond the induction phase.  In order to determine if 
MRD assessed at a later timpoint may have prognostic relevance for T-ALL within the context 
of our treatment regimen, we will be collecting MRD specimens at the start of the CNS phase 
(week 7 of therapy) in T-ALL patients who consent to an additional, optional marrow specimen 
at that timepoint. 
 
Using the PCR-based assay, approximately 15% of results are “indeterminate”, primarily due to 
failure to identify a clone.  An alternative deep sequencing approach for MRD detection has been 
developed and validated.(67) Like our PCR-based assay, this methodology focuses on clonal 
rearrangements of IgH and TCR genes to identify residual disease.  The deep sequencing 
methodology utilizes high-throughput sequencing to identify clonal rearrangements of these 
genes in diagnostic samples and to quantify MRD in follow-up samples.  In a study conducted by 
St. Jude Children’s Research Hospital (SJCRH), the deep sequencing methodology was 
compared with multiparameter flow cytometry and allele-specific oligonucleotide polymerase 
chain reaction (ASO-PCR) assays using diagnostic and follow-up samples from 106 patients 
with ALL. Deep sequencing detected MRD in all 28 samples shown to be positive by flow 
cytometry and in 35 of the 36 shown to be positive by ASO-PCR, and detected MRD in 10 and 3 
additional samples that were negative by flow cytometry and ASO-PCR, respectively.(67) 
 
In order to determine whether the deep sequencing methodology could be used for MRD 
assessment in those patients without an evaluable result using our standard ASO-PCR assay, we 
sent banked samples from patients treated on prior DFCI protocols to Sequenta, the 
biotechnology firm that performed the deep sequencing testing on samples from the SJCRH 
study.  Initially we sent 7 samples, a mix of patients who did and did not relapse, and did and did 
not have high MRD in their end-of-induction samples.  Results from DFCI ASO-PCR assay and 
Sequenta were concordant for all 7 samples.  We subsequently sent 73 additional samples to 
Sequenta for MRD assessment.  All samples were from patients with B-precursor phenotype.  27 
of the patient samples had MRD results from the ASO-PCR assay, including 18 patients with 
low end- induction MRD, of whom 8 subsequently relapsed; 9 patients with high end-of-
induction MRD, of whom 2 subsequently relapsed.  Samples were also sent from 46 patients for 
whom ASO calibration could not provide an end- induction MRD assessment.  Sequenta was 
able to identify leukemic clones and quantiate MRD in all 27 of the samples for which ASO-
PCR assay had been successful, and for 44 of the 46 samples for which ASO-PCR assay had 
been unsuccessful.  Among the latter, 3 patients had MRD levels at or above 0.1% of cells 
examined, the threshold used by the Consortium for ASO PCR.  This is approximately 10% of 
the samples with “indeterminate” PCR-MRD assay results, which is the expected proportion of 
patients with high end-induction MRD.   
   
Given these data, beginning in 2014, we will send diagnostic and Day 32 samples for all patients 
with ALL enrolled on Protocol 11-001 to Sequenta, whose deep sequencing assay is CLIA-
approved. This will allow us to evaluate the feasibility of obtaining MRD results using deep 
sequencing methodology in real time and to more fully evaluate concordance between PCR and 

Protocol 11-001 
Version Date: 02/24/2016 
 
 
 
18
deep sequencing results.  For patients enrolled on Protocol 11-001, Day 32 MRD will still be 
primarily assessed based on PCR results; however, for cases in which MRD is indeterminate by 
PCR assay, deep sequencing results will be utilized for risk stratification purposes.  No extra 
volume of sample will be obtained from patients; rather, the DFCI MRD lab will split the sample 
sent to them for MRD assessment, and forward some to Sequenta, so that MRD may be assessed 
in both labs simultaneously from the same sample.      
 
2.4.3 Vitamin D Screening and Supplementation 
 
Skeletal toxicities have been well-characterized as serious complications of therapy for 
childhood ALL.(38, 39)  Children undergoing treatment for ALL are at increased risk for 
fracture during and immediately following the completion of therapy.  On DFCI-ALL 
Consortium Protocol 00-01, which included a randomized comparison of dexamethasone and 
prednisone during post-induction treatment phases, dexamethasone was associated with superior 
event-free survival, but also more skeletal toxicities in older children/adolescents.(17)  On that 
study, 14% of patients experienced a fracture, and older children and adolescents receiving 
dexamethasone appeared to be at increased risk for this toxicity.  On Protocol 11-001, 
dexamethasone will again be utilized during post-induction therapy, given its superior anti-
leukemia effect.  Identifying interventions which will minimize skeletal complications would be 
of great benefit in reducing the treatment-related morbidity experienced by patients.   
 
The potential role for supplementation with vitamin D and calcium in the context of ALL 
therapy has yet to be defined.  Vitamin D deficiency has been recognized as an important 
concern with regard to bone health, even for healthy children, emphasized by the recent Institute 
of Medicine report and the American Academy of Pediatrics recommendation for increased 
minimal daily vitamin D intake.(40-42)  Children undergoing leukemia treatment may be at 
increased risk for vitamin D deficiency.(43)  The feasibility of assessing vitamin D status and of 
correcting vitamin D deficiency has not been previously evaluated in the context of multi-
institutional clinical trial.  In addition, the impact of vitamin D status with regard to acute and 
long-term skeletal morbidities has not been thoroughly explored in this population.  Preliminary 
results from Protocol 05-001 investigating dietary micronutrient intake and treatment-related 
toxicity demonstrated that males undergoing treatment for ALL with low intakes of calcium are 
at increased risk for developing fractures, independent of age and leukemia risk group.(44)  In 
addition, in a report of patients with ALL treated with DFCI ALL Consortium therapy, low 
calcium intake was a predictor of low bone mineral density (as assessed by dual energy X-ray 
absorptiometry) in children with ALL.(45)   
 
Dietary interventions aimed at improving intake of calcium and vitamin D during treatment for 
ALL require further study.  We plan on assessing the feasibility of screening for vitamin D 
deficiency in patients at several time points in order to determine the prevalence of this 
deficiency in ALL patients and to explore the relationship of vitamin D status and skeletal 
toxicity (fracture and osteonecrosis).  We will also explore the feasibility of vitamin D and 
calcium supplementation in patients found to have vitamin D deficiency within the context of our 
multi-institutional clinical trial.     
 

Protocol 11-001 
Version Date: 02/24/2016 
 
 
 
19
2.4.4 Prospective Screening of High-Risk Subsets of Patients 
We will collect samples from patients at diagnosis to determine the feasibility of prospective 
screening for recently identified genetic predictors of outcome.  Many of these factors have not 
yet been validated prospectively, and their true frequency is not known.  Thus, one goal of 
prospective screening is to determine the frequency of these abnormalities in a population of 
newly diagnosed children and adolescents with ALL, and to explore their impact on end-
induction MRD levels and rates of relapse.  In addition, by demonstrating that it is possible to 
prospectively screen for these factors with a rapid turnaround of results, we will potentially be 
able to incorporate some or all of these factors into the risk classification scheme in the next 
DFCI ALL Consortium protocol, and, with a larger planned accrual on that trial, could test the 
impact of more intensive and/or novel therapies in patient populations with these abnormalities.   
The factors we plan to screen for include: absence of biallelic TCR deletions (ABGD) in 
patients with T-ALL, and IKZF1 deletions/mutations, CRLF2 over expression and JAK1/2 
mutations in patients with B-ALL.  
ABGD in T-ALL: There are few commonly accepted prognostic factors for patients with T-cell 
ALL.  Using banked samples from 47 T-ALL patients treated either on DFCI Protocol 00-01 or 
COG Protocol 9404 (which was based on the high-risk DFCI Consortium treatment regimen), we 
were able to demonstrate that ABGD, a characteristic of early thymocyte precursors, was 
strongly associated with early treatment failure in patients with T-cell ALL.(46)  This finding 
was confirmed in a validation cohort consisting of samples from T-ALL patients treated on St. 
Jude protocols.  This initial study had a case-control design, with nearly half the samples coming 
from patients who either failed to achieve remission or experienced an early relapse.   
Additionally, the diagnosis of ABGD was initially made using array comparative genomic 
hybridization (CGH).   A quantitative DNA-PCR assay for ABGD has been developed which 
may provide a reliable, more rapid screening of this abnormality.(46)     On Protocol 11-001, we 
will screen all T-ALL patients for ABGD using this qPCR assay to assess the frequency of this 
abnormality in newly diagnosed patients.  We will also study the correlation between ABGD and 
early T-cell phenotype (ETP), a recently characterized T-cell subset identified by gene 
expression profiling, flow cytometry and single nucleotide polymorphism array analyses.(47)  
This subset, characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with 
weak expression of stem cell or myeloid markers and weak expression of CD5), has, like ABGD, 
been correlated with a poorer prognosis in retrospective analysis.(47)   
IKZF1, CRLF2 and JAK mutations in B-ALL:   Alterations (primarily deletions) of IKZF1, a 
gene that encodes the lymphoid transcription factor IKAROS, have recently been identified as a 
potentially significant predictor of outcome in B-ALL.(48, 49)  In one series of 131 B-precursor 
ALL patients (including both standard and high-risk patients) with banked diagnostic samples, 
IKZF1 deletions were  identified in 14% of patients.(49) In another study, which included only 
high-risk Philadelphia chromosome-negative B-precursor ALL patients, 30% of 221 patients 
with assessable diagnostic samples were found to have IKZF1 alterations.(48)   In both of these 
reports, IKZF1 alterations/deletions were associated with a high risk of relapse.    
Elevated expression of CRLF2 (cytokine receptor-like factor 2) has been indentified in some 
patients with ALL, including subsets of high-risk patients and those with Down Syndrome.(50, 

Protocol 11-001 
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20
51)  In one report, ~14% of high-risk, Philadelphia chromosome-negative B-ALL with 
assessable diagnostic samples had CRLF2 overexpression.(50)  Nearly all of these cases were 
found to have either a translocation of the immunoglobulin heavy chain gene IGH to CRLF2 (in 
the pseudoautosomal region 1 of Xp22.3/Yp11.3) or to an interstitial deletion resulting in a 
P2RY8-CRLF2 fusion. CRLF2 rearrangements were significantly associated with IKZF1 
abnormalities (~80% of CRLF2-altered cases also had an IKZF1 deletion or mutation), as well as 
with activating mutations of JAK1 or JAK2.  Within this cohort, CRLF2 rearrangements were 
associated with a poor relapse-free survival, although on multivariate analysis, abnormality of 
IKZF1, and not CRLF2, was an independent predictor of outcome.(50)  
Reports of the frequency and prognostic significance of IKZF1 and CRLF2 alterations have all 
been based on analyses of stored samples, and have not yet been evaluated prospectively.   
Because these factors may be used in the future to risk-stratify patients and potentially test novel 
targeted therapies (such as JAK inhibitors), we plan to prospectively screen all B-ALL patients 
for alterations of IKZF1 and CRLF2.  CRLF2 overexpression will be screened using flow 
cytometry and CRLF2 rearrangements using FISH. All cases found to have CRLF2 
abnormalities will be screened for JAK mutations (given that a previous report suggests that 
nearly all cases with JAK mutations are found in those with CRLF2-overexpression).(50) IKZF1 
abnormalities were initially identified using single-nucleotide-polymorphism microarrays, 
transcriptional profiling, and resequencing,(48) but multiplex ligation dependent probe 
amplification (MLPA) has been shown to be a more rapid technique for accurate, high-
throughput screening for IKZF1 deletions,(49) and so we will use this methodology.   
2.4.5 BH3-profiling to identify patients at high risk of treatment failure 
Nearly all chemotherapy agents can induce the hallmarks of apoptosis by the intrinsic apoptotic 
pathway. Therefore, cancer cells likely require a block in apoptosis in order to survive. For 
instance, overexpression of the antiapoptotic protein BCL-2 provides a block in apoptosis that is 
frequently observed in cancer cells, including leukemia.(52) The measurement of protein levels 
of all members of the BCL-2 family of apoptosis regulators is too complex, cumbersome, and 
difficult to be used as a clinical measure.  The functional assay of BH3 profiling is an alternative 
methodology which has been used to identify the extent to which the blasts are ‘primed’ for 
apoptosis  and also the specific block in the apoptotic pathway a cancer cell uses to resist the 
effects of chemotherapeutic agents.(53) In specimens taken from lymphoma patients, BH3-
profiling was able to identify patient subsets with distinctive patterns of apoptotic defects which 
predicted response to conventional chemotherapy agents.(54) Furthermore, BH3 profiling 
permits evaluation of whether mitochondrial or extra-mitochondrial contributors dominate in 
causing chemotherapy resistance, which can facilitate identification of novel therapeutic targets.  
 
As an initial test of the hypothesis that mitochondrial preconditions may be important 
determinants of chemotherapy response in ALL, BH3 profiling was performed on diagnostic 
samples taken from patients treated on Protocol 05-001.  While only two samples from patients 
who subsequently relapsed were tested, their BH3 profiling indicated that they were significantly 
less ‘primed’ to undergo apoptotic cell death than any of the seven tested low-MRD patients who 
had not relapsed. Additionally, BH3 profiling of diagnostic samples from 10 adult patients with 
ALL showed that those patients who subsequently relapsed (N=7) were significantly less 
‘primed’ to undergo apoptotic cell death than the patients who did not relapse (N=3).  These 

Protocol 11-001 
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21
preliminary data support a more complete testing of the hypothesis that BH3-profiling of 
diagnostic specimens may predict subsequent response to chemotherapy.  We will collect 
diagnostic specimens from patients enrolled on Protocol 11-001 to explore the association 
between BH3-profiling and subsequent treatment response, including peripheral blast response to 
the 3-day steroid prophase, end-induction marrow MRD level and occurrence of relapse.  For 
those patients who experience a relapse, another sample will be obtained at relapse to compare 
the BH3-profile at diagnosis and relapse.  The BH3-profile of pediatric specimens will also be 
compared to those taken from adults with ALL enrolled on DFCI ALL Consortium clinical trials 
for patients aged 18-50 years with newly diagnosed ALL.   
2.4.6 Identification of new therapeutic targets  
In order to facilitate the identification of new therapeutic targets for ALL, diagnostic specimens 
from patients who are subsequently found to have high risk features (including high end-
induction MRD or T-cell phenotype with ABGD) and/or subsequently relapse will be used to 
develop primary xenografts in immunodeficient mice.  Primary xenograft (primagraft) tumor 
models are established by direct inoculation of patient samples into immunodeficient mice.  The 
rationale for this approach has been to remove the intermediary propagation of cells under 
artificial ex vivo conditions, which may alter the biology of the lymphoblast.  Methods for 
engrafting primary ALL cells in immunodeficient mice (primagrafts) have been well established, 
and primagrafts have been successfully used for drug testing. We will plan on assessing novel 
therapies, including histone modification inhibitors and apoptosis-modulating therapies, in 
primagraft models derived from VHR and relapsed patients.  Primagraft models derived from the 
lymphoblasts of standard risk patients will be developed to assess whether new therapies are 
specific for a given VHR subset or have more generalized anti-ALL activity.  Additionally, 
whole genome sequencing in paired diagnostic/relapse specimens will be performed to screen for 
potential therapeutic targets. 
 
2.4.7 Spinal Fluid Research Samples 
We also plan to collect spinal fluid (CSF) specimens from patients who have consented to the 
use of leftover samples for research.  Leftover CSF samples will be collected at the time the 
following therapeutic lumbar punctures are performed: Day 18, end-induction (Day 32), the 
fourth lumbar puncture during the CNS phase and the first lumbar puncture performed during the 
Consolidation II phase.  These CSF samples will be collected to support studies seeking to define 
a biochemical profile predictive of increased risk for cognitive toxicity. Such a profile may help 
guide future therapeutic approaches to minimize neurocognitive late effects.  Factors will be 
measured in CSF: total folate, homocysteine, homocysteic acid, homocysteine sulfinic acid, S-
adenosyl-homocysteine, S-adenosyl-methionine, cysteine sulfinic acid, tau protein, and myelin 
basic protein.   
 
2.5 
Treatment Regimen: Background 
 
The therapeutic backbone of this trial will be based upon previous DFCI ALL Consortium 
protocols for patients aged 1-18 years, specifically Protocol 05-001, which opened for enrollment 
in 2005. Outcome results for Protocols 91-01 (1991-5), 95-01 (1996-2000) and 00-01 (2000-4) 
are presented in Table 2.4: 

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23
patients with T-cell phenotype (T-ALL or T-lymphoblastic lymphoma) will be centrally 
reviewed at Boston Children’s Hospital/ DFCI so that we may prospectively identify cases at the 
time of diagnosis in a uniform manner. 
 
Since 2005, patients on the very high risk arm have been treated with an intensified regimen that 
includes two additional Consolidation I cycles (with agents including cyclophosphamide, 
cytarabine and etoposide) and a Consolidation II phase that is identical to that administered to 
high-risk patients.  As of July 2011, 6 relapses and 1 case of secondary AML had been observed 
in 59 VHR patients for whom survival data was available.  There had been no remission deaths.  
While these results are extremely premature, they are promising enough that we will continue to 
treat VHR patients using this intensified regimen.   In this way, we will be able to expand the 
cohort of VHR patients treated in a nearly uniform way to better assess whether the treatment 
strategy had any beneficial impact in terms of relapse risk. 
 
Philadelphia-chromosome-positive (Ph+) patients: On Protocol 05-001, children with Ph+ ALL 
were treated with imatinib mesylate, a selective inhibitor of the BCR-ABL protein kinase, 
commencing on Day 18 of the induction phase.  All Ph+ patients with a suitable related or 
unrelated donor were taken to allogeneic stem cell transplant (SCT) within weeks of achieving 
complete remission (CR).   This treatment strategy was based upon data generated in an era prior 
to the availability of imatinib and other similar tyrosine kinase inhibitors (TKIs) which 
demonstrated that allogeneic SCT in first CR was associated with superior outcome compared 
with chemotherapy.   A study conducted by the Children's Oncology Group between 2002-2006 
(COG AALL0031) evaluated whether imatinib mesylate could be incorporated into an intensive 
chemotherapy regimen for children with Ph+ ALL.  Patients received imatinib mesylate in 
conjunction with chemotherapy during postinduction therapy. Some children proceeded to 
allogeneic stem cell transplant after two cycles of consolidation chemotherapy with imatinib 
mesylate, while other patients received imatinib mesylate in combination with chemotherapy 
throughout all treatment phases. The 3-year EFS for the 25 patients who received intensive 
chemotherapy with continuous dosing of imatinib was 87.7 + 10.9%, which was superior to 
historic controls treated with chemotherapy alone (without imatinib), and at least as favorable as 
the other patients on the AALL0031 trial who underwent allogeneic transplantation.(57)  The 
follow-up COG study (AALL0622) is evaluating another TKI, dasatinib, given in conjunction 
with the same intensive chemotherapy backbone as the AALL0031 study.  In order to allow 
possible enrollment on this COG study, all Ph+ patients will be removed from Protocol 11-001 
by Day 15 of induction treatment.   
2.5.2 Phases of Treatment 
2.5.2.1 Steroid Prophase   
As on Protocol 05-001, therapy for all patients will commence with 3 days of 
methylprednisolone monotherapy.  We had previously demonstrated on Protocol 91-01 (1991-5) 
that there was variability amongst patients in peripheral blood response to a 3-day prednisone 
prophase, with 57% of patients experiencing >85% decrease in absolute peripheral blast counts 
and the remaining patients a more modest decrease.(58) On Protocol 05-001, patients were 
treated with a 3-day prophase with the goal of correlating gene expression profiles with 
peripheral blood response to steroid, as assessing gene expression changes in leukemic blasts 
induced by corticosteroids.   The 3-day prophase on this trial will allow us to continue these 

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research studies, as well as explore the correlation of BH3-profile at diagnosis with peripheral 
blood response to corticosteroids.  
2.5.2.2 Induction Therapy  
Beginning on Day 4 (after completing the steroid prophase), all patients will receive multi-agent 
remission induction with vincristine, prednisone, doxorubicin, methotrexate and a single dose of 
PEG-asparaginase.  This regimen is identical to that used in our previous Protocol 05-001, with 
the exception of the asparaginase preparation.  As noted above, patients will be randomized to 
receive either Calaspargase PEG (SC-PEG) or Oncaspar on Day 7 of induction.  Because of 
concerns regarding adrenal suppression after 1 month of steroids, we will institute a short steroid 
taper at the end of the induction phase, in accord with the long-standing practice of the BFM and 
other Childhood ALL clinical trial groups.    
  
2.5.2.3 Consolidation I   
As on Protocol 05-001, this phase will commence at the end of the remission induction phase, 
after documentation of complete remission.  For standard risk and high risk patients, this phase 
will involve one 3-week cycle consisting of one dose of high-dose methotrexate (5 gram/m2 over 
24 hours), vincristine (1 dose) and 6-mercaptopurine (14 days); high risk patients will also 
receive doxorubicin (with dexrazoxane) during this cycle. Early consolidation with high-dose 
methotrexate is a feature of many regimens for childhood ALL, and the results of randomized 
trials suggests that its addition may reduce both systemic and CNS relapses.(59),(60),(61)  
 
Very high-risk patients will continue to receive an intensified Consolidation I phase, as they did 
on Protocol 05-001.  After the first 3 weeks of Consolidation I, very high risk patients will 
receive 2 additional 3-week cycles consisting of  i) cyclophosphamide, low-dose cytarabine and 
6MP (Consolidation IB), and ii) high-dose cytarabine, etoposide, dexamethasone and 
asparaginase (Consolidation IC).   
2.5.2.4 CNS Treatment  
A major focus of our studies has been to improve the therapeutic index in the treatment of the 
CNS.  Because of concerns regarding neurocognitive sequelae in younger patients, as well as the 
risk of radiation induced second malignancies, we have attempted, in successive protocols, to 
reduce exposure to radiation by lowering the dose (to 1200 cGy) or substituting it with intensive 
intrathecal chemotherapy.   
 
Since 2000, all standard-risk patients have been treated without cranial radiation, instead 
receiving more frequent administration of intrathecal therapy during the first year of treatment, 
and will continue to be treated in this way on Protocol 11-001.  On Protocol 05-001, we 
substituted intensive intrathecal chemotherapy for cranial radiation for a subset of high risk 
patients: B-precursor patients with presenting leukocyte counts less than 100,000/mm3, and no 
CNS leukemia (that is, not CNS-3 and absence of cranial nerve palsy) at diagnosis.  All other 
high risk patients and all very high risk patients received 1200 cGy cranial radiation (1800 cGy 
for CNS-3 patients).  Thus, 71% of patients on Protocol 05-001 were treated without cranial 
radiation, compared with 24% on Protocol 91-01 (1991-5), 45% on Protocol 95-01 (1996-2000) 
and 57% on Protocol 00-01 (2000-2004).       
 

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On two recent studies, one conducted by the St. Jude Children’s Research Hospital (SJCRH) and 
the other by the Dutch Childhood Oncology Group (DCOG), all patients were treated without 
cranial radiation (although, on the SJCRH trial, 7% of patients received an allogeneic stem cell 
transplant in first remission for very high-risk features, including high MRD).  Each of these 
studies included four doses of high-dose methotrexate administered every 2 weeks during post-
induction consolidation, as well as an increased frequency of IT chemotherapy and frequent 
vincristine/dexamethasone pulses during the first 1 to 2 years of therapy. The overall EFS for 
these studies was 85.6% (SJCRH) and 81% (DCOG) and the 5-year cumulative incidence of 
isolated CNS relapse on each trial was between 2% and 3%.(62, 63) However, some patient 
subsets had significantly higher rates of CNS relapse. On the SJCRH study, clinical features 
associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the 
t(1;19) translocation, and the presence of blasts in the CSF at diagnosis.(62)    
 
Other groups have also reported excessive relapses when cranial radiation has been eliminated 
from patients with T-ALL.  Conter and colleagues reported the outcome of two groups of T-ALL 
patients (all steroid good responders) contemporaneously treated with nearly identical BFM-
based systemic chemotherapy, but one group (in Italy) received triple intrathecal chemotherapy 
as CNS preventative therapy and the other (in Germany) received 12 Gy cranial radiation.  The 
non-irradiated patients had a lower 3-year EFS (67% compared with 88% for irradiated patients), 
with a higher proportion of patients experiencing relapses involving the CNS (7.3% compared 
with 1.4%).(64) 
 
The data supporting the administration of cranial radiation in B-precursor patients with high 
presenting leukocyte counts is based primarily on the results of  POG Protocol 9906 for high risk 
B-precursor ALL.  On that study, all non-CNS-3 patients were treated without cranial radiation.  
The 2-year cumulative incidence of CNS relapse was 12%.  Univariate analysis revealed that 
presenting leukocyte count was the best predictor of subsequent CNS relapse: the 2-year 
cumulative incidence of CNS relapse was 24% for patients with presenting leukocyte counts > 
100,000/mm3 compared with 5% for those with presenting leukocyte counts < 100,000/mm3 
(p<0.01).  However, on a study conducted by the Israel National Study Group (INS) on which 
only 14% of patients received cranial radiation, relapses involving the CNS occurred in only 6 of 
189 non-irradiated patients (5-year isolated and combined CNS recurrence rates of 1.7% and 
3.1%, respectively).  There was only one CNS relapse observed in a non-irradiated, non-infant 
B-precursor patient with a presenting leukocyte count less than 100,000/mm3.(65)  On the BFM-
95 protocol, 12 Gy cranial radiation was administered to all T-ALL patients, and B-precursor 
patients with either CNS-3 involvement at diagnosis or very high-risk features; high presenting 
leukocyte count was not an indication for cranial radiation in B-precursor patients.  On that 
study, the 6-year cumulative incidence of isolated and combined CNS relapses were 1.8% and 
2.2%, respectively.(66)  
 
Based on these data, we will continue to administer cranial radiation to patients with any of the 
following features: T-cell phenotype, CNS-3 (or failure to clear CNS-2 status by Day 18 of the 
induction phase), or very high risk risk group classification.  Because it is unclear that B-
precursor patients with presenting leukocyte counts greater than 100,000/mm3 benefit from 
cranial radiation, these patients will be treated without cranial radiation on Protocol 11-001.  
Based on the presenting characteristics of patients enrolled on prior protocols, it is expected that 

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26
approximately 20% of all patients enrolled on Protocol 11-001 will receive cranial radiation 
compared with 30% on Protocol 05-001. 
2.5.2.5 Consolidation II Therapy  
Since 1981, post-remission consolidation for all patients has included 20-30 consecutive weeks 
asparaginase, as well as every three-week cycles of vincristine, 6-MP and corticosteroid.  
Standard risk patients also have received weekly low-dose methotrexate during this treatment 
phase, while high risk patients received doxorubicin every three weeks.   On Protocol 00-01, we 
randomized patients to receive either dexamethasone or prednisone during this phase of 
treatment, and demonstrated that dexamethasone was associated with significantly better 
EFS.(17)  Dexamethasone will continue to be the steroid used during the Consolidation II and 
Continuation phases of treatment, as it was on Protocol 05-001. 
 
On Protocol 11-001, patients will be randomized to receive either IV Calaspargase Pegol (SC-
PEG asparaginase) 2500 IU/m2 every 3 weeks (10 total post-induction doses) or IV Oncaspar 
2500 IU/m2 every 2 weeks (15 total post-induction doses).  Other changes in the Consolidation 
II phase of treatment on Protocol 11-001 (compared with Protocol 05-001) include the following: 
 
 For HR and VHR patients, there are a specified number of cycles (10) which should 
include high-dose dexamethasone.   This is to ensure a more uniform exposure to high-
dose dexamethasone for all HR/VHR patients, regardless of other treatment delays or 
side effects.  In the past, some patients received high-dose dexamethasone for many more 
than 10 cycles when asparaginase administration exceeded 30 weeks due to 
hypertriglyceridemia or thrombotic complications. 
 
 For SR patients (and HR/VHR patients after completion of doxorubicin), methotrexate 
will be administered on the same day as asparaginase, rather than 1 day after 
asparaginase.  
 
2.5.2.6 Continuation Therapy 
The continuation phase on Protocol 11-001 will be identical to that on Protocol 05-001.  Therapy 
will be discontinued after 24 months of complete continuous remission. 
 
 

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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria to be eligible to participate in the study: 
 
3.1.1 Confirmed diagnosis of acute lymphoblastic leukemia or lymphoblastic 
lymphoma 
 
3.1.1.1 For acute lymphoblastic leukemia: diagnosis should be 
made by bone marrow aspirate or biopsy demonstrating > 
30% involvement by lymphoblasts, with flow cytometry or 
immunohistochemistry confirming B-precursor or T-ALL 
phenotype.  While myeloid co-expression on blasts 
determined to be primarily lymphoid is allowed, patients with 
leukemia of ambiguous lineage are not eligible.   
  
3.1.1.1.1 
For patients with circulating blasts in the peripheral blood, 
flow cytometry confirmation of B-precursor or T-ALL phenotype is 
sufficient for registration onto the study.  Bone marrow aspirate 
and/or biopsy should be performed as soon as feasible, preferably 
prior to the initiation of any therapy. 
 
3.1.1.1.2 
Note: patients with mature B-cell (Burkitt’s) ALL are 
excluded from study.  Mature B-cell is defined by the presence of 
surface immunoglobulin and/or the t(8;14)(q24;q32), t(8;22), or 
t(2;8) translocation and/or c-myc-gene rearrangement by FISH or 
PCR. 
3.1.1.2  For lymphoblastic lymphoma: diagnosis may be made by 
i) biopsy of involved site (eg, node, mediastinal mass), or ii) 
by cytology from pleural fluid or other fluid collection or iii) 
by marrow aspirate/biopsy demonstrating < 30% 
involvement by lymphoblasts (confirmed by flow cytometry, 
immunohistochemistry, cytogenetics and/or FISH studies) in 
a patient with evidence of lymphomatous masses by 
radiographic studies.  Note: marrow aspirate and/or biopsy 
must be performed in patients with lymphoblastic lymphoma 
prior to study entry to confirm that patient does not meet 
definition of ALL.  In rare circumstances, lymphoblastic 
lymphoma patients may be registered prior to marrow 
aspirate/biospy if it is felt that the procedure cannot be safely 
performed; permission in advance by principal investigator or 
designee is required. 
   
3.1.2 Prior Therapy: No prior therapy is allowed except for the following: 

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28
 Corticosteroids: Short courses of corticosteroid (defined as   < 7 days of 
corticosteroids within the 4-weeks preceding registration) are allowed prior to 
registration.  Note: If patient has received pre-treatment with corticosteroids, 
they should not receive steroid prophase, but should be treated as specified in 
Section 6.7.   
 Participants who have been on corticosteroids chronically 
(defined as more than 7 days of corticosteroids within the 4-
weeks preceding registration or more than 28 days of 
corticosteroids over the preceding 6 months) are not eligible.   
 IT Cytarabine:  A single dose of intrathecal cytarabine (at the time of the 
diagnostic lumbar puncture) is allowed prior to registration. If patient has 
received IT cytarabine prior to registration, Day 1 IT cytarabine (Section 6.1) 
should not be administered. 
 Emergent Radiation Therapy: Emergent radiation to the mediastinum or other 
life-threatening masses is allowed prior to registration. 
 
3.1.3  Age: 365 days to < 22 years.    
3.1.4 Laboratory Criteria: Participants must have direct bilirubin < 1.4 mg/dL (23.9 
micromoles/L)  Note: A total bilirubin of <1.4 mg/dL (23.9 micromoles/L) is 
acceptable to meet this requirement 
 
 
 
3.1.5 Ability of parent or guardian to understand and the willingness to sign a written 
informed consent document. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for the study. 
 
3.2.1 Participants who have received more than 7 days of corticosteroids in the preceding 
4 weeks or more than 28 days of corticosteroids in the preceding 6 months are not 
eligible.  
  
3.2.2 Participants who have received any chemotherapy or radiotherapy for previous 
malignancy are not eligible.  Participants who have ever previously received any 
anti-neoplastic agent, including methotrexate, 6-mercaptopurine, 6-thioguanine, 
vincristine cyclophosphamide, cytarabine (except for IT cytarabine), or any 
anthracycline, for any reason (eg, rheumatologic or autoimmune condition) are not 
eligible. 
 
3.2.3 Participants may not be receiving any other investigational agents. 
3.2.4 Participants known to be HIV-positive are excluded (Note: HIV testing is not 
required prior to enrollment).  HIV-positive individuals on combination 
antiretroviral therapy are ineligible because of the potential for 

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29
pharmacokinetic interactions with Calaspargase Pegol (SC-PEG asparaginase). In 
addition, these individuals are at increased risk of lethal infections when 
treated with myelosuppressive therapy. Appropriate studies will be undertaken 
in participants receiving combination antiretroviral therapy when indicated. 
 
3.2.5 Uncontrolled intercurrent illness including, but not limited to ongoing infection 
with vital sign instability (hypotension, respiratory insufficiency), life-threatening 
acute tumor lysis syndrome (eg, with renal failure), symptomatic congestive 
heart failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.2.6 Pregnant women are excluded from this study because many of the agents used on 
this protocol have potential for teratogenic and/or abortifacient effects. Because 
there is an unknown but potential risk of adverse events in nursing infants 
secondary to treatment of the mother with these chemotherapy agents, breastfeeding 
should be discontinued if the mother is enrolled.  
3.2.7 Individuals with a history of a previous malignancy are ineligible because cases of 
secondary leukemia/lymphoma arising after a previous malignancy are biologically 
distinctive and may require different therapies.  Also, exposure to previous anti-
neoplastic treatment may alter the ability to tolerate or respond to the agents utilized 
in this protocol.  Exception: Individuals with a previous malignancy treated with 
surgery only (no chemotherapy or radiotherapy) more than 5 years prior to 
registration may be enrolled. 
  
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
Individuals of both genders and all racial and ethnic backgrounds are eligible for 
this study. 
 

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2. 
Complete the protocol-specific eligibility checklist. To be eligible for 
registration to the study, the participant must meet each inclusion and 
exclusion criteria listed on the eligibility checklist. 
  
3. 
Fax or email the eligibility checklist(s) and all pages of the consent form(s) to 
the 
DFCI 
Study 
Team 
at 
Email 
 
 
  
4. 
The DFCI Study Team will (a) review the eligibility checklist and consent and 
(b) register the participant on the study with ODQ. 
  
5. 
The ODQ Registrar will send an email or fax confirmation of the registration 
and randomized treatment assignment to the DFCI Study Team immediately 
following the registration.   
 
6. 
The DFCI Study Team will email the registration confirmation and 
randomized treatment assignment to the outsite site.  
 
 
7. 
Treatment on study should only begin after confirmation of registration is 
received.   
 
The registration procedures outside of business hours, on weekends, and holidays are as 
follows: 
 
1. Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments. 
 
2. Complete the protocol-specific eligibility checklist. To be eligible for 
registration to the study, the participant must meet each inclusion and 
exclusion criteria listed on the eligibility checklist. 
 
3. Call the ODQ registration line at 
 and follow the instructions for 
registering participants after hours.  Leave detailed contact information for the 
ODQ registrar responsible for registering your participant.   
 
4. The ODQ Registrar will (a) validate eligibility and (b) register the participant 
on the study. 
 
5. ODQ will confirm registration by telephone, and email/fax confirmation will be 
sent on the next business day.  Randomized treatment will be assigned and 
communicated on the next business day. 
 
6. Treatment on study should only begin after confirmation of registration is 
received.  On nights, weekends, and holidays, treatment may begin after 

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telephone confirmation (prior to communication of randomized treatment 
assignment).   
 
7. Fax or email the eligibility checklist(s) and all pages of the consent form(s) to 
the 
DFCI 
Study 
Team 
at 
Email 
 
 
 
If you have any questions, the ODQ can be reached at telephone 
 
 
The following source documents need to be forwarded to the Coordinating Center (Dana-
Farber/Children’s Hospital Cancer Center) as soon as they are available.  Final risk group 
classification will only be made once these documents are received by the Coordinating 
Center.   
 Copy of pathology reports confirming diagnosis of leukemia (bone marrow 
aspirate or biopsy indicating > 30% marrow involvement) or lymphoblastic 
lymphoma 
 Copy of marrow pathology (for leukemia) and scan (for lymphoblastic 
lymphoma) reports confirming complete remission at end of remission 
induction phase. 
 Copy of diagnostic flow cytometry reports (leukemia patients only) 
 Copy of results of diagnostic cytogenetics, FISH and PCR (if 
performed)(leukemia patients only) 
 CBC with differential from diagnosis and from end of induction 
 
After receipt of source documents and review of MRD results (if applicable), Lead 
Institution will call or email the participating site to verify final risk group assignment. 
  
 
5. RISK GROUP CLASSIFICATION 
 
5.1 
Risk Group Definitions 
5.1.1 Standard Risk: All of the criteria must be met: 
 
 
 Age:  365 days to < 10 years. 
 
 
 
• WBC count: Highest pre-treatment WBC <50,000/mm3 (prior to registration). 
  CNS leukemia: No evidence of CNS leukemia by morphology, defined by meeting 
all of the following   criteria: 
1. Diagnostic lumbar puncture (Day 1) without any CSF blast cells on cytospin 
(CNS-1) or fewer than 5 WBC/hpf in CSF with blast cells noted on cytospin 
(CNS-2).  If traumatic tap (>10 RBC's on CSF cell count) with > 5 WBC 
cells are seen, use Steinherz/Bleyer algorithm (see 5.1.6) to determine if 
patients should be considered CNS-2 or CNS-3 for purposes of risk group 
assignment. 
2. CNS-1 CSF on Days 18 and 32.  SR patients with CNS-2 CSF on Days 18 
or 32 will be re-classified and re-consented as high risk (Section 5.1.2).   
SR patients with CNS-3 CSF (> 5 WBC/hpf with blast cells) on Day 18 
will be re-classified and re-consented as high risk and on Day 32 will be 

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considered Induction Failure (Section 6.8.4).  If traumatic tap (>10 RBC's 
on CSF cell count) with > 5 WBC cells are seen, use Steinherz/Bleyer 
algorithm (see 5.1.6) to determine if patients should be considered CNS-2 
or CNS-3 for purposes of risk group assignment. 
3. Absence of a cranial nerve palsy at diagnosis. 
 
Immunophenotype: Predominance of B-precursor cell surface antigens on 
lymphoblasts. 
 
Chromosomal abnormalities: Absence of t(9;22), MLL gene translocations and 
hypodiploidy < 44 chromosomes as determined  by karyotype, PCR or FISH 
analysis.  If chromosomal data unavailable, may continue to be treated as SR if 
all other risk group criteria are met. 
 
MRD (leukemia patients only): MRD level < 0.001 on a marrow sample 
obtained at end of remission induction therapy (Day 32).  SR patients with 
MRD levels > 0.001 at the end of remission induction therapy (Day 32) will be 
re-classified and re-consented as very high risk, and very high risk treatment 
will commence with Consolidation IB.  SR patients whose end-of-induction 
MRD status cannot be determined will remain SR.  
 
 
 
 
 
5.1.2 High Risk: Any one of the following criteria (except patients who meet any 
VHR criteria) 
 Age: 10 to < 22 years 
 WBC count: Highest pre-treatment WBC >50,000/mm3 (prior to registration). 
 
CNS leukemia: Evidence of CNS leukemia by morphology, defined by meeting 
any of the following criteria: 
1. Diagnostic lumbar puncture (Day 1) with 5 or greater WBC/hpf and blast 
cells on cytospin (CNS-3). If traumatic tap (>10 RBC's on CSF cell count) 
with > 5 WBC cells are seen, use Steinherz/Bleyer algorithm (see 5.1.6) to 
determine if patients should be considered CNS-2 or CNS-3 for purposes of 
risk group assignment.  
2. CNS-2 on Day 18 or 32.  Patients with CNS-2 CSF (fewer than 5 WBC per 
hpf in CSF, with blasts cells on cytospin) on Day 18 or 32 will be re-consented 
as high risk if otherwise considered standard risk.  
3. CNS-3 on Day 18. Patients with CNS-3 CSF (> 5 WBC/hpf with blast cells) 
on Day 18 will be re-consented as high risk if previously considered standard 
risk. If traumatic tap (>10 RBC's on CSF cell count) with > 5 WBC cells are 
seen, use Steinherz/Bleyer algorithm (see 5.1.6) to determine if patients 
should be considered CNS-2 or CNS-3 for purposes of risk group assignment. 
4. Presence of a cranial nerve palsy at diagnosis.  
 
Immunophenotype: Predominance of T-cell markers on lymphoblasts. Note: T-
ALL and T-lymphoblastic lymphoma patients with immunophenotype consistent 
with early T-cell precursor (ETP) as determined by DFCI/CH central review will 
be considered VHR. 
 
MRD (leukemia patients only): B-precursor HR patients with MRD level < 
0.001 on a marrow sample obtained at end of remission induction therapy (Day 
32) will continue to be treated as HR.  B-precursor HR patients with MRD 

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levels > 0.001 at the end of remission induction therapy (Day 32) will be re-
classified and re-consented as very high risk, and very high risk treatment will 
commence with Consolidation IB.  HR patients whose end-of-induction MRD 
status cannot be determined will remain HR.  MRD will not be used to change 
risk group of T-lineage patients. 
 
5.1.3 Very High Risk: Any of the following criteria 
 
Chromosomal abnormalities:  
 Presence of MLL gene translocations [such as t(4;11)] by karotype or FISH 
or molecular analyses. 
 Presence of hypodiploidy < 44 chromosomes by karyotype or FISH analysis.  
 
 ETP phenotype: For T-ALL/lymphoblastic lymphoma patients, presence of 
early T-cell precursor phenotype (ETP) as determined by DFCI/CH central 
review  
 
MRD status (leukemia patients only): B-precursor patients previously 
considered either standard or high risk with MRD >0.001 at end of remission 
induction therapy (Day 32).   
 
Patients who meet very high risk criteria will be re-consented as Very High Risk 
(VHR) if previously considered standard risk or high risk, and will commence 
with VHR treatment at the start of Consolidation IB. 
 
5.1.4 Special Situation: t(9;22) 
Patients found to have t(9;22) by cytogenetics, FISH and/or PCR will be removed 
from study by Day 15.  These patients will be eligible to enroll on the open COG 
Protocol for Philadelphia chromosome-positive ALL. 
5.1.5 Lymphoblastic Lymphoma: Lymphoblastic Lymphoma patients should be treated 
as Standard Risk, High Risk or Very High Risk based on age, immunophenotype, 
CNS status and cytogenetics, as specified above.  MRD will not be used in 
lymphoblastic lymphoma for risk-group classification. 
5.1.6 Steinherz/Bleyer Algorithm to Interpret Traumatic LP’s (>10 RBC per high 
power field) with > 5 WBC/hpf: 
 
CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf should be treated as CNS-3 
if: (CSF WBC/CSF RBC) > 2x (Blood WBC/Blood RBC).   
 
All other CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf in CSF specimen 
should be treated as CNS2. 
 
 
 
5.2 
Determination of Final Risk Group Status for patients with ALL 
 
Patients should begin treatment as per appropriate risk group based on available 
data at the time of diagnosis (eg, age, presenting leukocyte count, 
immunophenotype, CNS status) 

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 
Final risk group classification may differ from initial risk group based on results 
obtained during and immediately after remission induction therapy, based on: 
a) Presence of CNS blasts at Day 18 or 32  
b) Presence of MLL gene translocation or hypodiploidy (< 44 
chromosomes) determined by karyotype, FISH or other molecular 
studies: all patients re-classified as VHR regardless of initial risk 
group classification.  It is expected that re-classified patients will be 
able to begin VHR treatment at the end of remission induction 
treatment (beginning of Consolidation I) 
c) Presence of early T-cell precursor phenotype (ETP) in T-ALL patients as 
determined by DFCI/CH central review.  It is expected that re-
classified ETP patients will be able to begin VHR treatment at the end 
of remission induction treatment (beginning of Consolidation I).   
Note: See Section 5.1.3 for reclassification of lymphoblastic 
lymphoma patients. 
d) MRD level at end of remission induction therapy.   
i) SR patients: If MRD > 0.001, will be re-classified as VHR, and 
begin VHR treatment at the start of the second cycle of 
Consolidation I therapy (Consolidation IB). 
ii) HR B-lineage patients: If MRD > 0.001, will be re-classified as 
VHR and begin VHR treatment at the start of the second cycle of 
Consolidation I therapy (Consolidation IB). 
iii) MRD will not be used to change risk group classification of T-cell 
patients 
If end-of-induction MRD status cannot be determined, then patient 
will continue to be treated per initial risk group classification 
 Note: Final risk group status will be determined no later than 3 weeks from 
the date that morphologic complete remission is documented.  If MRD 
results are not available when participant has recovered from the 
Consolidation I phase and meets criteria to begin the next treatment phase, 
then the final risk group status will be assigned at that time based on 
available data (presenting characteristics, CNS status during remission 
induction, cytogenetics, etc).  Treatment should not be delayed while 
awaiting MRD results.   
 Note: Patients with high Day 32 MRD (>0.001) must sign a new consent 
form for the VHR treatment arm prior to initiating their next phase of 
therapy.  The newly signed VHR consent forms should be faxed to Study 
Coordinator at fax: (617) 632-3977 and to the ODQ fax: (617) 632-2295.   
 Note: Patients with hypodiploidy (<44 chromosomes), MLL gene 
rearrangements, ETP or high Day 32 MRD (>0.001) who decline 
reassignment to VHR treatment arm will be removed from the study. 
 

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Table 5.2: Determination of Final Risk Group based on MRD, Cytogenetics and CNS 
Status 
INTIAL GROUP CLASSIFICATION 
(Determined at diagnosis) 
FINAL GROUP CLASSIFICATION 
(Determined after cytogenetics and Day 32 MRD result 
known) 
 
Standard Risk  
 
Very High Risk:  
If MLL rearranged or hypodiploidy and/or MRD > 
0.001 at Day 32. 
High Risk: 
If: CNS-2 or CNS-3 CSF on Day 18 or CNS-2 on 
Day 32 
 Off Study:  Removed from protocol on Day 15 if 
found to have t(9;22) 
Standard Risk: 
If: None of the above 
 
High Risk 
Very High Risk: 
If MLL rearranged or hypodiploidy or ETP and/or 
B-lineage with MRD > 0.001 
Off Study:  Removed from protocol on Day 15 if 
found to have t(9;22) 
High Risk: 
If: None of the above. 
 
 
 
 

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6. TREATMENT PLAN  
 
Participants should begin treatment as soon as feasible after registration.  Active issues related to 
fever, anemia, thrombocytopenia, coagulopathy, and acute tumor lysis syndrome should be 
addressed prior to the initiation of leukemia-directed therapy whenever possible.  See Section 6.16 
for Supportive Care Guidelines. 
 
Participants will receive the following phases of treatment:  
 Steroid Prophase (3 days) 
 Remission Induction (29days) 
 Consolidation I (3 weeks for SR/HR patients, 9 weeks for VHR patients) 
 CNS Phase (3 weeks) 
 Consolidation II (27 weeks) 
 Continuation (until 24 months in complete continuous remission). 
 
Drugs and dosages to be administered in each phase are detailed below.  Allowable deviations to the 
schedule are outlined in Section 7.2.1.    Dose modifications for toxicity are detailed in Sections 
7.2.2 through 7.2.8.   Laboratory studies and therapy that are allowed at satellite sites/affiliate 
hospitals and in the home are detailed in Section 15. 
 
Additionally, all outpatient chemotherapy for each cycle must be prescribed by a physician, 
nurse practitioner or physician assistant, as per institutional standard, on the day that the patient 
is evaluated and found to meet criteria for that cycle. This means that only one cycle of 
outpatient chemotherapy may be prescribed at each visit, and refills for chemotherapy 
prescriptions are not allowed for study patients. Exception can be made for patients receiving 
Purixan® (6-MP oral suspension) who must be dispensed full bottles per medical insurance 
restrictions; in these cases, medical staff should review dosing with patient/family at the start of 
each cycle. Under no circumstances may other clinical staff call in prescriptions for 
chemotherapy for patients on study.  
 
 
 

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6.1 
STEROID PROPHASE (All patients) 
 
6.1.1 Starting Time: After confirmation of diagnosis, informed consent signed and 
patient registered 
6.1.2 Starting Criteria: All patients who are eligible and enrolled on study should begin 
treatment with this phase, with the following exception: patients who have already 
received steroid pre-treatment prior to beginning protocol therapy (See Section 
3.1.2 for allowable steroid pre-treatment).  Such patients should undergo lumbar 
puncture with intrathecal cytarabine, as in Section 6.1.4, and then proceed directly 
to Remission Induction Phase (Section 6.4 for Standard Risk and Section 6.5 for 
High Risk and Very High Risk). 
 
6.1.3 Steroid Prophase Therapy 
 
 
 
 
 
 
Day 1 
2 
3 
 
P 
P 
P 
ITAra  
 
 
       
 
 
 
*Perform Therapeutic Lumbar Puncture on Day 1. Send CSF for cell count with 
differential and/or cytology. 
 
*Complete blood count with differential must be performed at diagnosis and after 
completion of 3 full days of methylprednisolone (Day 4).  *Absolute blast count must 
be calculated at diagnosis and at Day 4 (Absolute blast count = peripheral blood 
WBC x % blasts) 
 
*All leukemia patients should have bone marrow and peripheral blood sample sent 
to develop MRD probe prior to starting systemic therapy (steroid prophase).  See 
Section 9.0:  CORRELATIVE/SPECIAL STUDIES.   
 
*Note: Antibiotic Prophylaxis should begin during the Prophase in all afebrile 
patients and continue until count recovery after expected hematologic nadir (ANC 
> 200 or APC > 500/mm3).  See Section 6.3. 

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6.1.4 Steroid Prophase Dosages, Schedules & Routes 
P  
Methylprednisolone 32 mg/m2/day IV divided every 8 hours (or three times per 
day) on days1-3.  
 
 Note: Only IV Methyprednisolone should be administered during Prophase.   
Administration of oral prednisone (40 mg/m2/day divided into three daily doses) 
instead of intravenous methylprednisolone during prophase is not allowed, except if 
discussed in advance with Principal Investigator.  
ITAra  Intrathecal Cytarabine given on Day 1, dosed by age: 
Age  
1 – 1.99 yrs 
2 - 2.99yrs 
>3 yrs 
Cytarabine  
20 mg 
30 mg 
40 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according 
to institute policy for safe administration. 
 
6.2 
Additional Lumbar Punctures for Patients with CNS Leukemia  
 
6.2.1 CNS blasts on Initial Lumbar Puncture (LP): Patients with CNS leukemia (CNS-2, CNS-3 or 
traumatic LP with blasts; regardless of RBC count) on initial Lumbar puncture (day 1) will 
receive additional IT Cytarabine (beginning on Days 4-6) twice-weekly until the CSF is 
clear, and then two additional doses will be given.   
 
Dose of IT cytarabine according to age as indicated above (Section 6.1.4). 
 
Note: 2 additional doses of IT chemotherapy (with clear CSF—no blasts) should be 
administered after first clear Lumbar Puncture.  If patients are still receiving twice weekly 
lumbar punctures with IT therapy at Day18, IT chemotherapy should be changed from IT 
cytarabine to IT Methotrexate/Cytarabine/Hydrocortisone on Day 18 (as dosed in Section 
6.4) and IT Methotrexate/Cytrabine/Hydrocortisone should be used for all subsequent 
lumbar punctures with IT therapy after Day 18, if any are still necessary (except if 
mucositis present, in which case IT Methotrexate may be held).        
 
6.2.2 Cranial Nerve Palsy: Patients with cranial nerve palsy at diagnosis but with no leukemia 
blasts in the CSF will receive twice weekly IT cytarabine as above (Section 6.2.1) until Day 18. 
 

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Table 6.2: Change in Treatment and Risk Group based on CNS Status during Remission 
Induction 
 
Day of Induction 
 
Day 1 
Day 18 
Day 32 
CNS-1 
No change in risk 
group 
No change in risk 
group 
No change in risk 
group 
CNS-2 
No change in risk 
group 
SR changed to HR 
SR changed to HR 
CNS-3 
SR changed to HR 
SR changed to HR 
Induction Failure 
CNS-1: no blast cells in cytospin, regardless of CSF cell count 
CNS-2: Fewer than 5 WBC on CSF cell count, with blasts on cytospin 
CNS-3: 5 or more WBC on CSF cell count, with blasts on cytospin 
 Traumatic tap:  > 10 RBC on CSF cell count. See Section 5.1.6 for interpretation of traumatic 
LP with blasts. 
 
 Day 1, CNS-2 , CNS-3 or traumatic LP with blasts: treat with twice weekly IT cytarabine 
until 3 clear lumbar punctures in a row 
 Day 18, CNS-2, CNS-3 or traumatic LP with blasts: treat with twice weekly IT MAH 
until 3 clear lumbar punctures in a row 
 Day 32: CNS-2 (in patient with previous CNS-1 status): Treat as per Section 6.8.6.   
 Day 32: CNS-3 (regardless of previous CNS status): Induction Failure (see Section 6.8.4) 
 Patients with persistent CNS leukemia throughout remission induction (CNS-2, CNS-3 or 
traumatic LP with blasts) who still have CNS leukemia at Day 32 (blasts seen on 
cytospin, regardless of CSF WBC or RBC count) are considered Induction Failures (See 
Section 6.8.4) 
 Standard Risk patients whose CNS status is CNS-3 anytime on or after Day 18 and prior 
to Day 32 should be reclassified as High Risk (HR consent required). 

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6.3 
Antibiotic Prophylaxis during Remission Induction Phase 
 
Antibiotic prophylaxis with a fluoroquinolone antibiotic (either levofloxaxin 
or moxifloxacin) will be initiated during the Steroid Prophase and continue 
throughout the Remission Induction phase until count recovery after 
expected hematologic nadir (ANC > 200 or APC > 500/mm3).  Patients unable 
to tolerate fluoroquinolones due to allergy or other toxicity should receive 
intravenous cefepime as prophylaxis.  If a patient is unable to tolerate 
fluoroquinolone or cefepime, contact Principal Investigator.   
 
Patients receiving broad-spectrum antibiotics for fever (See Section 6.16.2) or 
documented infection may discontinue prophylactic antibiotics.  Broad spectrum 
antibiotics for febrile neutropenia should be continued until ANC > 500/mm3, or 
per institutional guidelines. 
 
Because of the high risk of infection, treatment should begin on an inpatient basis 
and hospitalization of participants is encouraged throughout the induction phase.  
Outpatient treatment during the induction phase may be considered after recovery 
of the absolute neutrophil count (ANC) after the expected hematologic nadir. 
 

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6.4 
REMISSION INDUCTION PHASE (STANDARD RISK PATIENTS) 
 
6.4.1 Remission Induction Phase for SR Patients 
 
Day 4  5  6   7…     11 …   
18*…     25…  
          32+ 
 
 
P     
   
       
 
  
      begin taper 
 
 
 
 
 
V  
 
 
 
 V  
 
V  
     V   
 
 
D D  
 
         m     
 
 
   
 
    ASP 
 
 
 
 
 
 
 
  
 
 IT MAH 
 
 
              ITM 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
*On Day 18, perform marrow aspirate (only in leukemia patients who have consented to 
optional Day 18 bone marrow procedure) and therapeutic lumbar puncture with intrathecal 
chemotherapy (all patients). Collect Day 18 blood only if patients consented to additional 
research peripheral blood samples.   
+ On Day 32, perform marrow aspirate/biopsy (if marrow involvement at diagnosis) and 
therapeutic lumbar puncture with intrathecal chemotherapy. It is suggested that the marrow 
sample be sent for cytogenetics/FISH (if abnormal at diagnosis). 
+For Leukemia Patients: Day 32 Marrow sample must be sent for MRD analysis to 
determine final risk group assignment.  See Section 9.0:  CORRELATIVE/SPECIAL 
STUDIES. 
 
See 6.8.3  if peripheral blood criteria for remission are not met by Day 32.  
 
*Note: Antibiotic Prophylaxis should begin during the Prophase and continue through the 
Induction phase in all afebrile patients until count recovery after expected hematologic 
nadir (ANC > 200 or APC > 500/mm3).  See Section 6.3. 
 See Section 7.2.3 for dose modifications.  See Section 7.2.1 for allowable deviations in 
timing of medications/procedures and for allowable variation in dosing. 
 
6.4.2 Starting Time: After completion of steroid prophase (Section 6.1) 
6.4.3 Starting Criteria:  
 Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L) If direct bilirubin > 1.4 mg/dL 
(23.9 micromoles/L), go to Section 6.6, “Special Circumstance 1: 
Hyperbilirubinemia” 
 
6.4.4 Dosages, Schedules & Routes 
 
P  
Prednisone  
Prednisone or Prednisolone 40 mg/m2/day orally divided into two or three 
doses per day or methylprednisolone (solumedrol) 32 mg/m2/day IV 
divided every 8 hours (or three times per day) on Days 4-32.   
 
Note: A steroid taper (consisting of either prednisone or methylprednisolone) should 
be administered after completion of Induction course of 

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prednisone/methylprednisolone.  Steroid taper should commence: 1) after 
completion of end-induction restaging procedures (marrow and/or scans) as long as 
the results of these studies are consistent with complete remission (including 
peripheral blood count recovery) and patient will be proceeding to Consolidation I 
phase, or 2) after last dose of steroid on Day 32, whichever comes first.  Full-dose 
prednisone (40 mg/m2/day, or its methylprednisolone equivalent) should not be 
administered after Day 32.  Duration of corticosteroid taper is up to discretion of 
treating physician but should not exceed 7 days (i.e., all corticosteroid should be 
completed by Day 39).   
 
 
V  
Vincristine  
1.5 mg/m2 (maximum dose 2 mg) IV push or IV via minibag every week x 4 
(on Days 4, 11, 18 and 25).   
 
 
D      Doxorubicin  
Doxorubicin 30 mg/m2 IV on Days 4 and 5.   
  Give as IV push via CVL or via freshly placed peripheral IV.  
 May give as IV bolus over 15 minutes if administered via a central line. 
 No Dexrazoxane 
 
m  Methotrexate 
Methotrexate 40 mg/m2 IV push on Day 6.  Give at least 8 hours but not 
more than 24 hours, after last Doxorubicin dose. 
Note: Do not give methotrexate if effusions or ascites are present, or if 
creatinine is beyond upper limits normal for age.  See Section 7.2.3.  
 
ASP 
Asparaginase according to randomization. Give on Day 7.  Mix in 100 mL Normal Saline 
and give IV over 1 hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV x 1 dose, or 
 
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV x 1 dose.   
 
 
**All patients should have the following samples obtained:  
  Asparaginase enzyme levels (PK samples): Obtain samples prior to Asparaginase 
dose on Day 7, 5-10 minutes after completion of Asparaginase infusion on Day 7, 
then every week x 4 on Days 11, 18, 25, and 32 (when vincristine is due to be 
administered)  or within +3 days of these days. (see Section 9.2)  
  Asparaginase antibody levels: Obtain samples at Day 7 (pre-asparaginase dose) and 
at Day 32 (see Section 9.2), at the same time that Asparaginase enzyme level 
sample is obtained. 
  

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IT MAH  Intrathecal Methotrexate/Cytarabine/Hydrocortisone 
 
  
Give on Day 18.  Dose according to age: 
 
Age  
1 – 1.99 yrs 
2 - 2.99yrs 
>3yrs  
Methotrexate 
8mg 
10mg 
12mg 
Cytarabine 
20mg 
30mg 
40mg 
Hydrocortisone 
9mg 
12mg 
15mg 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 
ITM  
Intrathecal Methotrexate on Day 32. If peripheral blood criteria for remission are met, 
perform bone marrow aspirate and lumbar puncture.  Administer intrathecal 
methotrexate medications according to age: 
 
Age  
1 - 1.99yrs 
2 - 2.99yrs  
> 3yrs 
Methotrexate  
8mg 
10mg 
12mg 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration. 

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6.5 
REMISSION INDUCTION PHASE (HIGH RISK AND VERY HIGH RISK 
PATIENTS) 
 
6.5.1 Remission Induction Phase for HR/VHR patients 
Day 4  
5  
6  7…  
 
 
11 …  
18*…  
 
25…  
32+ 
 
 
P    
   
  
  
  
 
  
 
 
 
 
begin taper 
 
      V  
 
 
 
  
 
 
 
 
 V  
 
 V    
 
V 
 
 
Dd  Dd  
 
 m      
 
 
 
   
 
 
 
ASP 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  IT MAH 
 
 
 
ITM 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
*On Day 18, perform marrow aspirate (only in leukemia patients who have consented to 
optional Day 18 bone marrow procedure) and therapeutic lumbar puncture with intrathecal 
chemotherapy (all patients). Collect Day 18 blood only if patients consented to additional 
research peripheral blood samples.  + On Day 32, perform marrow aspirate/biopsy (if 
marrow involvement at diagnosis) and therapeutic lumbar puncture with intrathecal 
chemotherapy. It is suggested that the marrow sample be sent for cytogenetics/FISH (if abnormal 
at diagnosis). 
+For Leukemia Patients: Day 32 Marrow sample must be sent for MRD analysis to 
determine final risk group assignment.  See Section 9.0:  CORRELATIVE/SPECIAL 
STUDIES. 
. 
See 6.8.3 if peripheral blood criteria for remission are not met by Day 32.  
 
*Note: Antibiotic Prophylaxis should begin during the Prophase and continue through the 
Induction phase in all afebrile patients until count recovery after expected hematologic 
nadir (ANC > 200 or APC > 500/mm3).   See Section 6.3. 
 
See Section 7.2.3 for dose modifications.  See Section 7.2.1 for allowable deviations in 
timing of medications/procedures and for allowable variation in dosing. 
 
6.5.2 Starting Time: After completion of steroid prophase (Section 6.1) 
6.5.3 Starting Criteria:  
 Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L).  If direct bilirubin > 1.4 mg/dL 
(23.9 micromoles/L), go to Section 6.6, “Special Circumstance 1: 
Hyperbilirubinemia” 
 
P  
Prednisone  
Prednisone or Prednisolone 40 mg/m2/day orally divided into two or three 
doses per day or methylprednisolone (solumedrol) 32 mg/m2/day IV divided 
every 8 hours (or three times per day) on Days 4-32.   
 
Note:   A steroid taper (consisting of either prednisone or methylprednisolone) 
should be administered after completion of Induction course of 
prednisone/methylprednisolone.  Steroid taper should commence: 1) after 

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completion of end-induction restaging procedures (marrow and/or scans) as long as 
the results of these studies are consistent with complete remission (including 
peripheral blood count recovery) and patient will be proceeding to Consolidation I 
phase, or 2) after last dose of steroid on Day 32, whichever comes first.  Full-dose 
prednisone (40 mg/m2/day, or its methylprednisolone equivalent) should not be 
administered after Day 32.  Duration of corticosteroid taper is up to discretion of 
treating physician but should not exceed 7 days (i.e., all corticosteroid should be 
completed by Day 39).   
 
 
V  
Vincristine  
1.5 mg/m2 (maximum dose 2 mg) IV push or IV via minibag every week x 4 
(on Days 4, 11, 18 and 25).   
 
D       Doxorubicin  
30 mg/m2 IV preceded by Dexrazoxane 300 mg/m2 IV on day 4 and day 5. 
Suggested administration for both drugs: 
 
 Minute 0      Dexrazoxane over 15 minutes 
 Minute 15         Doxorubicin IV push via central line or freshly 
placed peripheral IV.  May give doxorubicin IV over 15 minutes if 
given via central venous line. 
 Goal is no more than 30 minutes maximum elapsed administration 
time combined for both drugs 
 May give doxorubicin prior to dexrazoxane if given via peripheral 
IV. 
 
m  
Methotrexate 
Methotrexate 40 mg/m2 IV push on Day 6.  Give at least 8 hours but not 
more than 24 hours, after last Doxorubicin dose. 
Note: Do not give methotrexate if effusions or ascites are present, or if 
creatinine is beyond upper limits normal for age.  See Section 7.2.3.  
 
 
 
 
 
 
 
 
 
ASP 
Asparaginase according to randomization. Give on Day 7. Mix in 100 mL Normal Saline 
and give IV over 1 hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV x 1 dose, or 
 
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV x 1 dose.   
. 
**All patients should have the following samples obtained:  
  Asparaginase enzyme levels (PK samples): Obtain samples prior to Asparaginase 
dose on Day 7, 5-10 minutes after completion of Asparaginase infusion on Day 7, 
then every week x 4 Days 11, 18, 25 and 32 (when vincristine is due to be 
administered)  or within +3 days of these dates. (see Section 9.2) 
 Asparaginase antibody levels: Obtain samples at Day 7 (pre-asparaginase dose) and 
at Day 32 (see Section 9.2), at the same time that Asparaginase enzyme level 
sample is obtained. 
  

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IT MAH  Intrathecal Methotrexate/Cytarabine/Hydrocortisone 
 
  
Give on Day 18.  Dose according to age: 
 
Age  
1 – 1.99 yrs 
2 - 2.99yrs 
>3yrs  
Methotrexate 
8mg 
10mg 
12mg 
Cytarabine 
20mg 
30mg 
40mg 
Hydrocortisone 
9mg 
12mg 
15mg 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 
ITM  
Intrathecal Methotrexate on Day 32. If peripheral blood criteria for remission are met, 
perform bone marrow aspirate and lumbar puncture.  Administer intrathecal 
methotrexate medications according to age: 
 
Age  
1 - 1.99yrs 
2 - 2.99yrs  
> 3yrs 
Methotrexate  
8mg 
10mg 
12mg 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration. 
 
 

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6.6 
Special circumstance: Induction Therapy for Patients with Hyperbilirubinemia on 
Day 4 
 
If direct bilirubin >1.4 mg/dl (23.9 micromoles/L), on Day 4, timing of chemotherapy is as follows: 
 
Prednisone  
Give Days 4 through 32 
Vincristine  
Give Days 4, 11 18 and 25 if direct bilirubin < 3.0 mg/dL (51.3 micromoles/L).  If 
direct bilirubin is > 3.0 mg/dL (51.3 micromoles/L), hold dose of 
vincristine. With a bilirubin at this level, it may be allowable under certain 
circumstances to administer vincristine at 50% dose but only with prior 
approval of Principal Investigator.  For dosing guidelines, see Section 6.4 
for SR and 6.5 for HR/VHR. 
Doxorubicin 
Hold until direct bilirubin <1.4 mg/dL (23.9 micromoles/L), then give (according to 
risk group status) on 2 consecutive days (dosing as per Section 6.4 SR and 
Section 6.5 HR/VHR).  HR/VHR should receive Dexrazoxane with 
doxorubicin as specified in Section 6.5.3.  If patient has not received 
doxorubicin because direct bilirubin is not < 1.4 mg/dL (23.9 micromoles/L), 
by Day 18 patient should be removed from study.   
Methotrexate 
Hold until direct bilirubin < 1.4 mg/dL, then give 8-24 hours after 2nd dose of 
doxorubicin.  
Asparaginase Hold until direct bilirubin is < 1.4 mg/dL (23.9 micromoles/L) ; Give 1 day after 
methotrexate dose is given at dose indicated in  Section 6.4 for SR and 
Section 6.5 for HR/VHR.   
IT MAH  
 
 Administer on Day 18 as indicated in Section 6.4 for SR and Section 6.5 for 
HR/VHR.  Hold intrathecal methotrexate if direct bilirubin still > 1.4 mg/dL 
(23.9 micromoles/L), at that time. 
 
Day 18 bone marrow aspirate should not be performed if any agents were delayed due to 
hyperbilirubinemia. 
 
Perform marrow aspirate/biopsy (if marrow involvement at diagnosis) and therapeutic 
lumbar puncture (with intrathecal chemotherapy) at end of remission induction therapy 
when peripheral blood counts recover, at least 3 weeks from doxorubicin.  It is suggested that 
the marrow sample be sent for cytogenetics/FISH (if abnormal at diagnosis).   
 
For ALL patients: Day 32 Marrow sample must be sent for MRD analysis to determine final 
risk group assignment.   
 
See Section 6.8.3 if peripheral blood criteria for remission are not met by Day 32. 
 
Note: If direct bilirubin remains persistently elevated above 1.4 mg/dL (23.9 micromoles/L)  
at Day 18, then participant should be removed from study. 

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6.7 
Special circumstance: Induction Therapy for Patients treated without Steroid 
Prophase 
 
Note: Direct bilirubin must be < 1.4 mg/dL (23.9 micromoles/L), if not, go to Section 6.6. 
First day of chemo = Day 4  
Doses of all agents the same as doses indicated in Section 6.4 for SR and Section 6.5 for 
HR/VHR.  Treat without Steroid Prophase. 
 
Prednisone  
 
 
Give Days 4 through 32. 
Vincristine  
 
 
Give Days 4, 11, 18 and 25 
Doxorubicin 
   Give on Days 4 and 5 according to risk group.  Dexrazoxane given to 
HR/VHR patients. 
Methotrexate 
   Give on Day 6. 
Asparaginase  
 
Give on Day 7, according to randomization.   
IT cytarabine               Administer on Day 4. 
IT methotrexate/cytarabine/hydrocortisone: Administer on Day 18 
IT methotrexate          Administer on Day 32, if peripheral blood criteria for remission all met. 
 
On Day 18, perform therapeutic lumbar puncture (with intrathecal chemotherapy).  
Leukemia patients who have consented to Day 18 marrow should have this procedure 
performed at the same time as therapeutic lumbar puncture. 
On Day 32, perform marrow aspirate/biopsy (if marrow involvement at diagnosis) and 
therapeutic lumbar puncture with intrathecal chemotherapy. It is suggested that the marrow 
sample be sent for cytogenetics/FISH (if abnormal at diagnosis). 
For Leukemia Patients: Day 32 Marrow sample must be sent for MRD analysis to determine 
final risk group assignment.   
 
See Section 6.8.3 if peripheral blood criteria for remission are not met by Day 32. 

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6.8 
COMPLETION OF REMISSION INDUCTION THERAPY  
 
6.8.1  Complete remission definition:   
Leukemia:  An interpretable bone marrow (a specimen with normal marrow elements present) with 
fewer than 1% malignant lymphoblasts by microscopic examination and peripheral blood without 
lymphoblasts, and an APC > 1000/mm3 and platelets > 100,000/mm3, and no evidence of 
extramedullary leukemia (no blasts in spinal fluid, at least 70% reduction in size of masses noted on 
imaging at diagnosis, as defined below for patients with lymphoblastic lymphoma).  Note: Patients 
are allowed to have > 1% normal myeloid or lymphoid blasts (hematogones) in their marrow 
consistent with recovery and still meet the definition of complete remission.   Normal recovery 
blasts may be distinguished from persistent malignant lymphoblasts by flow cytometry, 
immunohistochemistry or other studies.  Consult principal investigator with any questions. 
 
 
Lymphoblastic Lymphoma: At least a 70% reduction in size of largest nodes or masses noted at 
diagnosis.  Reduction may be measured as a decrease in a sum of the products of the two greatest 
diameters (SPD) of the largest dominant nodes or nodal masses. These nodes or masses should 
be selected according to the following features: 
a) they should be clearly measurable in at least two perpendicular dimensions, 
b) they should include mediastinal masses whenever this site was initially involved. 
In addition to this radiographic criterion, there should also be complete disappearance of all 
clinical evidence of disease by physical examination and no evidence of disease in spinal fluid or 
in bone marrow (if involved at initial diagnosis). Definition of marrow remission for 
lymphoblastic lymphoma patients with initial marrow involvement is the same as that used for 
patients with leukemia (above). 
 
When patient is documented to be in complete remission, proceed to Consolidation I (Section 6.9 
for Standard Risk, Section 6.10 for High Risk, and Section 6.11 for Very High Risk).   
 
6.8.2   Timing of Bone Marrow Examination and Therapeutic Lumbar Puncture 
Leukemia patients and Lymphoblastic Lymphoma patients with marrow involvement at 
diagnosis: Bone marrow aspirate/biopsy should be performed on (or as close as possible) to Day 
32 of remission induction, regardless of blood counts.  Sample for MRD analysis should be sent 
for all leukemia patients.  Therapeutic lumbar puncture (with intrathecal methotrexate) may be 
performed at the same time as this marrow aspirate/biopsy only if peripheral blood counts meet 
criteria for complete remission (APC > 1000/mm3 and platelets > 100,000/mm3) and there is no 
evidence of extramedullary leukemia.  If patient is in documented complete remission on Day 32, 
proceed to Consolidation I (Section 6.9 for Standard Risk, Section 6.10 for High Risk, and Section 
6.11 for Very High Risk).   Note: For patients with leukemia, it is essential that bone marrow 
sample for MRD analysis be sent at Day 32. 
Lymphoblastic Lymphoma patients without marrow involvement at diagnosis: Marrow 
aspirate/biopsy is not required at Day 32, but should be considered if there is delayed count 
recovery. Therapeutic lumbar puncture (with intrathecal methotrexate) should be performed at 
Day 32 (or as close as possible to this date) only if peripheral blood counts meet criteria for 

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complete remission (APC > 1000/mm3 and platelets > 100,000/mm3) and there is no evidence of 
extramedullary leukemia.    
 
6.8.3  Delayed Recovery:  
If complete remission is NOT achieved on Day 32 because either a) patient does not meet peripheral 
blood criteria, or b) marrow is too hypocellular to interpret (not enough marrow cells to perform 
adequate marrow differential), and <5% lymphoblasts are identified in the marrow (leukemia 
patients and lymphoblastic lymphoma patients with initial marrow involvement): 
 
6.8.3.1 
Patient does not meet peripheral blood criteria: 
1) For leukemia patients and lymphoblastic lymphoma patients with initial marrow 
involvement: perform bone marrow aspirate and biopsy on Day 32.  Day 32 
marrow aspirate from leukemia patients should be sent for MRD testing, 
regardless of peripheral blood counts.  Repeat marrow aspirate when peripheral 
blood counts meet criteria for remission, or by Day 53 if counts still not 
recovered.  Additional bone marrow aspirates/biopsies may be performed 
between Days 32-53 at discretion of treating physician.  For leukemia patients, 
send specimen from any bone marrow performed for MRD analysis, if possible. 
2) Do Not perform lumbar puncture.  Administer vincristine 1.5 mg/m2 
(maximum dose 2 mg) IV push or IV via minibag weekly until CR is 
achieved.  When peripheral blood criteria met, lumbar puncture with intrathecal 
methotrexate should be performed (may be performed at same time as bone 
marrow aspirate for leukemia patients and lymphoblastic lymphoma patients with 
initial marrow involvement). 
3) Patient will be removed from study if counts do not recover by Day 53 
 
6.8.3.2 
Hypocellular 
marrow 
(peripheral 
blood 
criteria 
met 
but 
marrow 
uninterpretable)--Leukemia patients and Lymphoblastic Lymphoma patients 
with initial marrow involvement only: 
1) Continue vincristine 1.5 mg/m2 (maximum dose 2 mg) IV push or IV via 
minibag weekly on Days 32, 39 and 46 or until CR achieved, whichever comes 
first. 
 
2) Repeat marrow aspirate and/or biopsy weekly until complete remission is 
documented. 
 
3) Complete remission must be documented by Day 53 for patients to remain on 
study. 
 
6.8.4  Induction Failure 
Leukemia: If >1% blasts (confirmed to be leukemic lymphoblasts by flow cytometry, 
immunohistochemistry or other studies) are identified in the marrow on Days 32, or on any 
marrow performed up through Day 53 (without a preceding marrow consistent with complete 

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remission), the patient will be classified as an Induction Failure and removed from protocol (contact 
Principal Investigator or designee prior to removing from protocol if patient is induction failure).  
Any patient with evidence of extramedullary leukemia on exam, in the spinal fluid or by 
radiographic imaging (<70% reduction in size of largest nodes or masses noted at diagnosis, or any 
new biopsy-proven masses) will also be considered an induction failure, regardless of marrow 
findings. 
 
Lymphoblastic Lymphoma: If end-induction imaging reveals persistent nodal involvement or 
masses (< 70% reduction in size of largest nodes or masses noted at diagnosis), the patient will 
be classified as an Induction Failure and removed from protocol (call Principal Investigator or 
designee if patient is an induction failure).   Any patient with new, biopsy-proven sites of disease 
will also be considered an induction failure.  In addition, any patient with evidence of persistent 
disease in bone marrow (confirmed by flow cytometry, FISH or other studies) or spinal fluid will 
also be considered an induction failure. 
    
 
6.8.5  Indeterminate marrow   
If > 5% blasts that are not clearly lymphoblasts based on morphology are identified in the marrow 
on Day 32 (or any marrow performed through Day 53), try to better characterize blasts by flow 
cytometry, FISH, immunohistochemistry or other studies.  Repeat marrows can be performed 
weekly for questionable cases.  Vincristine should be given if decision is made to repeat marrow in 
one week at a dose of 1.5 mg/m2/week (maximum dose 2 mg) IV push or IV via minibag. If marrow 
results are indeterminate, call Principal Investigator or designee to discuss management. 
 
6.8.6   CNS blasts at the end of induction: 
If patient with > 5 WBC/hpf in CSF with blast cells seen on cytospin (CNS-3) from lumbar 
puncture performed at end of induction (on Days 32, or after if delayed recovery), patient is 
considered Induction Failure, and is removed from protocol. 
 
If patient has had CNS blasts present throughout Induction Therapy (CNS-2 or 3) without clearance 
of CSF, and blasts persist at Day 32, then patient is considered an Induction Failure at that time, and 
is removed from protocol.  Note: If Day 32 lumbar puncture is clear of blasts, patient is not 
considered Induction Failure, even if patient has not yet had 3 negative lumbar punctures in a row 
by that time point.   
 
If blasts are identified in the CSF from lumbar puncture performed at end of induction but CSF 
WBC < 5 cells/hpf (CNS-2) in a patient otherwise with previously clear CSF (no lymphoblasts) and 
in peripheral blood and bone marrow remission: 
 SR patient reclassified to HR, and will be considered CNS-positive (to receive 
1800 cGy during CNS Intensification Phase) 
 If HR, will receive 1800 cGy during CNS Intensification Phase, regardless of 
prior radiation assignment.  
 Twice-weekly lumbar punctures with intrathecal methotrexate, cytarabine and 
hydrocortisone.  Dose IT chemo as per Section 6.5.  Continue twice weekly 
lumbar punctures until CSF is clear, and then two additional doses will be given. 

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53
 Do not proceed to Consolidation I Phase.  Instead, administer the following 
systemic chemotherapy (one cycle only): 
 
 
 
 
 
 
 
 
1) Vincristine 1.5 mg/m2 (maximum dose 2 mg) IV push weekly or IV via minibag.    
 
 
 
 
 
2) Doxorubicin 30 mg/m2 and dexrazoxane 300 mg/m2.  See Section 6.5 for 
administration guidelines.  .  
 
 
 
 
 
3) 6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning 
on Day 1. (Suggested administration guidelines: Give on an empty stomach, 
at least 2 hours after and 1 hour before food and/or milk). Note: If patient 
taking tablets, daily dose may be adjusted to accommodate available tablet 
strengths to achieve total 14-day amount. 
 
 If blasts have cleared by Day 53 patient should proceed to next phase of treatment 
(Consolidation I) when starting criteria for that phase are met. 
 If patient with new CNS-2 status at Day 32 has persistent CNS blasts at Day 53 
(regardless of CSF cell count), the patient will be classified as an Induction Failure 
and will be removed from protocol 
 
If patient has scan evidence of CNS disease (eg, leukemic infiltrate of cranial nerve) at end of 
remission induction, then the patient will be considered an Induction Failure and be removed from 
protocol. 
 
 
 
 
 

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6.9 
 CONSOLIDATION I PHASE: STANDARD RISK PATIENTS 
 
6.9.1  Starting Time: Patients must be in documented remission at all sites.   
6.9.2  Starting Criteria: APC> 1,000, platelets > 100,000, direct bilirubin < 1.4 mg/dL (23.9 
micromoles/L), SGOT < 8 x normal, creatinine normal for age, no mucositis, no 
ascites/effusions/significant edema. 
Suggested supportive care:  
 Bactrim should be held beginning on day of HD MTX infusion, and not 
re-started until MTX level is non-detectable detectable or <0.1 micromolar 
(as per institutional standard).   
 Nonsteroidal anti-inflammatory medications should also be held beginning 
on day of HD MTX infusion, and not re-started until MTX level is non-
detectable or <0.1 micromolar (as per institutional standard). 
 
See Section 7.2.4 for Dose Modifications.  See Section 7.2.1 for allowable deviations in 
timing of medications/procedures and for allowable variation in dosing. 
 
 
6.9.3  Consolidation I Phase for Standard Risk Patients 
 
One 3-week cycle of therapy, administered as follows: 
 
Days  1  
 
 
8  
 
15  
 
22 
  
 
V  
  
 
6MP--------------------- 
  
 
ITM 
  
 
HDM 
 
Note: Patients should continue to receive tapering doses of prednisone or methylprednisolone 
(as specified in Section 6.4) at the same time that they begin Consolidation I Phase. 
 
6.9.4  Dosages, Schedules & Routes 
   
V  
 
Vincristine   
2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1 
 
 
6MP  
6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty stomach, at least 2 
hours after and 1 hour before food and/or milk).  Note: If patient taking tablets, daily 
dose may be adjusted to accommodate available tablet strengths to achieve total 14-
day amount. 
 
ITM  
Intrathecal Methotrexate.  Administer on Day 1 (prior to starting methotrexate 
infusion, if possible) (Note: Induction Day 32 ITM can be considered to be Day 1 
Consolidation I ITM if given within 72 hours of beginning Consolidation I systemic 
chemotherapy).   
 
 
 
 
Dose according to age:  

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Age  
1 - 1.99yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate  
8mg 
10 mg 
12 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration. 
 
 HDM   High dose methotrexate.  Begin infusion on Day 1 
 Prehydrate with IVF containing NaHCO3 until urine specific gravity is < 1.010 and 
pH is > 7.0 and < 8.0.  Suggested prehydration: D5W + 75 mEq NaHCO3/L at 125 
mL/m2/hour for 6 hours 
 Hour 0: Total fluid while receiving methotrexate infusion: patient should receive total 
fluids of at least 125 mL/m2/hour with NaHCO3-containing fluids beginning at Hour 
0 and continuing until methotrexate level non-detectable or <0.1 micromolar (as per 
institutional standard).  Fluid volume may be adjusted to maintain dilute urine (sg < 
1.010) until methotrexate non-detectable (or <0.1 micromolar).  Fluid should contain 
NaHCO3, and amount of NaHCO3 should be adjusted to maintain urine pH > 7 and < 
8. Suggested starting concurrent IVF: D5W + 75 mEq NaHCO3/L at 125 mL/ 
m2/hour 
 Hour 0: Methotrexate 0.5 grams/m2 IV over 30 minutes. Suggested diluent: 10 mL 
D5W + 75 mEq NaHCO3/L to run at 20 mL/hour (along with concurrent IVF). 
 Hour 0.5-24: Methotrexate 4.5 grams/m2 continuous infusion IV over 23.5 hours.  
Suggested diluent: 470 mL D5W + 75 mEq NaHCO3/L to run at 20 mL/hour for 23.5 
hours (along with concurrent IVF).  
 Hour 24: Check MTX level. (Note: check level at completion of infusion) 
 Hour 36: Leucovorin 75 mg/m2 IV bolus x 1 dose, given 36 hours after start of MTX 
infusion 
 Hour 42: Leucovorin 15 mg/m2 IV bolus every 6 hours until methotrexate level is 
non-detectable or <0.1 micromolar (as per institutional standard).  Once MTX level is 
non-detectable 
(or 
<0.1 
micromolar), 
discontinue 
leucovorin 
and 
IV 
hydration/alkalinization. 
 Hour 48: Check methotrexate level.  Continue to check at least every 24 hours until 
methotrexate level non-detectable or <0.1 micromolar, as per institutional standard. 
 
Dose adjustments for high methotrexate levels 
 Hour 24: If level > 100 micromolar, increase total fluids to at least 200 mL/m2/hour 
and start leucovorin 100 mg/m2/dose IV bolus every 3 hours.  Check MTX level 
every 12 hours, if possible. Continue at this dose of leucovorin until level is < 5 
micromolar, then reduce dose of leucovorin to 15 mg/m2 IV every 3 hours.   Continue 
this dose of leucovorin until level is non-detectable or <0.1 micromolar (as per 
institutional standard). 
 Hour 48: If level > 0.18 but < 5 micromolar, increase total fluids to at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2 IV every 6 hours.  If level > 5 
micromolar, increase total fluids to at least 200 mL/m2/hour and change leucovorin 

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dosing to 15 mg/m2/dose IV every 3 hours. Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
 Hour 72: If level > 0.1 but < 5 micromolar, ensure total fluids are at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2/dose IV every 6 hours.  If level > 5 
micromolar, ensure total fluids are at least 200 mL/m2/hour and change leucovorin 
dosing to 15 mg/m2/dose IV every 3 hours. Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
Note: Dosing guidelines for fluids and leucovorin (above) may be modified 
depending on patient’s clinical status (such as rising creatinine, new effusions, etc).  
In rare circumstances, methotrexate infusion may be stopped early in the event of 
excessive toxicity (such as rising creatinine).  Any modifications should be discussed 
in 
advance 
with 
Lewis 
Silverman, 
MD, 
or 
designee.

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6.10 CONSOLIDATION I PHASE: HIGH RISK PATIENTS 
 
6.10.1  Starting Time: Patients must be in documented remission at all sites.   
6.10.2  Starting Criteria: APC> 1,000, platelets > 100,000, direct bilirubin < 1.4 mg/dL(23.9 
micromoles/L), SGOT < 8 x normal, creatinine normal for age, no mucositis, no 
ascites/effusions/significant edema. 
 
Suggested supportive care:  
 Bactrim should be held beginning on day of HD MTX infusion, and not 
re-started until MTX level is non-detectable or <0.1 micromolar (as per 
institutional standard).     
 Nonsteroidal anti-inflammatory medications should also be held beginning 
on day of HD MTX infusion, and not re-started until MTX level is non-
detectable or <0.1 micromolar (as per institutional standard). 
 MTX infusion should be started at least 8 hours and not more than 24 
hours following the dose of doxorubicin. 
 
See Section 7.2.4 for Dose Modifications.  See Section 7.2.1 for allowable deviations in 
timing of medications/procedures and for allowable variation in dosing. 
 
6.10.3  Consolidation I Phase for High Risk Patients 
 
One 3-week cycle of therapy, administered as follows: 
 
Cycle 1 
Days  1  
 
8  
 
15  
 
22 
  
 
V  
  
 
6MP------------------- 
  
 
Dd 
 
 
ITM 
  
 
 
HDM 
 
Note: Patients should continue to receive tapering doses of prednisone or methylprednisolone 
(as specified in Section 6.5) at the same time that they begin Consolidation I Phase. 
 
6.10.4  Dosages, Schedules & Routes 
 
  V  
 
Vincristine   2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1  
 
6MP  
6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on Day 
1. (Suggested administration guidelines: Give on an empty stomach, at least 2 
hours after and 1 hour before food and/or milk).  Note: If patient taking tablets, 
daily dose may be adjusted to accommodate available tablet strengths to achieve 
total 14-day amount. 
 

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Dd 
 
  Doxorubicin 30 mg/m2 IV preceded by dexrazoxane 300 mg/m2 IV on Day 1. 
Suggested administration for both drugs:  
 Minute 0  
Dexrazoxane over 15 minutes 
 Minute 15    Doxorubicin IV push via central line or freshly placed 
peripheral IV 
 Goal is no more than 30 minutes maximum elapsed administration time 
combined for both drugs 
 May give doxorubicin prior to dexrazoxane if given via peripheral IV 
 May give doxorubicin IV over 15 minutes if given via central line 
 
ITM   
Intrathecal Methotrexate.  Adminster on Day 1 (prior to starting methotrexate 
infusion, if possible).  (Note: Induction Day 32 ITM can be considered to be Day 1 
Consolidation I ITM if given within 72 hours of beginning Consolidation I systemic 
chemotherapy).   
 
 
 
 
Dose according to age:  
Age  
1 - 1.99yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate  
8mg 
10 mg 
12 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration. 
 
HDM   High dose methotrexate.  Begin infusion at least 8 hours but no more than 24 
hours following the dose of doxorubicin 
 Prehydrate with IVF containing NaHCO3 until urine specific gravity is < 1.010 and 
pH is > 7.0 and < 8.0.  Suggested prehydration: D5W + 75 mEq NaHCO3/L at 125 
mL/m2/hour for 6 hours 
 Hour 0: Total fluid while receiving methotrexate infusion: patient should receive total 
fluids of at least 125 mL/m2/hour with NaHCO3-containing fluids beginning at Hour 
0 and continuing until methotrexate level non-detectable or <0.1 micromolar (as per 
institutional standard).  Fluid volume may be adjusted to maintain dilute urine (sg < 
1.010) until methotrexate non-detectable (or <0.1 micromolar). Fluid should contain 
NaHCO3, and amount of NaHCO3 should be adjusted to maintain urine pH > 7 and < 
8. Suggested starting concurrent IVF: D5W + 75 mEq NaHCO3/L at 125 mL/m2/hour 
 Hour 0: Methotrexate 0.5 grams/m2 IV over 30 minutes. Suggested diluent: 10 mL 
D5W + 75 mEq NaHCO3/L to run at 20 mL/hour (along with concurrent IVF). 
 Hour 0.5-24: Methotrexate 4.5 grams/m2 continuous infusion IV over 23.5 hours.  
Suggested diluent: 470 mL D5W + 75 mEq NaHCO3/L to run at 20 mL/hour for 23.5 
hours (along with concurrent IVF).  
 Hour 24: Check MTX level. (Note: check level at completion of infusion) 
 Hour 36: Leucovorin 75 mg/m2 IV bolus x 1 dose, given 36 hours after start of MTX 
infusion 

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 Hour 42: Leucovorin 15 mg/m2 IV bolus every 6 hours until methotrexate level is 
non-detectable or <0.1 micromolar (as per institutional standard).  Once MTX level is 
non-detectable 
(or 
<0.1 
micromolar), 
discontinue 
leucovorin 
and 
IV 
hydration/alkalinization. 
 Hour 48: Check methotrexate level.  Continue to check every 24 hours until 
methotrexate level non-detectable or <0.1 micromolar, as per institutional standard. 
 
 
Dose adjustments for high methotrexate levels 
 Hour 24: If level > 100 micromolar, increase total fluids to at least 200 mL/m2/hour 
and start leucovorin 100 mg/m2/dose IV bolus every 3 hours.  Check MTX level 
every 12 hours if possible.  Continue at this dose of leucovorin until level is < 5 
micromolar, then reduce dose of leucovorin to 15 mg/m2 IV every 3 hours.   Continue 
this dose of leucovorin until level is non-detectable or <0.1 micromolar (as per 
institutional standard). 
 Hour 48: If level > 0.18 but < 5 micromolar, increase total fluids to at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2 IV every 6 hours.  If level > 5 
micromolar, increase total fluids to at least 200 mL/m2/hour and change leucovorin 
dosing to 15 mg/m2/dose IV every 3 hours.  Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
 Hour 72: If level > 0.1 but < 5 micromolar, ensure total fluids are at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2/dose IV every 6 hours.  If level > 5 
micromolar, ensure total fluids are at least 200 mL/m2/hour and change leucovorin 
dosing to 15 mg/m2/dose IV every 3 hours. Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
Note: Dosing guidelines for fluids and leucovorin (above) may be modified depending on 
patient’s clinical status (such as rising creatinine, new effusions, etc).  In rare 
circumstances, methotrexate infusion may be stopped early in the event of excessive 
toxicity (such as rising creatinine).  Any modifications should be discussed in advance 
with Lewis Silverman, MD, or designee. 
 

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60
 
6.11 CONSOLIDATION I: VERY HIGH RISK PATIENTS 
Consolidation I Therapy for Very High Risk Patients consists of 3 phases 
 Consolidation IA: vincristine, 6MP, doxorubicin/dexrazoxane, high dose methotrexate, ITM 
 Consolidation IB: cyclophosphamide, low-dose cytarabine, 6MP, ITM 
 Consolidation IC: high-dose cytarabine, etoposide, dexamethasone, asparaginase 
 
6.11.1  Starting Time: Patients must be in documented remission at all sites.   
6.11.2  Starting Criteria (Cycle IA): APC> 1,000, platelets > 100,000, direct bilirubin < 1.4 
mg/dL (23.9 micromoles/L), SGOT < 8 x normal, creatinine normal for age, no 
mucositis, no ascites/effusions/significant edema.  
 
Suggested supportive care:  
 Bactrim should be held beginning on day of HD MTX infusion, and not 
re-started until MTX level is non-detectable detectable or <0.1 micromolar 
(as per institutional standard).     
 Nonsteroidal anti-inflammatory medications should also be held beginning 
on day of HD MTX infusion, and not re-started until MTX level is non-
detectable or <0.1 micromolar (as per institutional standard). 
 MTX infusion should be started at least 8 hours and not more than 24 
hours following the dose of doxorubicin. 
 
See Section 7.2.4 for Dose Modifications.  See Section 7.2.1 for allowable deviations in 
timing of medications/procedures and for allowable variation in dosing. 
 
6.11.3  Consolidation IA (VHR patients): 
Days  1       
 
15       
22 
  
 
V  
 
 
 
 
  
 
6MP-------- 
  
 
Dd 
 
 
ITM 
  
 
 
 HDM 
    
Note: Patients should continue to receive tapering doses of prednisone or methylprednisolone 
(as specified in Section 6.5) at the same time that they begin Consolidation I Phase. 
 
 
 
6.11.4  Dosages, Schedules & Routes 
 
   
V  
 
Vincristine  2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1 
 
 
6MP  
6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty stomach, at least 
2 hours after and 1 hour before food and/or milk).  Note: If patient taking tablets, 
daily dose may be adjusted to accommodate available tablet strengths to achieve 
total 14-day amount. 
 

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Dd 
    Doxorubicin 30 mg/m2 IV preceded by dexrazoxane 300 mg/m2 IV on Day 1. 
 Suggested administration for both drugs:  
 Minute 0  
Dexrazoxane over 15 minutes 
 Minute 15     Doxorubicin IV push via central line or freshly placed 
peripheral IV 
 Goal no more than 30 minutes maximum elapsed administration time 
combined for both drugs 
 May give doxorubicin prior to dexrazoxane if given via peripheral IV 
 May give doxorubicin IV over 15 minutes if given via central line 
 
ITM   
Intrathecal Methotrexate.  Administer on Day 1, prior to starting methotrexate 
infusion if possible.  (Note: Induction Day 32 ITM can be considered to be Day 1 
Consolidation I ITM if given within 72 hours of beginning Consolidation IA 
systemic chemotherapy).   
 
 
 
Dose according to age:  
 
Age  
1 - 1.99yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate  
8 mg 
10 mg 
12 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 
HDM   High dose methotrexate.  Begin infusion at least 8 hours but no more than 24 
hours following the dose of doxorubicin 
 Prehydrate with IVF containing NaHCO3 until urine specific gravity is < 1.010 and 
pH is > 7.0 and < 8.0.  Suggested prehydration: D5W + 75 mEq NaHCO3/L at 125 
mL/m2/hour for 6 hours 
 Hour 0: Total fluid while receiving methotrexate infusion: patient should receive total 
fluids of at least 125 mL/m2/hour with NaHCO3-containing fluids beginning at Hour 
0 and continuing until methotrexate level non-detectable or <0.1 micromolar (as per 
institutional standard). Fluid volume may be adjusted to maintain dilute urine (sg < 
1.010) until methotrexate non-detectable (or <0.1 micromolar).  Fluid should contain 
NaHCO3, and amount of NaHCO3 should be adjusted to maintain urine pH > 7 and < 
8. Suggested starting concurrent IVF: D5W + 75 mEq NaHCO3/L at 125 mL/m2/hour 
 Hour 0: Methotrexate 0.5 grams/m2 IV over 30 minutes. Suggested 
diluent: 10 mL D5W + 75 mEq NaHCO3/L to run at 20 mL/hour (along 
with concurrent IVF). 
 Hour 0.5-24: Methotrexate 4.5 grams/m2 continuous infusion IV over 23.5 
hours.  Suggested diluent: 470 mL D5W + 75 mEq NaHCO3/L to run at 
20 mL/hour for 23.5 hours (along with concurrent IVF).  
 Hour 24: Check MTX level (Note: check level at completion of 
infusion).  

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 Hour 36: Leucovorin 75 mg/m2 IV bolus x 1 dose, given 36 hours after 
start of MTX infusion 
 Hour 42: Leucovorin 15 mg/m2 IV bolus every 6 hours until methotrexate 
level is non-detectable.  Once MTX level is non-detectable (or <0.1 
micromolar), discontinue leucovorin and IV hydration/alkalinization or 
<0.1 micromolar (as per institutional standard). 
 Hour 48: Check methotrexate level.  Continue to check every 24 hours 
until methotrexate level non-detectable or <0.1 micromolar, as per 
institutional standard. 
 
 
Dose adjustments for high methotrexate levels 
 Hour 24: If level > 100 micromolar, increase total fluids to at least 200 mL/m2/hour 
and start leucovorin 100 mg/m2/dose IV bolus every 3 hours.  Check MTX level 
every 12 hours.  Continue at this dose of leucovorin until level is < 5 micromolar, 
then reduce dose of leucovorin to 15 mg/m2 IV every 3 hours.   Continue this dose of 
leucovorin until level is non-detectable or <0.1 micromolar (as per institutional 
standard). 
 Hour 48: If level > 0.18 but < 5 micromolar, increase total fluids to at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2 IV every 6 hours.  If level > 5 
micromolar, increase total fluids to at least 200 mL/m2/hour and change leucovorin 
dosing to 15 mg/m2/dose IV every 3 hours.  Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
 Hour 72: If level > 0.1 but < 5 micromolar, ensure total fluids are at least 200 
mL/m2/hour and continue leucovorin at 15 mg/m2/dose IV every 6 hours.  If level > 5 
micromolar, ensure total fluids are at least 200 mL/m2/hour and change leucovorin 
dosing to 15 mg/m2/dose IV every 3 hours. Continue this dose of leucovorin until 
level is non-detectable or <0.1 micromolar (as per institutional standard). 
Note: Dosing guidelines for fluids and leucovorin (above) may be modified depending on 
patient’s clinical status (such as rising creatinine, new effusions, etc). In rare 
circumstances, methotrexate infusion may be stopped early in the event of excessive 
toxicity (such as rising creatinine). Any modifications should be discussed in advance 
with Lewis Silverman, MD, or designee. 
 

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6.11.5  
 
Consolidation IB (VHR patients) 
The second phase of VHR Consolidation I (Consolidation IB) may start approximately 21 days 
after the start of Consolidation IA, and only when there is no or nearly fully resolved mucositis 
and when APC ≥ 750, and platelets ≥ 75,000 and rising. Other starting criteria for starting 
Consolidation IB:  creatinine normal for age, SGOT < 8 x normal, direct bilirubin < 1.4 
mg/dL(23.9 micromoles/L).   
Peripheral blood for MRD should be drawn prior to starting cycle.  See Section 9.2. 
 
Days  1    2…       
 
9…  
15 
  
Cyc 
  
 
 
Ara  
 
 
Ara  
      
 
 
 
6MP------------------------------- 
ITM 
 
6.11.6 
Dosages, Schedules & Routes 
 
Cyc  Cyclophosphamide 1000 mg/m2 IV over 1 hour on Day 1 
 
Suggested administration: 
 Prehdyration: NS 20 mL/kg IV over 1 hour, then D5 ½ NS at 125 ml/m2/hour until 
urine s.g. < 1.010 
 Optional: Prior to hour 0  - Mesna 360 mg/m2 IV over 15 minutes in concurrent IVF 
just prior to Cyclophosphamide.  
 Hour 0: Cyclophosphamide 1000 mg/m2 IV in 125 mL/m2 D5 ½ NS over 1 hour 
 Posthydration (Begin Hour 1):  D5 ½ NS at 125 mL/m2/hour x 4 hours 
 
Optional: Hour 3:  Mesna 360 mg/m2 IV over 15 minutes in concurrent IVF  
 
Note: Use of Mesna is not required, and its administration is at the discretion of treating 
physician.  Duration of pre- and post-hydration is also at the discretion of treating 
physician. 
 
Ara Cytarabine (ara-C) 75 mg/m2/day IV push on Days 2-5 and 9-12. 
 
6MP 6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on Day 1. 
(Suggested administration guidelines: Give on an empty stomach, at least 2 hours after and 1 
hour before food and/or milk).  Note: If patient taking tablets, daily dose may be adjusted to 
accommodate available tablet strengths to achieve total 14-day amount. 
 
 
 

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ITM IT methotrexate.  Administer on Day 1. 
Dose according to age: 
Age  
1 - 1.99yrs 
2 - 2.99yrs  
> 3yrs 
Methotrexate  
8mg 
10mg 
12mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 

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6.11.7 Consolidation IC (VHR patients) 
The third phase of VHR Consolidation I (Consolidation IC) should start approximately 21 days 
after the start of Consolidation IB, and only when there is no or nearly fully resolved mucositis 
and when APC ≥ 750 and platelets ≥ 75,000, and rising.   
Criteria to adnimister Day 8 Asparaginase: Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L). 
Suggestion: check amylase prior to administration of asparaginase.   
Peripheral blood for MRD should be drawn prior to starting cycle.  See Section 9.2. 
 
 
Days  1  
 
 
2       
3  
 
4  
 
5…    8 
 
 
 
HDAra  
HDAra 
 
 
 
 
 
 
 
 
 
Etop  
Etop  
Etop 
 
 
Dex--------------------------------------------- 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
ASP  
 
6.11.8 Dosages, Schedules & Routes 
 
HDAra 
High-dose Cytarabine (ara-C) 2 grams/m2/dose IV every 12 hours for a total of four 
doses beginning on Day 1.  Suggested Administration Guidelines:  Give each dose of 
cytarabine in 300 mL/m2 D5 ¼ NS over 3 hours at 100 mL/m2/hour 
 
Suggested Supportive Care: Dexamethasone ophthalmic ointment/drops:  apply to both 
eyes every 6 hours beginning with 1st dose of Cytarabine and continue until 48 hours 
after completion of Cytarabine. 
 
 
Etop    
Etoposide  (VP16) 100 mg/m2/dose IV daily on Days 3, 4,  and 5 (three doses total).  
Suggested Adminstration Guidelines: Give each dose in 250 mL/m2 D5 1/2 NS over 1 
hour. 
 
Dex 
Dexamethasone 18 mg/m2/day orally or IV divided twice daily (bid) on Days 1-5 (ten 
total doses) 
 
ASP 
Asparaginase according to randomization, beginning on Day 8.  Mix in 100 mL Normal 
Saline and give over 1 hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV every 3 weeks, 
or   
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV every 2 weeks.   
 
 
 

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Note:  Asparaginase should continue through CNS phase and Consolidation II phase for 30 
total weeks (10 total post-induction doses of SC-PEG given every 3-weeks or 15 total post-
induction doses of Oncaspar given every 2-weeks). 
 
Note: All patients should have asparaginase enzyme (PK) samples obtained immediately 
prior to first dose of asparaginase and then prior to every subsequent dose of asparaginase.. 
Asparaginase antibody sample should also be drawn immediately prior to first dose of 
asparaginase (see Section 9.2.3).  
 
 
 
 
  
 

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6.12 CNS PHASE FOR STANDARD RISK PATIENTS 
 
6.12.1  Starting time: 21 days from start of Consolidation I, as soon as starting criteria are 
met.  See Section 7.2.1.2 for allowable deviations in timing. 
6.12.2  Starting Criteria: APC> 1,000, platelets > 100,000, direct bilirubin < 1.4 mg/dL 
(23.9 micromoles/L), SGOT < 8 x normal, no or nearly fully resolved mucositis. 
Suggestion: check amylase prior to administration of asparaginase). 
 
Note: Asparaginase should only be administered on Day 1 for SR patients if all criteria 
for starting CNS phase are met. 
 
See Section 7.2.7 for Dose Modifications.  See Section 7.2.1 for allowable deviations 
in timing of medications/procedures and for allowable variation in dosing. 
 
6.12.3   Dosages, Schedules & Routes  
 Vincristine 2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag x 1 dose on Day 
1. 
 
 6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty stomach, at least 2 
hours after and 1 hour before food and/or milk).  Note: If patient taking tablets, daily 
dose may be adjusted to accommodate available tablet strengths to achieve total 14-
day amount. 
 
 Dexamethasone 6 mg/m2/day orally divided twice daily (bid) for 5 days beginning on 
Day 1. 
 
 Asparaginase according to randomization on Day 1.  Mix in 100 mL Normal Saline 
and give over 1 hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV every 3 weeks, 
or   
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV every 2 weeks.   
 
Note:  Asparaginase should continue through CNS phase and Consolidation II phase for 30 
total weeks (10 total post-induction doses of SC-PEG given every 3-weeks or 15 total post-
induction doses of Oncaspar given every 2-weeks). Direct bilirubin should be < 1.4 mg/dL 
(23.9 micromoles/L) for all doses of asparaginase, including 2nd dose of asparaginase in the 
CNS phase. 
 
Note: All patients should have asparaginase enzyme (PK) samples obtained immediately 
prior to first dose of asparaginase and then prior to every subsequent dose of asparaginase. 
Asparaginase antibody sample should also be drawn immediately prior to first dose of 
asparaginase (see Section 9.2.3). 

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 Intrathecal Methotrexate/Cytarabine/Hydrocortisone twice weekly x 4 doses 
Age  
1 - 1.99 yrs 
2 - 2.99yrs  
> 3yrs 
Methotrexate 
8mg 
10mg 
12mg 
Cytarabine 
20mg 
30mg 
40mg 
Hydrocortisone 
9mg 
12mg 
15mg 
 
 
 
 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration.  

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6.13  
CNS PHASE: HIGH RISK AND VERY HIGH RISK PATIENTS 
 
6.13.1 Starting time: 21 days from start of Consolidation I, as soon as starting criteria are 
met.  For VHR patients, starting time is 21 days from start of Consolidation IC.  
See Section 7.2.1.2 for allowable deviations in timing.  
 
6.13.2 Starting Criteria: APC> 1,000, platelets > 100,000, direct bilirubin < 1.4 mg/dL 
(23.9 micromoles/L), SGOT < 8 x normal, no or nearly fully resolved mucositis.  
Suggestion: check amylase prior to administration of asparaginase. 
 
Note: Asparaginase should only be administered on Day 1 for HR patients if all criteria for starting 
CNS phase are met. 
For VHR leukemia patients and T-ALL patients: Bone marrow aspirate for 
MRD assessment should be performed at the same time as first lumbar puncture of 
CNS phase and blood for MRD should be drawn prior to starting cycle. See 
Section 9.2. Note: This bone marrow aspirate is optional for non-VHR T-
ALL patients, but required for VHR leukemia patients.   
 
See Section 7.2.7 for Dose Modifications.  See Section 7.2.1 for allowable deviations 
in timing of medications/procedures and for allowable variation in dosing. 
 
6.13.3  Dosages, Schedules & Routes  
 Vincristine 2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag x 1 dose on Day 1. 
 Doxorubicin 30 mg/m2 IV bolus and Dexrazoxane 300 mg/m2 IV bolus.  Give on Day 1.    
Suggested administration for both drugs:  
 Minute 0  
Dexrazoxane over 15 minutes 
 Minute 15     Doxorubicin IV push via central line or freshly placed 
peripheral IV 
 Goal no more than 30 minutes maximum elapsed administration time 
combined for both drugs 
 May give doxorubicin prior to dexrazoxane if given via peripheral IV  
 May give doxorubicin IV over 15 minutes if given via central line  
 
 6-mercaptopurine 50 mg/m2/day orally nightly x 14 consecutive days beginning on Day 1. 
(Suggested administration guidelines: Give on an empty stomach, at least 2 hours after 
and 1 hour before food and/or milk).  Note: If patient taking tablets, daily dose may be 
adjusted to accommodate available tablet strengths to achieve total 14-day amount. 
 
 Dexamethasone 18 mg/m2/day orally divided twice daily (bid) for 5 days beginning on Day 1. 
 
 Asparaginase according to randomization on Day 1.  Mix in 100 mL Normal Saline and give 
over 1 hour.  
  
 
 

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A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV every 3 weeks, 
or   
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV every 2 weeks.   
 
   
 
Note:  Asparaginase should continue through CNS phase and Consolidation II phase for 30 
total weeks (10 total post-induction doses of SC-PEG given every 3-weeks or 15 total post-
induction doses of Oncaspar given every 2-weeks). Direct bilirubin should be < 1.4 mg/dL 
(23.9 micromoles/L) for all doses of asparaginase, including 2nd dose of asparaginase in the 
CNS phase.Note: VHR patients who began asparaginase during the Consolidation IC phase 
should continue to receive asparaginase per randomization at the frequency indicated in 
Section 6.11.7: that is, during the CNS phase, asparaginase should only be administered 21 
days after the previous dose of SC-PEG Asparaginase or 14 days after the previous dose of 
Oncaspar (and not necessarily on Day 1 of CNS phase). 
 
Note: All patients should have asparaginase enzyme (PK) samples obtained immediately 
prior to first dose of asparaginase and then prior to every subsequent dose of asparaginase. 
Asparaginase antibody sample should also be drawn immediately prior to first dose of 
asparaginase (see Section 9.2.3). 
 
 Intrathecal Methotrexate/Cytarabine/Hydrocortisone twice weekly x 4 doses  
 
Age  
1 - 1.99 yrs 
2 - 2.99 yrs  
> 3 yrs 
Methotrexate 
8 mg 
10 mg 
12 mg 
Cytarabine 
20 mg 
30 mg 
40 mg 
Hydrocortisone 
9 mg 
12 mg 
15 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for 
dilution). 
 Intrathecal medications should be filtered prior to or during administration or 
according to institute policy for safe administration.  
 
6.13.4 Cranial Radiation:  
To be administered only to:      
 VHR patients and  
 HR B-precursor ALL patients with any of the following criteria: 
 CNS-3 at diagnosis or at Day 18  (or any time after Day 18 but prior to Day 32) 
 CNS-2 at Day 18 or at end of remission induction  
 T-ALL (all patients, regardless of CNS status) 
 Lymphoblastic lymphoma patients (regardless of phenotype) who meet any of the 
following criteria: 

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 CNS-3 at diagnosis or at Day 18 (or any time after Day 18 but prior to Day 32)  
 CNS-2 at Day 18 or at end of remission induction 
 
  
Dosage of Cranial Radiation:  1200 cGy cranial radiation delivered as 150 cGy daily 
fractions for 8 days.  NOTE:  Cranial radiation should start as close as possible to the 
administration of doxorubicin/vincristine. 
 
 Exception: Dosage of 1800 cGy (180 cGy fractions for 10 days) should be 
administered to patients with the following characteristics: 
 CNS-3 at diagnosis or at Day 18 
 CNS-2 at Day 18 or at end of remission induction  
 
See Table 6.13 (below) for summary of radiation dose for high risk/very high 
risk patients based on presenting characteristics, CNS status  
 
 
 
TABLE 6.13: RADIATION DOSE FOR HIGH RISK/VERY HIGH RISK PATIENTS 
 
PATIENT CHARACTERISTICS 
Radiation Dose 
High Risk B-precursor ALL 
 CNS-1 at Days 1, 18 and 32, or 
 CNS-2 at Day 1 but clear by Day 18 
None 
High-Risk B-precursor  or T-cell Lymphoblastic Lymphoma  
 CNS-1 at Days 1, 18 and 32, or 
 CNS-2 at Day 1 but clear by Day 18 
None 
High-Risk T-cell ALL  
 CNS-1 at Days 1, 18 and 32, or 
 CNS-2 at Day 1 but clear by Day 18 
1200 cGy 
High Risk ALL or Lymphoblastic Lymphoma, any phenotype 
 CNS-2 on Day 18 or 32 
 CNS-3 on Day 1 or 18, or 
 Cranial nerve palsy at diagnosis 
1800 cGy 
Very High Risk ALL or Lymphoblastic Lymphoma  
 CNS-1 at Days 1, 18 and 32, or 
 CNS-2 at Day 1 but clear by Day 18 
1200 cGy 
Very High Risk ALL or Lymphoblastic Lymphoma 
 CNS-2 at Days 18 or 32, or 
 CNS-3 at Days 1 or 18, or 
 Cranial nerve palsy at diagnosis 
1800 cGy 
CNS-1: no blast cells in cytospin, regardless of CSF cell count 
CNS-2: Fewer than 5 WBC on CSF cell count, with blasts on cytospin 
CNS-3: 5 or more WBC on CSF cell count, with blasts on cytospin 
Traumatic LP: > 10 RBC on CSF cell count.  See Section 5.16 for interpretation of traumatic LP 
with blasts. 

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6.14 CONSOLIDATION II PHASE  
 
6.14.1 Starting Time for All Patients  
Starting time: after recovery from CNS Therapy (21 days from start of systemic 
chemotherapy administered during CNS Therapy and as soon as starting criteria are 
met).  See Section 7.2.1.2 for allowable deviations in starting time. 
 
6.14.2 Criteria to begin Consolidation II Cycles 
APC = (Total WBC) x %(Monos + Polys + Bands) 
 
 To begin 1st week of each 3-week chemotherapy cycle: 
 APC > 750/mm3  
 Platelets > 75,000/mm3  
 Mucositis:  none or mild (defined in Section 7.2.8.3). 
 SGOT < 8 x normal 
 Direct bilirubin < 1.4 mg/dl (23.9 micromoles/L) 
 
 If criteria are not met, hold chemo for 1-7 days, and then re-check. 
 In unusual circumstances, chemotherapy cycles may be started even when not all of 
these criteria have been met if approved in advance by Principal Investigator or 
designee.  
 Note: These criteria do not apply to scheduled doses of asparaginase. 
 
6.14.3   Criteria to continue cycle (Days 2 - 21): 
 APC > 500/mm3  
 Platelets > 50,000/mm3 
 Mucositis: none or mild 
 SGOT < 8 x normal 
 Direct bilirubin < 1.4 mg/dl (23.9 micromoles/L) 
 Note: These criteria do not apply to scheduled doses of asparaginase 
 
6.14.4   Criteria to administer asparaginase 
 No clinical pancreatitis 
 No new, untreated deep venous thrombosis 
 Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L) 
 Note: Asparaginase should be administered regardless of blood counts, 
mucositis, or SGOT. 
 
 
See Section 7.2.8 for Dose Modifications.  See Section 7.2.1 for allowable deviations 
in timing of medications/procedures and for allowable variation in dosing. 
 

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6.14.5 CONSOLIDATION II THERAPY FOR STANDARD RISK PATIENTS 
  
Week  
 
1* 
 
2 
 
3 
 
4 
 
5 
 
6 . . . .  
 
 
 
 
 
  
 
V 
 
 
 
 
 
V 
 
 
 
 
 
  
 
Dex  
 
 
 
 
Dex 
        6MP  
      6MP  
 
 
 
 
 
6MP  
 
6MP  
 
 
 
 
 
 
  
 
m 
           m               m 
 
m 
 
m 
 
m 
  
 
Arm A ASP      SC-PEG 
 
 
 
 
SC-PEG  
 
Arm B ASP 
Oncaspar 
 
 
Oncaspar 
 
 
Oncaspar 
 
Continue Asparaginase (according to randomization) for 30 weeks (10 post-induction doses of SC-
PEG or 15 post-induction doses of Oncaspar).  Proceed to Continuation Therapy after 30 post-
remission weeks of asparaginase have been administered. 
 
* IT MAH - to be given every 9 weeks x 6 doses.  First lumbar puncture with IT MAH during 
Consolidation II is 9 weeks after start of CNS treatment.  After 6 doses of IT MAH (given every 9 
weeks) completed, change to IT MAH every 18 weeks until end of therapy.  IT medications should 
only be given at the start of a chemotherapy cycle.  
 
All outpatient chemotherapy for each cycle must be prescribed by a physician, nurse 
practitioner or physician assistant, as per institutional standard, on the day that the patient is 
evaluated and found to meet criteria for that cycle. This means that only one cycle of 
outpatient chemotherapy may be prescribed at each visit, and refills for chemotherapy 
prescriptions are not allowed for study patients. Exception can be made for patients receiving 
Purixan® (6-MP oral suspension) who must be dispensed full bottles per medical insurance 
restrictions; in these cases, medical staff should review dosing with patient/family at the start 
of each cycle. Under no circumstances may other clinical staff call in prescriptions for 
chemotherapy for patients on study.   
 
See Section 7.2.8 for Dose Modifications.  Allowable delays in chemotherapy/procedures and 
allowable variation in dosing specified in Section 7.2.1. 
 
Dosages, Schedules & Routes 
V  
 
Vincristine      
2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1      
of cycle 
 
Dex  
Dexamethasone   
 6 mg/m2/day orally divided twice daily (bid) for 5 days on beginning 
on Day 1 of cycle 
 
6MP 
 
6-mercaptopurine 
 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty 
stomach, at least 2 hours after and 1 hour before food and/or milk).  
Note: If patient taking tablets, daily dose may be adjusted to 

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accommodate available tablet strengths to achieve total 14-day 
amount. 
 
m 
 
Methotrexate 
 
  30 mg/m2 IV push or IM once a week  (Days 1, 8 and 15 of each 
cycle).  Hold systemic methotrexate on the week IT Methotrexate is 
given. 
 
ASP 
Asparaginase according to randomization. Mix in 100 mL Normal Saline and give over 
1 hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV every 3 weeks, 
or   
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV every 2 weeks.   
 
Note: Administer asparaginase only if direct bilirubin < 1.4 mg/dL (23.9 
micromoles/L).  Asparaginae may be administered regardless of blood counts (see 
Section 6.14.4 for full criteria).   
 
Note:  Asparaginase should continue through Consolidation II phase for 30 total 
weeks (10 total post-induction doses of SC-PEG given every 3-weeks or 15 total post-
induction doses of Oncaspar given every 2-weeks). 
 
Note:  All patients should have asparaginase enzyme (PK) samples obtained 
immediately prior each dose of asparaginase. Asparaginase antibody samples should 
be drawn during the Consolidation II phase at two time points as indicated in Section 
9.2.3. 
 
 
 
IT MAH Intrathecal Methotrexate/Cytarabine/Hydrocortisone 
 
Give as close to every 9 weeks as possible for 6 doses, then give as close to every 18 weeks. Always 
give IT medications at the start of a chemo cycle. First dose is given 9 weeks after first lumbar puncture 
administered during CNS treatment.  
 
Age  
1 - 1.99yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate 
8 mg 
10 mg 
12 mg 
Cytarabine 
20 mg 
30 mg 
40 mg 
Hydrocortisone 
9 mg 
12 mg 
15 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 Hold systemic methotrexate on the week IT Methotrexate is given 

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6.14.6 CONSOLIDATION II THERAPY FOR HIGH RISK AND VERY HIGH 
RISK PATIENTS 
 
Week  
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 . . . .  
 
 
V 
 
 
 
 
 
V 
 
 
Dex  
 
 
 
 
Dex 
 
 
6MP  
6MP  
 
 
6MP  
6MP 
 
 
Dd  
 
 
 
 
D(d) 
 
 
(m)** 
 
 
Arm A ASP      SC-PEG 
 
 
 
 
SC-PEG  
 
Arm B ASP 
Oncaspar 
 
 
Oncaspar 
 
 
Oncaspar 
 
Continue Asparaginase (according to randomization) for 30 weeks (10 post-induction doses of SC-
PEG or 15 post-induction doses of Oncaspar).   
 
 Repeat this 3 week sequence of treatment until ready for next phase of therapy. Proceed to 
Continuation Therapy after all of the following have been administered: 
 Cumulative doxorubicin dosage of 300 mg/m2 +/- 15 mg/m2  
 30 post-remission weeks of asparaginase  
 10 
cycles 
with 
high-dose 
dexamethasone 
(18 
mg/m2/day), 
including 
dexamethasone administered during the CNS phase (but, for VHR patients, not 
including dexamethasone administered during Consolidation IC phase). 
 
IT MAH – frequency of administration depends on whether or not patient received cranial 
radiation.  If no cranial radiation, first IT dose is given 9 weeks after first lumbar puncture 
during CNS Therapy. If patient received cranial radiation, first IT dose is given 18 weeks after 
first lumbar puncture during CNS Therapy. IT medications should only be given at the start of a 
chemotherapy cycle. 
 
All outpatient chemotherapy for each cycle must be prescribed by a physician, nurse 
practitioner or physician assistant, as per institutional standard, on the day that the patient is 
evaluated and found to meet criteria for that cycle. This means that only one cycle of 
outpatient chemotherapy may be prescribed at each visit, and refills for chemotherapy 
prescriptions are not allowed for study patients. Exception can be made for patients receiving 
Purixan® (6-MP oral suspension) who must be dispensed full bottles per medical insurance 
restrictions; in these cases, medical staff should review dosing with patient/family at the start 
of each cycle. Under no circumstances may other clinical staff call in prescriptions for 
chemotherapy for patients on study.   
 
 
Allowable delays in chemotherapy/procedures specified in Section 7.2.   
 

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See Section 7.2.8 for Dose Modifications. Allowable delays in chemotherapy/procedures and 
allowable variation in dosing specified in Section 7.2.1. 
 
Dosages, Schedules & Routes 
V  
 
Vincristine      
2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1 
of cycle 
 
Dex  
Dexamethasone   
 18 mg/m2/day orally divided twice daily (bid) for 5 days beginning on 
Day 1 of cycle. 
 
Note:  Patients should receive a total of 10 cycles with high-dose dexamethasone (18 
mg/m2/day), including the CNS phase (but not including the Consolidation IC 
phase for VHR patients).  After 10 cycles have been administered at this dose, the 
dose of dexamethasone for all subsequent cycles should be 6 mg/m2/day orally 
divided twice daily (bid) for 5 days beginning on Day 1 of chemotherapy cycle, 
even if patientis still reciving Asparaginase and/or Doxorubicin. 
 
6MP 
 
6-mercaptopurine 
 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty 
stomach, at least 2 hours after and 1 hour before food and/or milk).  
Note: If patient taking tablets, daily dose may be adjusted to 
accommodate available tablet strengths to achieve total 14-day 
amount. 
 
 
Dd 
Doxorubicin 30 mg/m2 IV preceded by Dexrazoxane 300 mg/m2 IV on Day 1 of 
cycle. 
Suggested administration for both drugs:  
 Minute 0  Dexrazoxane over 15 minutes 
 Minute 15      Doxorubicin IV push via central line or freshly placed 
peripheral IV 
 Goal: no more than 30 minutes maximum elapsed administration time 
combined for both drugs 
 May give doxorubicin prior to dexrazoxane if given via peripheral IV 
 May give doxorubicin IV over 15 minutes if given via central line  
 
**Stop doxorubicin when total cumulative dose is 300 mg/m2 + 15mg/m2 (cumulative dose of 300 
mg/m2+ 15 mg/m2 is to allow for variability  in cumulative drug dosing; for those patients 
receiving 24 mg/m2  as a result of dose reduction it is not possible to receive exactly 300 mg/m2).  
After achieving cumulative dose of 300 mg/m2 + 15 mg/m2 of doxorubicin, begin weekly 
methotrexate at the start of the next cycle as indicated below.  
 
When doxorubicin completed and weekly methotrexate started, give as follows: 
m  
Methotrexate 
 30 mg/m2 IV push or IM once a week, beginning on Day 1 of a cycle. 
Maximum dose for previously irradiated patients is 40 mg/m2.  Hold systemic 
methotrexate on the week IT Methotrexate is given. 

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ASP 
Asparaginase according to randomization. Mix in 100 mL Normal Saline and give over 1 
hour.  
  
 
 
 
A. SC-PEG Asparaginase (Calaspargase Pegol) 2500 IU/m2/dose IV every 3 weeks, 
or   
 
  
 
 
 
B. Oncaspar 2500 IU/m2/dose IV every 2 weeks.   
 
Note: Administer asparaginase only if direct bilirubin < 1.4 mg/dL (23.9 
micromoles/L) .  Asparaginae may be administered regardless of blood counts (see 
Section 6.14.4 for full criteria).   
 
Note:  Asparaginase should continue through Consolidation II phase for 30 total 
weeks (10 total post-induction doses of SC-PEG given every 3-weeks or 15 total post-
induction doses of Oncaspar given every 2-weeks). 
 
Note: All patients should have asparaginase enzyme (PK) samples obtained 
immediately prior each dose of asparaginase. Asparaginase antibody samples should 
be drawn once mid-Consolidation II and once a the end of Consoldiation II (see 
section 9.2.3). 
 
 
IT MAH  Intrathecal Methotrexate/Cytarabine/Hydrocortisone 
 
No prior cranial radiation: Give as close to every 9 weeks as possible for 6 doses, 
then give as close to every 18 weeks. Always give IT medications at the start of a 
chemo cycle. First dose is given 9 weeks after first lumbar puncture administered 
during CNS treatment. 
 
Prior cranial radiation: Give as close to every 18 weeks as possible - at the start of a 
chemo cycle.  First dose is given 18 weeks after first lumbar puncture administered 
during CNS treatment.  
 
Age  
1 - 1.99 yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate 
8 mg 
10 mg 
12 mg 
Cytarabine 
20 mg 
30 mg 
40 mg 
Hydrocortisone 
9 mg 
12 mg 
15 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration  
 Hold systemic methotrexate on the week IT Methotrexate is given 
 

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6.15 CONTINUATION PHASE (for Standard, High Risk and Very High Risk Patients) 
 
6.15.1 Starting Time: Completion of all components of Consolidation II Phase  
For SR: Completion of all post-induction doses of asparaginase 
For HR/VHR:  Completion of all post-induction doses of asparaginase, 
administration of 10 cycles high-dose dexamethasone (during CNS and 
Consolidation II phase), and administration of total cumulative dose of 
doxorubicin of 300 mg/m2 + 15 mg/m2 
 
6.15.2 Starting Criteria for Chemotherapy for All Patients 
 
 
 
APC = (Total WBC) x %(Monos + Polys + Bands) 
 
 To begin 1st week of each 3-week chemotherapy cycle: 
 APC > 750/mm3  
 Platelets > 75,000/mm3  
 Mucositis:  none or mild (defined in Section 7.2.8.3). 
 SGOT < 8 x normal 
 Direct bilirubin < 1.4 mg/dl (23.9 micromoles/L) 
 
 If criteria are not met, hold chemo for 1-7 days, and then re-check. 
 In unusual circumstances, chemotherapy cycles may be started even when not all of 
these criteria have been met if approved in advance by Principal Investigator or 
designee.  
 
6.15.3   Criteria to continue cycle (Days 2 - 21): 
 APC > 500/mm3  
 Platelets > 50,000/mm3 
 Mucositis: none or mild 
 SGOT < 8 x normal 
 Direct bilirubin < 1.4 mg/dl (23.9 micromoles/L) 
 
See Section 7.2.8 for Dose Modficiations.  Allowable delays in chemotherapy/procedures and 
variation in dosing specified in Section 7.2.1.

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6.15.4 Continuation Phase Treatment Schema (all patients) 
 
Week  
1 
2  
 
 
3 
  
V 
  
Dex 
  
6MP 
      6MP 
  
m 
      m 
 
m 
  
 
 
Repeat this 3-week sequence of treatment until 2 years of CCR. 
 
Intrathecal medications at the start of cycles every 9-18 weeks, depending on prior cranial 
radiation. IT medications should only be given at the start of a chemotherapy cycle. Allowable 
delays in chemotherapy/procedures specified in Section 7.2.1.2. 
 
All outpatient chemotherapy for each cycle must be prescribed by a physician, nurse 
practitioner or physician assistant, as per institutional standard, on the day that the patient is 
evaluated and found to meet criteria for that cycle. This means that only one cycle of 
outpatient chemotherapy may be prescribed at each visit, and refills for chemotherapy 
prescriptions are not allowed for study patients. Exception can be made for patients receiving 
Purixan® (6-MP oral suspension) who must be dispensed full bottles per medical insurance 
restrictions; in these cases, medical staff should review dosing with patient/family at the start 
of each cycle. Under no circumstances may other clinical staff call in prescriptions for 
chemotherapy for patients on study.   
 
See Section 7.2.8 for Dose Modifications. 
 
6.15.5   Dosages, Schedules & Routes 
 
V  
 
Vincristine      
2 mg/m2 (maximum dose 2 mg) IV push or IV via minibag on Day 1 
of cycle 
 
Dex  
Dexamethasone   
 6 mg/m2/day orally divided twice daily (bid) for 5 days beginning on 
Day 1 of cycle 
 
6MP 
 
6-mercaptopurine 
 50 mg/m2/day orally nightly x 14 consecutive days beginning on 
Day 1. (Suggested administration guidelines: Give on an empty 
stomach, at least 2 hours after and 1 hour before food and/or milk).  
Note: If patient taking tablets, daily dose may be adjusted to 
accommodate available tablet strengths to achieve total 14-day 
amount. 
 
m 
 
Methotrexate 
 
  30 mg/m2 IV push or IM once a week  (Days 1, 8 and 15 of each 
cycle).  Maximum dose for previously irradiated patients is 40 mg/m2. 
Hold systemic methotrexate on the week IT Methotrexate is given. 

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IT MAH: Intrathecal Methotrexate/Cytarabine/Hydrocortisone 
 
 No prior Cranial Radiation:   
Give as close to every 9 weeks as possible for 6 doses (post-CNS therapy), then give as close 
to every 18 weeks.  
 
 Previous Cranial Radiation:  
Give as close to every 18 weeks as possible.  
 
Always give IT medications at the start of a chemotherapy cycle 
 
Doses of IT medication: 
 
Age  
1 - 1.99 yrs 
2 - 2.99 yrs 
> 3 yrs 
Methotrexate  
8 mg 
10 mg 
12 mg 
Cytarabine  
20 mg 
30 mg 
40 mg 
Hydrocortisone  
9 mg 
12 mg 
15 mg 
 
 Mix in 6 ml preservative-free normal saline (or use institutional guidelines for dilution). 
 Intrathecal medications should be filtered prior to or during administration or according to 
institute policy for safe administration. 
 Hold systemic methotrexate on the week IT Methotrexate  is given 
 
 

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6.16 
General Concomitant Medication and Supportive Care Guidelines 
No investigational or commercial agents or therapies other than those described in this 
protocol document may be administered with the intent to treat the participant’s leukemia. 
 
6.16.1  
Supportive Care at Diagnosis 
6.16.1.1 
IV Hydration and Alkalinization: Prior to the initiation of 
therapy, hydration with or without alkalinization (depending 
on institutional guidelines) to prevent acute tumor lysis 
syndrome is suggested.  Institutional guidelines may be used 
to achieve adequate hydration and alkalinization.  Suggested 
hydration: 1.5-2x maintenance IV hydration.  If alkalinization 
is used, suggested goal urine pH 7-8 specific gravity < 1.010. 
Alkalinization may be omitted if patient is receiving 
rasburicase.  IV hydration may be discontinued at the 
discretion of the treating physician when patient is 
considered no longer at risk for developing acute tumor lysis 
syndrome.   
6.16.1.2 
 Allopurinol or Rasburicase: Patients should have uric 
acid levels closely monitored, and should begin either 
allopurinol or urate oxidase (rasburicase) to treat or prevent 
elevated uric acid levels.  If allopurinol is used, the suggested 
dose is 200-400 mg/m2/day. Intravenous rasburicase may be 
used, especially if there is evidence of ongoing significant 
tumor lysis syndrome, markedly elevated uric acid levels, 
hyperleukocytosis, inability to tolerate oral medications, or 
inability to tolerate vigorous IV fluid hydration.  Rasburicase 
should not be administered to patients with known or 
suspected G6PD deficiency. Allopurinol and/or rasburicase 
may be discontinued at discretion of treating physician when 
patient is considered no longer at risk for developing acute 
tumor lysis syndrome.   
 
6.16.1.3 
 Gastritis Prophylaxis: It is recommended that gastritis 
prophylaxis be instituted at onset of corticosteroid treatment 
to minimize gastric irritation. Options include oral antacids 
(eg, calcium carbonate), sucralfate or proton pump inhibitors.  
H2 blockers are not prohibited, but are not recommended as 
they may contribute to myelosuppression. 
6.16.1.4 
Transfusions: Patients should receive transfusions of 
packed red blood cells and platelets if significant anemia or 
thrombocytopenia is present at diagnosis.  Transfusion 
threshold may be per institutional standards.  In general, it is 
suggested that platelet counts be at or above 50,000/uL at the 
time of a lumbar puncture or as per institutional guidelines.  

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Note that packed red blood cells may contribute to 
hyperviscosity, so red blood cell transfusion should be 
administered with caution in the setting of hyperleukocytosis.  
All blood products should be leukodepleted and irradiated. 
6.16.1.5 
Coagulopathy: It is suggested that a screen for 
disseminated intravascular coagulation (DIC) be sent at 
diagnosis, and abnormalities corrected with fresh frozen 
plasma and cryoprecipitate prior to undergoing invasive 
procedures, if possible.   
6.16.1.6 
 Leukemic Eye Infiltrates: It is suggested that patients 
have an ophthalmologic evaluation at or soon after diagnosis 
to screen for leukemic infiltrates or retinal hemorrhages that 
may be impacting vision.  It is not necessary to delay 
treatment prior to an ophthalmologic evaluation.  If initial 
ophthalmologic examination positive for infiltrates, it is 
suggested that follow-up examinations be obtained to 
document improvement/resolution and no visual 
compromise.  Patients with progressive infiltrates or visual 
impairments may receive emergent radiation to eyes.     
6.16.1.7 
 No added salt diet: Consider prescribing "no added salt" 
diet at diagnosis and during the remission induction phase 
because of fluid retention associated with corticosteroids. 
6.16.1.8 
 Stool softeners and Laxatives: Stool softeners and 
laxatives should be used prophylactically during remission 
induction to prevent vincristine-associated constipation. 
 
6.16.2 Infection Prophylaxis and Management of Fever During Steroid Prophase and 
Remission Induction Phase (See Section 6.3) 
6.16.2.1 
Antibiotic prophylaxis 
Antibiotic prophylaxis with a fluoroquinolone antibiotic (either levofloxaxin 
or moxifloxacin) should be initiated during the Steroid Prophase and 
continue throughout the Remission Induction phase until count recovery 
after expected hematologic nadir (ANC > 200 or APC > 500/mm3).    Patients 
unable to tolerate fluoroquinolones due to allergy or other toxicity should receive 
intravenous cefepime as prophylaxis.  If a patient is unable to tolerate 
fluoroquinolone or cefepime, contact Principal Investigator.  Patients receiving 
broad-spectrum antibiotics for fever or documented infection may discontinue 
prophylactic antibiotics.   
 
Because of the high risk of infection, treatment should begin on an inpatient basis 
and hospitalization of participants is encouraged throughout the induction phase.  

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Outpatient treatment during the induction phase may be considered after recovery 
of the absolute neutrophil count (ANC) after the expected hematologic nadir.   
6.16.2.2 
Fever 
All patients with fever (defined as > 38.5°C on a single occasion, or > 38°C on 
two occasions within 12 hours, or as per institutional guidelines) should be 
hospitalized and treated immediately with broad spectrum antibiotics, 
regardless of absolute neutrophil count.  It is recommended that empiric 
coverage consist of broad-spectrum antibiotic(s) (eg, cefepime or ceftazidime, or 
an aminoglycoside plus extended-spectrum penicillin, or as per institutional 
standard).  Once initiated, empiric antibiotics should be continued until ANC 
recovery past expected hematologic nadir, although the exact agents used may be 
modified per discretion of treating clinician.  Antifungal therapy should be started 
for the persistence of fever, or emergence of new fever in neutropenic patients 
after 3 days of broad-spectrum antibiotic coverage, or sooner based on clinical 
status as determined by treating clinician, or per institutional guidelines.  
Radiographic studies should be considered for patients with persistent or recurrent 
fever to screen for invasive fungal disease, bacterial abcesses, or other infections.   
  
6.16.3 Suggested Supportive Care During Treatment 
6.16.3.1 
 Pneumocystis Prophylaxis: 
Trimethoprim/sulfamethoxazole (Bactrim) prophylaxis 
should be instituted for all children from the time they enter 
complete remission and continued until 6 months after the 
cessation of treatment.  Prophylactic 
trimethoprim/sulfamethoxazole (Bactrim) dosage is 5 
mg/kg/day TMP 2-3 days per week, with a maximum total 
dose of 320 mg/day.   Doses may be given once or twice 
daily. If unable to take trimethoprim/sulfamethoxazole, 
alternative PCP prophylaxis (such as Dapsone or 
Atovaquone) should be instituted.   Bactrim may be held for 
a short period of time if blood counts are low, but should be 
reinstated once counts have recovered and appropriate 
adjustments in chemotherapy dosing have been made. Try to 
avoid permanently discontinuing or holding Bactrim for 
prolonged periods because of myelosuppression.   
6.16.3.2 
Management of Febrile Neutropenia: For patients with 
ANC < 500/μL and fever (defined as temperature between 
38.0° and 38.5°C twice in 12 hours, or ≥ 38.5°C, or per 
institutional guidelines), empiric parenteral broad spectrum 
antibiotics should be instituted after obtaining appropriate 
cultures.  The specific antibiotics may be per institutional 
standards.  It is recommended that vancomycin or other 
appropriate coverage for strep viridans be included in empiric 

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antibiotics for fever occurring in VHR patients after high-
dose cytarabine (Consolidation IC).  If fever persists, 
systemic antifungal therapy and radiographic studies should 
be considered, as described in Section 6.16.2.2.  
 
6.16.3.3 
 Blood Transfusions: All transfused blood products 
should be irradiated and leukodepleted.   
 
6.16.3.4 
 Growth Factors: Filgastrim (G-CSF), GM-CSF and 
granulocyte transfusions shall be considered individually for 
patients with protracted granulocytopenia and/or severe 
infection, and may be administered at discretion of treating 
physician.  Erythopoeitin may also be administered at 
discretion of treating physician. 
 
6.16.3.5 
Use of Corticosteroids other than as anti-leukemic agent: 
The use of corticosteroids to treat other conditions (eg, 
premedication for blood products, treatment of allergic 
reactions, reactive airways disease) is allowed, and may be 
instituted at the discretion of the treating physician.  
Prolonged use of corticosteroids (more than a few days at a 
time) beyond that which is outlined in this protocol as part of 
anti-leukemic treatment should be discussed in advance with 
Principal Investigator or designee, before being instituted.  
The use of corticosteroids as antiemetic agents is 
discouraged, but not prohibited. 
 
6.16.3.6 
 Leucovorin after Intrathecal Chemotherapy: Leucovorin 
may be given after intrathecal chemotherapy containing 
methotrexate for patients with Down Syndrome or those who 
have experienced excessive toxicity with prior intrathecal 
methotrexate.  Leucovorin may be added at discretion of 
treating physician.  Suggested dosing (if given): Give 
leucovorin beginning 24 hours after lumbar puncture at 15 
mg/m2/dose orally three times a day for 3 doses only. 
6.16.3.7 
 Vitamins: Try to avoid Folic Acid supplements so as to 
not interfere with efficacy of methotrexate (a folate 
antagonist). 
 
 

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6.17 Duration of Therapy 
 
Therapy for all patients should be discontinued 104 weeks (+/- 2 weeks) after 
complete remission has been documented, even if there have been significant delays 
or dose modifications during treatment.  Therapy should not be stopped in the middle 
of a 3-week continuation cycle.  Participants will be considered “off treatment” Day 
21 days after the start of the last cycle they receive during the continuation phase of 
treatment.   
Protocol treatment will be discontinued if any of the following occur: 
 Failure to achieve remission at the end of the Remission Induction Phase 
 Patient found to have Ph+ (BCR/ABL) ALL 
 Disease recurrence 
 Development of a second malignancy 
 Participant decides to withdraw from the study 
 General or specific changes in the participant's condition or compliance with 
protocol therapy render the participant unacceptable for further treatment in the 
opinion of the treating investigator 
 
6.18 Duration of Follow Up  
 
All participants (including those who stop treatment early) will be followed 
indefinitely for disease and survival status, except if a participant withdraws from the 
study and specifically declines such follow-up.  
6.19 Criteria for Removal from Study 
 Death 
 Lost to follow-up 
 Withdrawal of consent for any further data submission 
  

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7. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
 
Dose delays and modifications will be made using the recommendations listed below. 
Toxicity assessments will be done using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 
7.1 
Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with the agents administered 
in this study appear below. 

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7.1.1 Adverse Event List for Calaspargase Pegol (SC-PEG-asparaginase), 
Oncaspar, Erwinia Asparaginase 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Pain at IM injection 
site, fatigue 
Rash 
Allergic 
reaction/anaphylaxis 
(possibly severe and 
life-threatening), 
nausea, vomiting, 
abdominal pain, 
drowsiness, lethargy,  
headache 
Prompt: 
Within 2-3 
weeks 
Hypoalbuminemia, 
prolonged partial 
thromboplastin time 
(PTT), prothrombin 
time (PT), and 
bleeding time 
(secondary to 
decreased synthesis 
of fibrinogen, 
antithrombin III & 
other clotting 
factors),  
 
hyperglycemia, loss 
of appetite, abnormal 
liver function tests, 
pancreatitis, 
asymptomatic 
elevation of 
amylase/lipase, 
elevated serum 
ammonia 
seizures (L), 
peripheral edema, 
ascites, azotemia and 
decreased renal 
function, 
coagulopathy leading 
to hemorrhage or 
thrombosis,  
disseminated 
intravascular 
coagulation (DIC)  
myelosuppression, 
infections, 
depression, 
confusion, 
hallucinations, EEG 
changes, 
hypertriglyceridemia,, 
hyperlipidemia 
Delayed/Late:  
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
elevated blood urea 
nitrogen and 
creatinine, fatty liver 
deposits, 
hepatomegaly 
 
 
 

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7.1.2 Adverse Event List for Cyclophosphamide: 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea and vomiting 
Hemorrhagic cystitis 
(may be prevented with 
extra intravenous fluid or 
Mesna) 
Transient blurred 
vision, nasal stuffiness 
with rapid 
administration, 
arrhythmias (rapid 
infusion), skin rash, 
anaphylaxis, SIADH 
Prompt: 
Within 2-3 
weeks 
Hair Loss, 
Myelosuppression, 
Mucositis 
 
Cardiac toxicity with 
high dose (CHF, 
hemorrhagic 
myocarditis,  
hyperpigmentation,  
nail changes 
Delayed/Late:  
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
Mouth sores 
 
Infertility (very 
unlikely at the doses to 
be used in this 
protocol), 
Second malignancy 
(leukemia) 
Lung damage 
(pulmonary fibrosis) 
 

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7.1.2 Adverse Event List for Cytarabine (Ara-C)-Intravenous 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea, vomiting 
Flu-like symptoms: 
fever, aches, fatigue, 
Rash 
Conjunctivitis* 
Acute Neurologic 
toxicity*: dizziness, 
ataxia, slurred speech, 
altered mental status, 
coma, seizures (rarely 
can be irreversible) 
Prompt: 
Within 2-3 
weeks 
Hair Loss, 
Mucositis, 
Myelosuppression 
 
Pulmonary edema 
Delayed/Late:  
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
 
*High-dose cytarabine only  
7.1.3 Adverse Event List for Dexrazoxane 
 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
 
Inflammation of the vein 
into which it was 
injected/pain during 
infusion, 
Headaches 
Prompt: 
Within 2-3 
weeks 
 
 
Myelosuppression, 
Hair Loss, 
Changes in the liver 
function tests/irritation of 
the liver 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
 

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7.1.4 Adverse Event List for Doxorubicin 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
nausea, vomiting, 
loss of appetite, 
pink/red color to 
urine, sweat, tears, 
saliva 
diarrhea 
allergic reaction, 
rash,  
if extravasation 
occurs can lead to 
severe tissue injury. 
Prompt: 
Within 2-3 
weeks 
myelosuppression, 
hair loss 
mucositis, liver 
function test 
abnormalities 
colitis  
Delayed:  
occurring 
anytime later 
during 
therapy or 
after the 
completion of 
treatment 
 
Asymptomatic changes 
on echocardiogram 
(thin left ventricular 
wall, increased 
afterload)  
Discoloration of 
hands, feet and 
fingernails, 
secondary 
malignancy (L), 
Arrhythmia, acute 
CHF, progressive 
ventricular 
dysfunction leading 
to CHF  
 

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7.1.5 Adverse Event List for Etoposide 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of 
every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea and vomiting 
 
Transient 
hypotension 
during infusion; 
anaphylaxis-
including chills, 
fever, tachycardia, 
dyspnea, 
bronchospasm, 
hypotension 
Prompt: 
Within 2-3 
weeks 
Hair Loss, 
Myelosuppression, 
 
Diarrhea 
Peripheral 
neuropathy 
Delayed/Late:  
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
Secondary cancer 
(leukemia, 
myelodysplasia) 
 
 
7.1.6 Adverse Event List for Intrathecal Cytarabine 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
nausea, vomiting 
headache, CSF 
pleocytosis 
rash, fever, 
drowsiness (L), 
meningisimus, 
seizures (L), paresis 
Prompt: 
Within 2-3 
weeks 
 
 
 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
learning disability  

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7.1.7 Adverse Event List for Intrathecal Hydrocortisone 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
 
headache, CSF 
pleocytosis, nausea, 
vomiting, fever 
rash, somnolence, 
meningisimus, 
seizures (L), paresis 
Prompt: 
Within 2-3 
weeks 
 
 
somnolence, ataxia 
Delayed/Late
: occurring 
anytime later 
during 
therapy or 
after the 
completion of 
treatment 
 
learning disability (L) 
progressive CNS 
deterioration 
 
7.1.8 Adverse Event List for Intrathecal Methotrexate 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
headache, CSF 
pleocytosis 
vomiting, fever, rash, 
somnolence, 
meningisimus, paresis 
Prompt: 
Within 2-3 
weeks 
 
seizures, mucositis 
myelosupperssion, 
somnolence, ataxia 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
learning disability  
Leukoencephalopathy,
progressive CNS 
deterioration 
 
 

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7.1.9 Adverse Event List for Mercaptopurine  
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
 
 
Nausea and vomiting 
Prompt: 
Within 2-3 
weeks 
Myelosuppression, 
Abnormal liver 
function tests 
(transaminities, 
hyperbilirubinemia) 
Hair Loss, 
Mucositis 
 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
 
 
7.1.10 Adverse Event List for Methotrexate (Intravenous) 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Nausea/Vomiting 
(frequent with high 
dose, uncommon with 
low dose) 
 
Seizures (convulsions) 
Blurred vision, 
Headache, altered mental 
status 
Prompt: 
Within 2-3 
weeks 
Mucositis, 
Myelosuppression, 
Liver function test 
abnormalities 
(transaminitis) 
Hair Loss, 
Abnormal kidney 
function 
Rash, 
photophobia 
 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
Learning disabilities, 
Leukoencephalopathy, 
leading to confusion, 
seizueres, mental 
deterioration (can be 
irreversible) 
 
 
 

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7.1.11 Adverse Event List for Prednisone, Prednisolone, Methylprednisolone, 
Dexamethasone 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 
days of 
receiving drug 
insomnia, 
hyperphagia 
gastritis, 
hyperglycemia 
 
Prompt: 
Within 2-3 
weeks 
personality changes, 
adrenal axis 
suppression, acne  
facial erythema, poor 
wound healing, 
infections (bacterial, 
fungal, parasitic, viral), 
edema 
pancreatitis, 
increased intraocular 
pressure, 
hypertension, 
psychosis, vertigo, 
headache  
Delayed/Late:  
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
Cushing syndrome 
(moon facies, truncal 
obesity) 
striae, easy bruising, 
muscle weakness, 
osteopenia, cataracts 
fractures (L), growth 
suppression, peptic 
ulcer and GI 
bleeding, 
pseudotumor cerebri, 
fatty infiltration of 
liver, osteonecrosis  
 
7.1.12 Adverse Event List for Leucovorin 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
 
rash 
Prompt: 
Within 2-3 
weeks 
 
 
 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
 
 
 
 

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7.1.13 Adverse Event List for Vincristine 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 
children out of every 
100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
jaw pain, headache 
extravasation (rare) 
but if occurs can 
lead to local 
ulceration 
Prompt: 
Within 2-3 
weeks 
alopecia, 
constipation 
weakness, abdominal 
pain, mild brief 
myelosuppression 
paralytic ileus, 
ptosis, diplopia, 
night blindness, 
hoarseness, vocal 
cord paralysis, 
SIADH, seizures, 
defective sweating 
Delayed/Late: 
occurring 
anytime later 
during therapy 
or after the 
completion of 
treatment 
loss of deep tendon 
reflexes 
peripheral parasthesias 
(including numbness, 
tingling and pain), 
clumsiness, wrist drop, 
foot drop, abnormal 
gait  
difficulty walking or 
inability to walk, 
sinusoidal 
obstruction 
syndrome (SOS, also 
known as VOD),  
blindness, optic 
atrophy, urinary tract 
disorders (including 
bladder atony, 
dysuria, polyuria, 
nocturia and urinary 
retention), 
autonomic 
neuropathy with 
postural 
hypotension, 8th 
cranial nerve 
(dizziness, 
nystagmus, vertigo 
and hearing loss)   
 
 
 

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7.2 
Dose Modifications/Delays and Toxicity Management 
  
7.2.1 Allowable Dosing Variations/Delays (All Phases) 
7.2.1.1 Allowable Dosing Variation 
Variations in drug dosages within 10% of calculated doses are acceptable to allow for ease of 
drug administration (rounding) and minor changes in BSA/weight.   
 
7.2.1.2 Allowable Deviations in Timing of Therapy 
All attempts should be made to administer therapy and perform procedures on days indicated in 
protocol.  Therapy/procedures may be delayed due to toxicity, as indicated in Dose Modification 
sections.  Delays due to intercurrent illnesses are allowed, but therapy should be re-started as 
soon as possible.  Changes in times of therapy/procedures up to +/- 3 days during Induction, 
Consolidation I, CNS therapy and Consolidation II, and up to +/- 7 days during Continuation, are 
allowed for scheduling reasons (weekends, holidays, and patient or provider availability). If 
longer delays are anticipated for reasons other than severe illness or toxicity, contact Principal 
Investigator or designee for prior approval.   
 
For medications to be given multiple times per day (for example, IV methylprednisolone during 
the Induction Phase), all attempts should be made to administer medications at the intervals 
specified in the protocol.  Variations of   +/- 3 hours from the specified intervals are acceptable 
to allow some flexibility in medication administration given the complex care needs of many 
patients.   
 
If doxorubicin is given by peripheral IV, dexrazoxane may be given immediately after rather 
than prior to doxorubicin.  Goal: no more than 30 minutes duration for administration of both 
doxorubicin and dexrazoxane, regardless of the order in which the medications are given. 
 
High-dose methotrexate infusion is intended to be given over 24 hours.  Variation of +/- 1 hour in 
duration of infusion is allowed to account for variability in pumps and other unavoidable factors.  
For all other chemotherapy infusions (IV Oncaspar, IV SC-PEG Asparaginase, 
Cyclosphosphamide, Etoposide), variation in protocol-specified infusion duration of +/- 15 minutes 
is allowed. 
 
 
7.2.1.3 Allowable Deviation in Route of Administration 
For patients who are unable to receive IV or IM methotrexate during the continuation phase due 
to travel or other unusual circumstances, a dose of methotrexate may be given orally, but no 
more than 3 times over the total duration of treatment. If it is necessary to give methotrexate by 
mouth more than 3 times, the Principal Investigator must be contacted in advance for approval.   
 
For patients unable to tolerate oral dexamethasone during post-induction treatment phases, IV 
dexamethasone may be used (same dose as oral dosing). 
 

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During all phases of therapy, vincristine may be given either by IV push or IV via minibag per 
institutional standard. 
 
7.2.1.4 Allowable Deviation for Bilirubin 
A total bilirubin of < 1.4 mg/dL (23.9 micromoles/L) is sufficient to meet the bilirubin criteria 
for enrollment and starting or continuing a cycle during all phases of treatment. For patients 
receiving Erwinia asparaginase, direct bilirubin may be checked once per week (ie, does not 
need to be checked prior to each dose).  
7.2.2 Allowable Deviations In Therapy Due to Significant Illness 
7.2.2.1 Significant Illness at the end of Induction Therapy 
In some circumstances when patients have severe life-threatening illness (e.g.disseminated 
candidiasis) and are not expected to tolerate myelosuppressive chemotherapy for an extended 
period of time, but are in documented CR at end of remission induction therapy, Consolidation I 
and CNS therapy may be delayed and patients may proceed with less intensive chemotherapy, 
such as vincristine (as dosed in Section 6.8.3.2) or some or all of the agents included in 
Consolidation II or Continuation cycles (Sections 6.14 and 6.15).  Additional post-induction 
agents (e.g. steroid, methotrexate, 6MP, doxorubicin with dexrazoxane) may be added in step-
wise fashion as tolerated.  All such changes must be discussed with and approved by Lewis 
Silverman, MD or designee.  If CNS phase is to be significantly delayed, patients should receive 
IT medications every 9 weeks (if possible) until patient is able to commence with CNS phase.  
Patients should receive Consolidation I and CNS therapy as soon as possible. 
 
7.2.2.2 Significant Illness at the end of Consolidation I  
In some circumstances when patients have severe life-threatening illness and are not expected to 
tolerate intensive chemotherapy for an extended period of time, CNS therapy may be delayed 
and patients may proceed with modified Consolidation II or Continuation cycles, including some 
or all of the agents typically included in those cycles (including vincristine, dexamethasone, 
6MP, methotrexate, and for HR/VHR patients, doxorubicin/dexrazoxane) as dosed in Sections 
6.14 and 6.15.   Agents may be added in subsequent cycles in a step-wise fashion as tolerated.  
Asparaginase may be given, according to randomization; once started it should be continued for 
30 consecutive weeks if tolerated.  All such changes must be discussed with and approved by 
Lewis Silverman, MD or designee.  Patients should receive IT medications every 9 weeks (if 
possible) until able to commence with CNS phase.  Patients should begin CNS phase as soon as 
possible 
   
 
7.2.2.3 Significant Illness During Consolidation I for VHR 
patients 
In circumstances when patients have severe illnesses, and are not expected to tolerate intensive 
chemotherapy for an extended period of time, Cycle IB or IC may be held even if other starting 
criteria are met.  Patients may proceed with modified Consolidation II or Continuation cycles, 

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including some or all of the agents typically included in those cycles (including vincristine, 
dexamethasone, 6MP, methotrexate, and doxorubicin/dexrazoxane) as dosed in Sections 6.14 
and 6.15.   Agents may be added in subsequent cycles in a step-wise fashion as tolerated.  In 
general, asparaginase should not be given until Consolidation IC is administered, but exceptions 
can be made on an individual basis after discussion with Principal Investigator.  All 
modifications must be discussed with and approved by Lewis Silverman, MD or designee.  
Patients should receive IT medications every 9 weeks (if possible) until able to commence with 
Consolidation IB/IC.  All attempts should be made to proceed with Consolidation IB and IC as 
soon as possible.  
 
7.2.2.4 Significant Illness During Consolidation II/Continuation 
In circumstances when patients have severe illnesses, and are not expected to tolerate 
myelosuppressive chemotherapy for an extended period of time, chemotherapeutic medications 
can be held even if other starting criteria are met.  During Consolidation II, all attempts should 
be made to continue asparaginase, unless otherwise contraindicated (See Section 7.2.8.5); if held 
for life-threatening illness, asparaginase should be resumed as soon as possible.  Other agents 
(vincristine, steroid, 6MP, methotrexate, doxorubicin/dexrazoxane, IT chemotherapy) may be 
added back in stepwise fashion as tolerated.  Weekly methotrexate may be substituted for 
doxorubicin in HR/VHR patients, but doxorubicin should be restarted in place of methotrexate as 
soon as possible.  All such modifications must be discussed with and approved in advance by 
Lewis Silverman, MD, or designee.  
 
If a patient has protracted myelosuppression during Consolidation II/Continuation (start of cycle 
delayed > 3 weeks due to low blood counts), vincristine and dexamethasone pulses can be given 
every 3-weeks while awaiting count recovery only with prior approval of Lewis Silverman, MD, 
or designee.  In cases of protracted myelosuppression, a diagnostic marrow aspirate/biopsy is 
recommended prior to initiation of vincristine/dexamethasone pulses. 
 
 
 
 
 
 
 
   
 

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7.2.3 Remission Induction: Dose Modifications 
 
 
 
 
Doxorubicin:  If hyperbilirubinemia at Day 4, see Special Circumstances (Section 6.6) 
 
 
 
 
Prednisone:  All attempts should be made to avoid modifying or holding any doses.  
Medically treat hypertension and ketotic hyperglycemia. 
 
Vincristine: 
All attempts should be made to avoid delaying or modifying dose.  A dose 
of vincristine may be delayed for up to 3 days for ileus, SIADH, vocal 
cord paralysis, cranial neuropathy or life-threatening illness; if 
vincristine dose is held more than 3 days for toxicity, that week’s dose 
should be held altogether and not made up.  After delay or missed dose, 
vincristine should be given at 100% dose (no dose reduction); dose 
reductions are allowed if discussed in advance with Principal 
Investigator or designee. If days of administration are changed, the 
interval between any two vincristine doses should not be less than 6 
days.  If direct bilirubin > 3.0 mg/dl (51.3 micromoles/L), hold dose of 
vincristine. With a bilirubin at this level, it may be allowable under 
certain circumstances to administer vincristine at 50% dose but only 
with prior approval of Principal Investigator. 
 
Methotrexate  Do not give dose if patient has effusions, ascites, other fluid collections, or 
creatinine above normal limits for age.  If hyperbilirubenima at Day 4, see 
Section 6.6 regarding the timing of dose. 
 
 
 
 
Asparaginase:  
 Hold for clinical pancreatitis, deep venous thrombosis.   
 Allergic Reaction to Induction Dose of PEG asparaginase (Oncaspar 
or SC-PEG): Stop infusion for clinical hypersensitivity reaction.  
Patient should be switched to Erwinia asparaginase for all future 
doses of asparaginase (See Section 7.2.8.5) 
 If hypersensitivity reaction occurs within first 30 minutes of 
asparaginase infusion during induction phase, then patient 
should receive four doses of Erwinia twice-weekly during the 
induction phase.  Dose of Erwinia: 25000 IU/m2, given IM.  
First dose of Erwinia should be given sometime between Days 
8-11 of induction, if possible.   
 If hypersensitivity reaction to PEG asparaginase occurs in the at 
or after 30 minutes of the asparaginase infusion has been 
completed, no doses of Erwinia should be given during 
induction phase; Erwinia asparaginase should commence with 
1st post-induction asparaginase dose (CNS Phase for SR/HR 
patients, Consolidation IC for VHR patients). 
 
 

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Intrathecal Therapy: 
 
 If patient has moderate/severe mucositis on Day 18, omit IT 
Methotrexate (give IT cytarabine/hydrocortisone only) 
 Do not hold or modify doses of Intrathecal Cytarabine for mucositis 
or blood counts.  If patient had previous neurologic toxicity 
attributed to intrathecal cytarabine, subsequent doses may be held 
after discussion with Lewis Silverman, MD, or designee. 
 If patient has any mucositis on Day 32, do not perform lumbar 
puncture and do not administer ITM (or proceed to Consolidation I) 
until recovered.  BM aspirate and biopsy may still be performed. 
 
  
 
 
Mucositis Criteria:  
 
 
 Mild = red mucosa - no open ulcers 
 Moderate = open sores, but taking p.o. normally 
 Severe = open sores associated with decreased p.o. and/or increased 
salivation 
 

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7.2.4 Consolidation I (SR/HR) and Consolidation IA (VHR): Dose Modifications 
7.2.4.1 Mucositis:  
 Start of cycle: If mucositis evident prior to beginning Consolidation I, hold start of cycle 
until mucositis has significantly improved or resolved.  If anticipated delay due to 
mucositis is likely to be 7 or more days, may give vincristine 1.5 mg/m2/dose (maximum 
dose 2 mg) IV push or IV via minibag weekly until mucositis resolved  (as long as no 
constipation or significant neuropathy). 
 During cycle: Hold 6 MP for moderate/severe mucositis developing during 
Consolidation I/IA and do not re-start within the cycle.   
7.2.4.2  Creatinine elevated above normal for age:  
If creatinine elevated above upper limit of normal for age prior to start of cycle, hold high dose 
methotrexate.  Proceed with remainder of chemotherapy.  Attempt to give full cycle of 
Consolidation I/IA in 3 weeks if creatinine level has normalized.  If still not normalized, proceed 
to next scheduled phase of chemotherapy.  For patients who do not receive high-dose 
methotrexate during Consolidation I/IA, it may be given during Consolidation II (weekly MTX 
should not be given during a Consolidation II cycle in which HD MTX is given).  Note: High 
dose methotrexate should not be given during Consolidation II if patient has received cranial 
radiation during the CNS phase.   
7.2.4.3 Edema/ascites/effusions:   
If present at start of cycle, and considered significant by treating physician, then high dose 
methotrexate should be held.  Follow guidelines for elevated creatinine (Section 7.2.4.2).   
7.2.4.4 Low Blood Counts:  
Hold 6MP if APC < 500 or platelets < 50K during cycle and do not re-start within the cycle. 
7.2.4.5 Abnormal Liver Function Tests:   
Hold 6MP if SGOT> 8x normal or direct bilirubin >1.4 mg/dL (23.9 micromoles/L), during 
cycle. 
 
7.2.5 Consolidation IB: Dose Modifications (VHR Patients) 
7.2.5.1 Low Blood Counts:   
Hold 6MP if APC < 500 or platelets < 50K during cycle and do not re-start.  Delay cytarabine if 
APC < 500 or platelets < 50K on Day 9 (when 2nd 4-day course is due to begin), and begin this 
4-day course once APC > 500 and platelets > 50K.  Once a 4-day course of cytarabine 
commences, give all 4 doses of that course regardless of blood counts.    If Day 9 cytarabine 
cannot be given within 14 days from when it was initially due because of low blood counts, it 
should be omitted from cycle. 
7.2.5.2 Abnormal Liver Function Tests:   
Hold 6MP if SGOT> 8x normal or direct bilirubin >1.4 mg/dL (23.9 micromoles/L) during cycle 
and do not restart within the cycle.  Hold Day 9 cytarabine if direct bilirubin >1.4 mg/dL (23.9 

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micromoles/L) on the day it is due; administer at full dose once direct bilirubin is < 1.4 mg/dL 
(23.9 micromoles/L).  If Day 9 cytarabine cannot be given within 14 days from when it was 
initially due because of hyperbilirubinemia, it should be omitted from cycle. 
7.2.5.3 Mucositis: 
Hold 6MP for moderate/severe mucositis and do not restart within the cycle.  Hold Day 9 
cytarabine if moderate/severe mucositis on the day it is due; administer at full dose once 
mucositis improves.  If Day 9 cytarabine cannot be given within 14 days from when it was 
initially due because of mucositis, it should be omitted from cycle. 
 
7.2.6 Consolidation IC (VHR Patients) 
7.2.6.1 Etoposide: Slow infusion rate in case of hypotension.  
Premedication with diphenydramine, corticosteroids, and 
acetaminophen allowed if hypersensitivity reaction.  Doses 
can only be held if discussed in advance with Lewis 
Silverman, MD or designee. 
 
7.2.6.2 Asparaginase: For dose modifications due to toxicity, refer 
to Section 7.2.8.5. 
 
7.2.7 CNS Treatment Phase: Dose Modifications 
 
7.2.7.1 Intrathecal medications: 
 
 
 
 
• Attempt to avoid dose reduction by re-evaluating patient in 2-3 days 
 
 
 
 
 
• If APC <500 or PLT <50K and/or moderate mucositis (open sores-red mucosa, but 
taking p.o. normally), decrease methotrexate dose in IT therapy by 50%. 
 
 
 
 
 
• If APC <300 or PLT <25K and/or severe mucositis (decreased p.o. and increased 
salivation, mucosal ulcers), omit IT methotrexate and administer IT cytarabine and 
hydrocortisone  
 
 
 
 
 
• If SGOT > 8 x normal and/or direct bilirubin > 1.4 mg/dL (23.9 micromoles/L): 
omit IT methotrexate and administer IT cytarabine and  hydrocortisone. 
 
7.2.7.2 6- mercaptopurine: 
Hold for APC <500 or PLT <50K, SGOT > 8 x normal, direct bilirubin > 1.4 
mg/dL (23.9 micromoles/L) and/or moderate/severe mucositis (defined in Section 
7.2.3).  Do not restart within cycle once held. 
 
7.2.7.3 Asparaginase:  Refer to Section 7.2.8.5. 

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7.2.7.4  Vincristine:    
•  Hold vincristine for severe constipation or neuropathy that is not responsive to 
maximum supportive care.  
•   Hold vincristine for cranial nerve abnormalities (such as ptosis).   
 
7.2.8 Consolidation II and Continuation Therapy: Dose Modifications 
 
7.2.8.1 Modifications for Blood Counts 
 
Desired Hematologic Nadirs: 
o APC 
500 - 750/mm3, and  
o Platelets 50,000 - 100,000/mm3. 
 
 
 
 
Dose intensity is important and any delays in chemotherapy should be as short as possible. 
 
 
 
If APC < 500 or Platelets < 50,000 during cycle (weeks 2 and 3): 
 
 
 
• Consider holding Trimethoprim/sulfamethoxazole (Bactrim) and/or other potentially 
myelosuppresive, non-chemotherapeutic agents prior to reducing doses of any 
chemotherapy. 
 
 
 
 
• Hold methotrexate and 6-MP for remainder of cycle if APC <500 or platelets < 50,000.  
Do not make up missed doses of methotrexate and 6-MP.  At the start of next cycle, 
consider reducing doses of myelosuppresive chemotherapy.  Suggested adjustments: 
reduce both agents by 20% at start of the next cycle. 
 
• Consider testing for TPMT (thiopurine methyltransferase) activity and/or mutation 
status for patients with excessive or protracted myelosuppression.  If low TPMT 
activity and/or mutation identified, 6MP should be dose-reduced preferentially over 
methotrexate. 
 
  
 
 
 
• It is suggested that Doxorubicin doses should be reduced by 20% only if an initial 
reduction of 6-MP does not prevent further cycles with nadirs that are too low.  If 
doxorubicin is dose-reduced, dexrazoxane should be dose-reduced to keep ratio of 
dexrazoxane:doxorubicin = 10:1.  Doxorubicin Dose may be reduced by 20% only 
once!  There are no further dose reductions of doxorubicin if patient is already 
receiving 80% dose doxorubicin.   
  
 
 
 
• Asparaginase should be given regardless of blood counts. 
 
 
If APC<750 or platelets <75 K when cycle is due: 
 

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• Consider holding Trimethoprim/sulfamethoxazole (Bactrim) and/or other potentially 
myelosuppresive, non-chemotherapeutic agents prior to reducing doses of any 
chemotherapy. 
 
 
 
 
 
• Hold all chemotherapy except asparaginase until criteria are met to start cycle.  At the 
start of next cycle, consider reducing the doses of myelosuppressive chemotherapy.  
Suggested adjustments: reduce methotrexate, 6MP, and/or doxorubicin as above.   
 
 
 
 
• It is suggested that Doxorubicin doses should be reduced by 20% only if appropriate 
reduction of 6-MP does not prevent delayed cycles or nadirs that are too low.  If 
doxorubicin is dose-reduced, dexrazoxane should be dose-reduced to keep ratio of 
dexrazoxane: doxorubicin = 10:1.  Doxorubicin Dose may be reduced by 20% only 
once!  There are no further dose reductions of doxorubicin if patient is already 
receiving 80% dose doxorubicin.   
  
 
 
 
• Asparaginase should be given regardless of blood counts. 
 
  
If nadirs too high: Consider dose escalation of 6MP/methotrexate (doxorubicin should 
not be dose-escalated). 
 
 
 
• Suggested dose escalation: Increase dosages of methotrexate and 6-mercaptopurine in 
20% increments according to patient tolerance.  Consider escalating only agent per 
cycle, alternating which agent is escalated in successive cycles.   
 
 
 
• Dosages of 6-MP should not exceed 150% (75 mg/m2/day for 14 days). 
 
 
 
• Maximum weekly dose of methotrexate: 
 - Standard Risk and non-irradiated High Risk: 150% dose (45 mg/m2/dose) 
 - High Risk with prior cranial radiation and all Very High Risk: 133% dose (40 
mg/m2/dose)  
 If Doxorubin was previously reduced, dose may be escalated back to 100% if nadirs 
exceed goal nadirs.  Doxorubicin dose should not exceed 100% (30 mg/m2/dose). 
 
7.2.8.2 Abnormal LFT's:   
 
 
 
• Hold start of cycle if SGOT (AST) >8 times normal or direct bilirubin >1.4mg/dl (23.9 
micromoles/L).  Begin cycle when levels have fallen below these values. (SGPT/ALT 
is not a criterion) 
•    Suggested dose adjustment of chemotherapy for abnormal LFT’s: 
• high risk/very high risk patients (Consolidaton II): reduce 6-MP by 20%.  If 
elevation of SGOT/direct bilirubin recurs, then reduce doxorubicin by 20%.  If 
doxorubicin is dose-reduced, dexrazoxane should be dose-reduced to keep ratio 
of dexrazoxane: doxorubicin = 10:1. Doxorubicin Dose may be reduced by 
20% only once!  There are no further dose reductions of doxorubicin if patient is 
already receiving 80% dose doxorubicin.  If elevation of SGOT/direct bilirubin 
recurs with 80% dose doxorubicin, continue to reduce doses of 6-MP with 
subsequent cycles by 20% each cycle. 
• standard risk patients (Consolidation II): reduce methotrexate by 20%.  If 
elevation of SGOT/direct bilirubin recurs, then reduce 6-MP by 20% with 

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subsequent cycles.  Alternate 20% reductions of methotrexate and 6-MP with 
subsequent cycles if elevation of SGOT/direct bilirubin recurs. 
• continuation therapy (all patients): same as standard risk patients during 
intensification (above). 
• Consider Re-escalation of chemotherapy as tolerated if LFTs remain within 
normal range on dose-reduced chemotherapy after 1 or more cycles (suggested 
escalation by 20% increments). 
 
 
 
• If SGOT (AST) >8 times normal or a direct bilirubin >1.4mg/dl (23.9 micromoles/L), 
during cycle, hold 6-MP and methotrexate.  These drugs may be resumed during the 
same cycle or at the start of the next cycle when levels have fallen below these values.   
Do not make up missed doses.  Consider dose reductions when agents are resumed.  
Suggested adjustments: reduce doses of these agents as suggested above when they are 
resumed (and reduce doxorubicin at the start of then next cycle if patient receiving this 
agent).  Do not make up missed doses of 6MP/methotrexate.  
 •    Asparaginase should be given regardless of SGOT (AST).  Hold asparaginase if 
direct bilirubin is > 1.4 mg/dL (23.9 micromoles/L).  Restart asparaginase without 
dose modification once direct bilirubin is < 1.4 mg/dL (23.9 micromoles/L).   
7.2.8.3  Mucositis 
  
mild = red mucosa - no open ulcers 
 
 
 
moderate = open sores, but taking p.o. normally 
 
 
 
severe = open sores associated with decreased p.o. and/or increased salivation 
 
 
 
 
 
 
 
•  Hold start of cycle for moderate/severe mucositis.  When mucositis resolves, begin 
cycle, consider reducing doses of methotrexate/6-MP/doxorubicin as suggested above 
for abnormal LFTs (depending on risk group and phase of therapy). 
 
 
 
• Hold week 2 or 3 methotrexate for moderate/severe mucositis.  Restart when mucositis 
resolves. May restart during the same cycle or at the next of the cycle.  Consider 
reducing doses when methotrexate restarted (suggested: 20% dose reduction). Do not 
make up missed doses of methotrexate. 
 
 
 
• Hold 6-MP for severe mucositis. Restart when mucositis resolves. May restart during 
the same cycle or at the start of the next cycle.  Consider reduced doses when restarting 
(suggested: 20% dose reduction). Do not make up missed doses of 6-MP. 
•    If patient has recurrent mouth sores, consider evaluation for HSV and prophylactic 
acyclovir. 
 
 
 
7.2.8.4  Cardiac Studies 
 
 
 
• Hold doxorubicin if patient has symptomatic congestive heart failure.  Do not restart. 
 
 
 
• Asymptomatic echocardiographic changes (eg, decreased shortening fraction or 
ejection fraction): Call Principal Investigator, Lewis Silverman, MD or designee to 
discuss management.  Doxorubicin may be held for asymptomatic abnormal 
echocardiogram after discussion with Principal Investigator or designee, and may be 
restarted if shortening fraction or ejection fraction improves. 
 
7.2.8.5 Asparaginase 

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• Patient should be observed after asparaginase dose as per institutional practice for 
possible allergic reaction. 
 
 
 
• Clinical Hypersensitivity: Symptoms may include rash, urticaria, lip/tongue swelling, 
respiratory symptoms, wheezing, hypotension 
 
 
 
 
 
For any clinical hypersensitivity reaction to SC-PEG asparaginase or 
Oncaspar: 
Switch to twice-weekly Erwinia IM (intramuscular).  Dose of Erwinia: 25,000 
IU/m2 IM twice weekly.  
 If a patient is unable to tolerate Erwinia IM due to behavioral issues or pain 
related to frequent IM injections, Erwinia IV (intravenous) may be administered. 
Dose of IV Erwinia: 25,000 IU/m2 IV 3x/ week (Monday, Wednesday, Friday), 
infused in 100 mL of normal saline over 1 hour. Once a patient has switched to 
IV Erwinia, they may not be switched back to IM Erwinia The first dose of IM 
Erwinia should be administered approximately one week (or as soon as 
feasible) after the dose of Oncaspar or SC-PEG that caused the 
hypersensitivity reaction.  
 A PK sample should be obtained on the day of the first Erwinia dose, just prior to 
administration. Additional PK samples and antibody samples will not be 
collected for patients once they switch to Erwinia.  
 If Erwinia dose is held or delayed, the PK should be collected prior to the correct 
corresponding asparaginase dose number (not by the week number). 
 Direct bilirubin should be checked once per week in patients receiving Erwinia 
asparaginase.  Bilirubin does not need to be checked prior to each dose of 
Erwinia. 
 Calculation of number of doses of Erwinia to be given: 
o For patients randomized to IV SC-PEG (intended to receive 10 post-
induction doses of SC-PEG):  6 doses ( 3 weeks) of IM Erwinia (given 
twice-weekly) replaces each dose of IV SC-PEG 
 Total # IM Erwinia doses to be administered= 6 x total # of 
remaining post-induction doses of SC-PEG the patient would have 
received (ie, 10 minus the # doses of post-induction SC-PEG 
doses that a patient has already received) 
 For IV Erwinia: 9 doses given 3 x weekly in 100 mL of 
normal saline over 1 hour (3 weeks) replace each dose of 
IV SC-PEG.  Total # IV Erwinia doses to be 
administered= 9 x total # of remaining post-induction 
doses of SC-PEG the patient would have received (ie, 10 
minus the # doses of post-induction SC-PEG doses that a 
patient has already received) 
 Note: Be sure to take into account the IM Erwinia doses 
and subtract them when doing the calculation of number of 
doses of IV Erwinia to be given. 
 
 

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o For patients randomized to IV Oncaspar (intended to receive 15 post-
induction doses of Oncaspar): 4 doses (2 weeks) of IM Erwinia (given 
twice-weekly) replaces each dose of IV Oncaspar 
 Total # IM Erwinia doses= 4 x total # of remaining post-induction 
doses of Oncaspar the patient would have received (15 minus the 
# doses of post-induction Oncaspar doses that a patient has 
already received) 
 For IV Erwinia: 6 doses give 3x weekly in 100 mL of 
normal saline over 1 hour (2 weeks) replace each dose of 
IV Oncaspar. Total # Erwinia doses= 6 x total # of 
remaining post-induction doses of Oncaspar the patient 
would have received (15 minus the # doses of post-
induction Oncaspar doses that a patient has already 
received) 
 Note: Be sure to take into account the IM Erwinia doses 
and subtract them when doing the calculation of number of 
doses of IV Erwinia to be given. 
 
o If hypersensitivity reaction to SC-PEG or Oncaspar occurred within first 
30 minutes of infusion, that dose is not included in the total # of post-
induction asparaginase doses a patient has already received 
o If hypersensitivity reaction to SC-PEG or Oncaspar occurred 30 minutes 
or more after the infusion began, then that dose should be counted as an 
administered post-induction dose when calculating the # of post-induction 
asparaginase doses a patient has already received.  
 If patient develops clinical hypersensitivity to Erwinia, asparaginase is 
discontinued 
 If Erwinia is unavailable, asparaginase is discontinued.   
 
 
 
 
Silent Allergy:  If after the first post-induction dose of asparaginase is administered 
(during Consolidation IC, CNS or Consolidation II), patient has 2 consecutive NSAA 
levels that are non-detectable (<0.025 IU/mL), then patient will be considered to have 
silent inactivation and will be switched to twice-weekly IM Erwinia asparaginase.   
IM Erwinia should be administered as described above for patients with clinical 
hypersensitivity.  The first dose of Erwinia IM should be administered 
approximately one week (or as soon as feasible) after the last dose of asparaginase. 
 
Note: A non-detectable pre-dose level will only be considered to be consistent with silent 
inactivation if the level was obtained prior to an asparaginase dose which had been 
administered without any delay from protocol-proscribed intervals (ie, 2-weeks between 
Oncaspar doses and 3-weeks between SC-PEG doses).  Levels that are obtained more than 
3 days after proscribed intervals may not be used for determination of silent inactivation. 
 
 

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Inform pharmacy at time of allergic reaction that preparation will be 
switched with the next dose of asparaginase. A PK sample should be obtained on 
the day of the first IM Erwinia dose, just prior to administration.  Additional PK 
samples will not be collected for patients once they switch to Erwinia. 
 
Calculation of number of doses of Erwinia to be given for patients with silent allergy: 
 The goal is for patients to receive a total of 30 weeks of asparaginase depletion during 
post-induction therapy. 
 If patients have never had any detectable nadir asparaginase activity levels after post-
induction treatment doses, then they should receive 30 weeks of Erwinia asparaginase 
after silent allergy/inactivation is identified. 
 If patient had detectable nadir asparaginase activity levels after post-induction doses of 
either Oncaspar or SC-PEG prior to the development of silent allergy/inactivation, then 
those doses may be counted as “effective” asparaginase doses, and the number of weeks 
following those doses should be taken into account when determining how many weeks 
of Erwinia asparaginase should be given to total 30 weeks.  For instance: 
o If 2 weeks after the 1st post-induction dose of Oncaspar, patient had a detectable 
nadir asparaginase activity level, but then did not have any detectable nadir levels 
after subsequent doses, then the patient should receive 28 weeks of Erwinia 
asparaginase (30 total weeks-2 weeks of “effective” asparaginase after the first 
dose of Oncaspar) 
o If 3 weeks after the 1st post-induction dose of SC-PEG, patient had a detectable 
nadir asparaginase activity level, but then did not have any detectable nadir levels 
after subsequent doses, then the patient should receive 27 weeks of Erwinia 
asparaginase (30 total weeks-3 weeks of “effective” asparaginase after the first 
dose of SC-PEG) 
 
  
 
 
If Erwinia is used after determination of silent inactivation, give 25,000 IU/m2 
IM twice weekly to complete 30 weeks of asparaginase therapy. 
 If clinical hypersensitivity reaction develops to Erwinia, asparaginase is 
discontinued. 
 If Erwinia is unavailable, asparaginase is discontinued.   
IV Erwinia (3x/week) may be used instead of IM Erwinia if patient unable to 
tolerate IM injections to due behavioral problems or pain, as described above for 
clinical hypersensitivity. Give 25,000 IU/ m2 IV 3x/week to complete 30 weeks of 
asparaginase therapy. Infuse IV Erwinia in 100 mL of normal saline over 1 hour. 
 
 
 
 
• CNS events (bleed, thrombosis, infarction): Hold asparaginase.  Resume when all 
clinical symptoms have resolved (and evidence of recanalization on CT/MRI in case 
of thrombus).  In cases of significant CNS events, asparaginase may be permanently 
held after discussion with Dr. Lewis Silverman or designee.  See Section 19.2. 
 
 
 
• Deep vein thrombosis: Hold asparaginase. Begin treatment with anticoagulant 
medication.  Resume asparaginase after coagulation status stabilized and clinical 
symptoms have resolved.  If recurrent DVT on anticoagulation after restarting 
asparaginase, hold permanently.  See Section 19.2. 

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• Lipemic Blood: Triglyceride levels do not need to be routinely followed for 
patients receiving asparaginase.  If triglyceride levels are monitored, fasting levels 
are preferable. Hold asparaginase if a patient is found to have a triglyceride level 
>2000 mg/dl (>22.8 mmol/L).  When triglyceride level drops below this level, 
resume 
asparaginase 
therapy 
without 
dose 
modification. 
For 
recurrent 
hypertriglyceridemia, lipid-lowering agents may be used at discretion of treating 
clinician. 
 
 
 
• Severe pancreatitis (abdominal pain with amylase or lipase elevation above 
institutional normal limits for >72 hours duration and/or development of pancreatic 
pseudocyst or life-threatening complication): Permanently stop asparaginase. 
 
 
 
• Mild to moderate pancreatitis (defined as abdominal pain of <72 hours duration with 
amylase and/or lipase elevation):  Hold asparaginase.  Resume when signs, 
symptoms and laboratory values return to baseline.  Asparaginase may be 
discontinued after recurrent episodes of mild/moderate pancreatitis.  Please call 
Principal Investigator, Lewis Silverman, MD or designee to discuss.   
 
 
 
• Asymptomatic hyperamylasemia (for patients with amylase elevation >3x upper 
limit of normal, but no abdominal pain): If no concurrent cranial radiation, hold 
asparaginase for elevated amylase level (>3 X normal), and resume when level 
normalizes.  For patients receiving cranial radiation, check lipase level if amylase is 
elevated but patient is asymptomatic; if lipase elevated above normal, hold 
asparaginase.  Resume when laboratory values normalize.  If lipase within normal 
limits when patient is receiving cranial radiation, do not hold asparaginase. 
               •   Elevated Direct bilirubin: Hold asparaginase if direct bilirubin is > 1.4 mg/dl (23.9 
micromoles/L). Restart asparaginase without dose modification once direct bilirubin 
is <1.4 mg/dl (23.0 micromoles/L). 
•  Asparaginase Intolerance: For patients who are unable to receive more than 10 weeks 
of asparaginase (due to allergy to all preparations, severe or recurrent pancreatitis, 
other severe toxicities): 
1. Standard Risk patients at the start of the next 3-week cycle, patient should 
receive 3 cycles of High Risk Consolidation II chemotherapy  (that is, three cycles 
with doxorubicin + dexrazoxane instead of weekly methotrexate, higher dose 
dexamethasone, as well as vincristine and 6MP), so that cumulative dose 
doxorubicin is 150 mg/m2 +/- 15 mg/m2 then proceed to Continuation Therapy.   
Dexrazoxane should be given prior to doxorubicin, as specified in High risk 
Consolidation II chemotherapy. 
2. High Risk/Very High Risk patients: Hold asparaginase.  Continue 
Consolidation II chemotherapy until completion of doxorubicin (300 mg/m2 +/- 15 
mg/m2) and 10 post-induction chemotherapy cycles with high dose dexamethaone 
(18 mg/m2/day x 5 days), then proceed to Continuation Therapy. 
 
7.2.8.6  Vincristine 
 
 
 
• Hold vincristine for severe constipation or neuropathy that is not responsive to 
maximum supportive care. Suggested guidelines for reintroducing vincristine: Re-
introduce at 50% dose when patient is improved, and escalate in 25% increments to 
100% dose as tolerated. 

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•   Hold vincristine for cranial nerve abnormalities.  Reintroduce when improved or 
resolved.  Suggested guidelines for reintroducing vincristine as above.  
 
• For mild neuropathy (such as gait abnormalities or parasthesias), vincristine may be 
dose-reduced instead of held, as per discretion of treating physician.  Attempt to 
dose escalate when symptoms improve. 
 If direct bilirubin > 3.0 mg/dl (51.3 micromoles/L), hold dose of vincristine. With a 
bilirubin at this level, it may be allowable under certain circumstances to administer 
vincristine at 50% dose but only with prior approval of Principal Investigator. 
 
 
7.2.8.7 Dexamethasone 
   
 
 
 
• Severe steroid withdrawal symptomatology (myalgias, arthralgias, etc) may   be 
treated with a taper. Total dose of steroid received per cycle (including taper) should 
not exceed total dose indicated in protocol (that is 5-day total of steroid).  Suggested 
initial taper: use a 4-day full course followed by 2-3 day rapid taper.  For severe 
withdrawal symptomatology in HR/VHR patients that persists despite taper and pain 
medications, lower (SR) dosing of dexamethasone (6 mg/m2/day, with ot without 
taper) during Consolidation II may be used at discretion of treating clinician.  
 
 
 
• For symptomatic avascular necrosis (osteonecrosis), permanently stop steroids.  
Steroids should only be discontinued in patients who have both symptoms (eg, bone 
or joint pain) with confirmatory radiographic findings (eg, plain film, MRI).  
Steroids should not be permanently discontinued for asymptomatic radiographic 
changes found incidentally on radiographic studies unless approved in advance by 
Principal Investigator. 
 
 
 
• For bone fractures, hold corticosteroid until fractures are healed, then resume 
without dose modification.  Do not make up missed doses.  Healing may be 
documented by radiographic changes, symptomatic improvement or clearance by an 
orthopedist.  For vertebral compression fractures or other fractures for which healing 
is not easily documented by radiographs, resolution of symptoms (eg, pain) may be 
used as a sign of healing.  
•  Steroids may be held at discretion of treating physician after episode of pancreatitis. 
All attempts should be made to reintroduce steroids as soon as possible.  Do not 
make up missed doses. 
•  For HR/VHR patients who experience severe behavioral or mood changes during 
Consolidation II, dose reduction to SR dose is allowed.   For severe behavioral or 
mood changes for patients receiving SR dose of corticosteroids, corticosteroids may 
be stopped or given less frequently only after discussion with Lewis Silverman, MD 
or designee. 
•  Rarely, preparation may be changed to prednisone for intolerable side effects.  If 
changed, change preparation as follows:  
 If patient receiving dexamethasone 6 mg/m2/day, change to prednisone 40 
mg/m2/day divided twice daily for five days on week 1 of each cycle. 
 If patient receiving dexamethasone 18 mg/m2/day, change to prednisone 120 
mg/m2/day divided twice daily for five days on week 1 of each cycle.   

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Principal Investigator or designee must be contacted for prior approval of such a 
change. 
 
7.2.8.8  IT Chemotherapy 
•  IT chemotherapy may be modified or held in case of seizures (attributable to prior IT 
chemotherapy), leukoencephalopathy, or other significant neurologic complications.  
IT methotrexate may be held (IT ara-C/hydrocortisone given instead) or all IT 
chemotherapy may be delayed or held for such conditions.  All such changes in IT 
chemotherapy must be discussed in advance with Principal Investigator, Lewis 
Silverman, MD, or designee. 
 
 

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8. DRUG FORMULATION AND ADMINISTRATION  
8.1 
Asparaginase: Calaspargase Pegol  
(SC-PEG E. coli L-asparaginase, EZN-2285) IND# 100594 (05/19/10) 
Source and Pharmacology: Calaspargase Pegol is a modified version of the enzyme E. coli-L-
asparaginase. EZN- 2285 is a conjugate of L-asparaginase with numerous molecules of SC 
monomethoxypolyethylene glycol (SC-PEG) with a molecular weight of approximately 5,000 
daltons. For Calaspargase Pegol, the PEG is covalently attached to the epsilon-amino acid side 
chains of the lysines in L-asparaginase. L-asparaginase is an enzyme composed of four identical 
subunits with one active site per tetramer. For Calaspargase Pegol, the linkage is a urethane 
bond, which is a more stable linkage compared with the less stable ester bond found in 
Oncaspar®. L-asparagine is a nonessential amino acid synthesized by the transamination of L-
aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to 
synthesize asparagine is notably lacking in malignancies of lymphoid origin. Asparaginase 
depletes L-asparagine from leukemic cells (especially lymphoblasts) by catalyzing the 
conversion of L-asparagine to aspartic acid and ammonia. Recently, an additional indirect 
mechanism of action of L-asparagine has been suggested. According to this mechanism 
asparaginase may reduce the levels of plasma albumin and other serum proteins which are 
responsible for clearance of lipids and therapeutic corticosteroids. This may in turn result in 
enhanced corticosteroid exposure.  
 
There is limited information from pharmacokinetic studies of Calaspargase Pegol in humans. 
Animal data show comparable kinetics to pegaspargase (Oncaspar®). The following information 
pertains to pegaspargase (Oncaspar®) for reference: In predominately L-asparaginase naive adult 
patients with leukemia and lymphoma, initial plasma levels of L-asparaginase following 
intravenous administration of pegaspargase were determined. Apparent volume of distribution 
was equal to estimated plasma volume. L-asparaginase was measurable for at least 15 days 
following the initial treatment with pegaspargase. The approximate t½ in adult patients is 5.73 
days. The enzyme could not be detected in the urine. The half-life is independent of the dose 
administered, disease status, renal or hepatic function, age, or gender. In a study of newly 
diagnosed pediatric patients with ALL who received either a single intramuscular injection of 
pegaspargase (2,500 IU/m2), E. coli L-asparaginase (25,000 IU/m2), or Erwinia (25,000 IU/m2), 
the plasma half-lives for the three forms of L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 
days, and 0.65 ± 0.13 days, respectively. The plasma half-life of pegaspargase is shortened in 
patients who are previously hypersensitive to native L-asparaginase as compared to non-
hypersensitive patients. L-asparaginase is cleared by the reticuloendothelial system and very 
little is excreted in the urine or bile. Cerebrospinal fluid levels are < 1% of plasma levels. 
 
Children’s Oncology Group Study AALL07P4 compared the pharmacokinetics of Calaspargase 
Pegol and Oncaspar®. Data from the first 18 pharmacokinetics-evaluable patients that received 
Calaspargase Pegol at 2500 IU/m2 (n=11) or Oncaspar® at 2500 IU/m2 (n=7) showed a similar 
Cmax for Calaspargase Pegol and Oncaspar® (1604 ± 257 mIU/mL and 1406 ± 220 mIU/mL, 
respectively). The half-life of Calaspargase Pegol (12.65 ± 2.9 days [results from only 9 
patients]) and the half-life of Oncaspar® (4.85 ± 1.1 days) suggested that at the same dose of 
2500 IU/m2 for both drugs, Calaspargase Pegol is associated with a more prolonged exposure to 
asparaginase than Oncaspar®. 

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Formulation and Stability: Calaspargase Pegol is supplied as an isotonic sterile solution in 
phosphate-buffered saline, pH 7.3, for injection only. The solution is clear, colorless, and 
contains no preservatives. Calaspargase Pegol is supplied in single-use vials. Calaspargase Pegol 
activity is expressed in international units (IU). One IU of L-asparaginase is defined as that 
amount of enzyme required to generate 1 μmol of ammonia per minute at pH 7.3 and 37oC. Each 
single-use vial contains 3,750 IU/5 mL (750 IU/mL). Each milliliter of Calaspargase Pegol 
contains: SC-PEG E. coli L-asparaginase 750 IU, Monobasic sodium phosphate, USP,1.29 mg, 
Dibasic sodium phosphate, USP, 5.58 mg, Sodium chloride, USP 8.5 mg, Water for injection, 
USP qs to1 mL. Store refrigerated at +2°C to +8ºC (36°F to 46°F). Use only one dose per vial; 
do not re-enter the vial. 
Discard unused portions. Do not save unused drug for later administration. 
 
Do not use Calaspargase Pegol  (SC-PEG asparaginase) if the drug: 
 Has been frozen. 
 The infusion bag has been stored at room temperature for more than 48 hours 
or at 4°C 
 (39°F) for more than 72 hours. 
 Has been shaken or vigorously agitated. 
 Is cloudy or discolored, or precipitate is present. 
 
Do not use Calaspargase Pegol if the vial has been stored at room temperature (+15°C to +25°C; 
59°F to 77°F) for more than 48 hours. If, during refrigerated storage, the storage temperature 
deviates from +2°C to +8ºC (36°F to 46°F), the affected product should be immediately removed 
from inventory and placed into refrigerated quarantine. The sponsor or its designee should be 
contacted immediately and provided with the storage temperature records covering the entire 
period of time the storage temperature deviated outside the prescribed range. Upon review of the 
storage temperature records provided by the study site, a determination of Calaspargase Pegol 
stability disposition will be made by the sponsor or its designee. Quarantined Calaspargase Pegol 
must not be administered to participants until such time that the sponsor or its designee provides 
written documentation that the product’s stability was not affected by the temperature deviation. 
If it is determined that the stability of the quarantined product was affected, arrangements must 
be made to replace the inventory at the site and for the return of the quarantined product for 
destruction.  
 
Prior to administration, dilute Calaspargase Pegol by adding the dose to a 100 mL bag of 0.9% 
Sodium Chloride Injection, USP (normal saline, NS). Calaspargase Pegol should not be prepared 
in Dextrose 5% in Water (D5W). Avoid excessive agitation; do not shake. Calaspargase Pegol 
diluted in NS is stable for up to 48 hours at room temperature and for up to 72 hours at 4oC. 
Calaspargase Pegol vial contains no preservatives and as with all parenteral drug products, 
aseptic technique should be used during the preparation of the diluted solution. The expiration 
time of Calaspargase Pegol should be determined by the local institution guidelines for 
compounding sterile products and may be shorter, but must not exceed, the times listed for 
stability. 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
For IV administration: Calaspargase Pegol, diluted in a 100 mL NS bag, should be given through 
a running infusion line over a period of 1 hour. Avoid excessive agitation. DO NOT SHAKE. Do 

Protocol 11-001 
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114
not use if cloudy or if precipitate is present. Although Calaspargase Pegol should be prepared in 
an infusion bag containing NS, Calaspargase Pegol may be administered through an intravenous 
line that is running D5W or NS. While compatibility with a combination of NS and D5W has not 
been tested, the combination is expected to be acceptable as well. Calaspargase Pegol is also 
compatible with lines containing sodium bicarbonate. No compatibility studies of Calaspargase 
Pegol and total parenteral nutrition (TPN) or antibiotics have been conducted, and therefore 
Calaspargase Pegol should not be mixed with TPN or antibiotics. Also, co-administration with 
allopurinol or rasburicase should not occur as there have been no compatibility studies conducted 
with Calaspargase Pegol. No in-line filter is required for Calaspargase Pegol administration. 
Serious allergic reactions can occur in patients receiving Oncaspar® and are presumed to occur 
with Calaspargase Pegol. The risk of serious allergic reactions is higher in patients with known 
hypersensitivity to other forms of L-asparaginase. Have available during and after the infusion: 
Antihistamine, Epinephrine, Oxygen, IV Corticosteroids and IV Fluids. Observe patient for ONE 
hour after administration for signs of hypersensitivity reactions. 
Supplier: To be supplied by Sigma-Tau Pharmaceuticals, Inc. Order Forms, Return Forms, and 
Drug Accountability Forms and directions are available in the Pharmacy Manual.  
 
8.2 
Asparaginase: Pegasparagase (PEG-asparaginase, Oncaspar®,) NSC #624239  
Source and Pharmacology: Pegaspargase is a modified version of the enzyme L-asparaginase. 
Lasparaginase is modified by covalently conjugating units of monomethoxypolyethylene glycol 
(PEG), molecular weight of 5,000, to the enzyme, forming the active ingredient PEG-L-
asparaginase. The Lasparaginase (L-asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in 
the manufacture of Pegaspargase is derived from Escherichia coli. L-asparagine is a nonessential 
amino acid synthesized by the transamination of L-aspartic acid by a reaction catalyzed by the 
enzyme L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in 
malignancies of lymphoid origin. Asparaginase depletes L-asparagine from leukemic cells 
(especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic acid and 
ammonia. In predominately L-asparaginase naive adult patients with leukemia and lymphoma, 
initial plasma levels of L-asparaginase following intravenous administration of pegaspargase 
were determined. Apparent volume of distribution was equal to estimated plasma volume. L-
asparaginase was measurable for at least 15 days following the initial treatment with 
Pegaspargase. The approximate t½ in adult patients is 5.73 days. The enzyme could not be 
detected in the urine. The half-life is independent of the dose administered, disease status, renal 
or hepatic function, age, or gender. In a study of newly diagnosed pediatric patients with ALL 
who received either a single intramuscular injection of pegaspargase (2,500 IU/m2 ), E. coli L-
asparaginase (25,000 IU/m2 ), or Erwinia (25,000 IU/m2 ), the plasma half-lives for the three 
forms of L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days, 
respectively. The plasma half-life of pegaspargase is shortened in patients who are previously 
hypersensitive to native L-asparaginase as compared to non-hypersensitive patients. L-
asparaginase is cleared by the reticuloendothelial system and very little is excreted in the urine or 
bile. Cerebrospinal fluid levels are < 1% of plasma levels. 
Formulation and Stability: Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 
IU ± 20%, monobasic sodium phosphate, USP 1.20 mg ± 5 % dibasic sodium phosphate, USP 
5.58 mg ± 5%, sodium chloride, USP 8.50 mg ± 5%, water for injection, USP qs to 1.0 mL. The 
specific activity of pegaspargase is at least 85 IU per milligram protein. Available in 5 mL vials 
as sterile solution for injection in ready to use single-use vials, preservative free. Keep 

Protocol 11-001 
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refrigerated at 2°C to 8°C (36°F to 46°F). Do not use if stored at room temperature (+15°C to 
+25°C; 59°F to 77°F) for more than 48 hours. DO NOT FREEZE. Do not use product if it is 
known to have been frozen. Freezing destroys activity, which cannot be detected visually. If, 
during refrigerated storage, the storage temperature deviates from +2°C to +8°C (36°F to 46°F), 
the affected product should be immediately removed from inventory and should not be used.  
Prior to administration, dilute pegaspargase by adding the dose to a 100mL bag of 0.9% Sodium 
Chloride Injection, USP (normal saline, NS). Avoid excessive agitation; do not shake. 
Pegasparagase diluted in NS is stable for up to 48 hours at room temperature (15°C to 25°C; 
59°F to 77°F) and for up to 72 hours at 4oC (39°F). Pegaspargase vial contains no preservatives 
and as with all parenteral drug products, aseptic technique should be used during the preparation 
of the diluted solution. The expiration time of pegaspargase should be determined by the local 
institution guidelines for compounding sterile products and may be shorter than the times listed 
for stability. 
Guidelines for Administration: For IV administration: pegaspargase, diluted in a 100 mL NS 
ba, should be given through a running infusion line over a period of 1 hour. Avoid excessive 
agitation. DO NOT SHAKE. Do not use if cloudy or if precipitate is present. Although 
pegaspargase should be prepared in an infusion bag containing NS, it may be administered 
through a venous line that is running D5W or NS. While compatibility with a combination of NS 
and D5W has not been tested, the combination is expected to be acceptable as well. 
Pegaspargase is also compatible with lines containing sodium bicarbonate. No compatibility 
studies of pegaspargase and total parenteral nutrition (TPN) or antibiotics have been conducted, 
and therefore pegaspargase should not be mixed with TPN or antibiotics. Also, co-administration 
with allopurinol or rasburicase should not occur as there have been no compatibility studies 
conducted with pegaspargase. 
 
Have available during and after the infusion: Antihistamine, Epinephrine, Oxygen, IV 
Corticosteroids and IV Fluids. Because pegaspargase is long acting, hypersensitivity reactions 
may not appear for hours after drug administration. Observe patient after administration for signs 
of hypersensitivity reactions. 
Supplier: Pegaspargase (Oncaspar®) is commercially available from Sigma-Tau 
Pharmaceuticals, Inc. (Sigma-Tau) and can be purchased through the usual ordering channels 
(wholesalers).  
8.3 
Asparaginase: Erwinia  
(Erwinaze®,Erwinia chrysanthemi, Erwinase®, Crisantaspase)  
Source and Pharmacology: L-asparagine is a nonessential amino acid synthesized by the 
transamination of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. 
Erwinia L-asparaginase is asparaginase obtained from cultures of Erwinia chrysanthemi (E. 
carotovora). Lymphoblastic neoplastic cells are asparagine-dependent. Reduction of plasma 
asparagine levels achieved by administration of L-asparaginase produces an anti-neoplastic 
effect. Peak levels of Erwinia L-asparaginase are achieved in the blood 1 to 2 hours after IM 
administration. The fall in enzyme levels follows first order kinetics with a half-life of 7 to 13 
hours. L-asparaginase is cleared by the reticuloendothelial system and very little is excreted in 
the urine or bile. Cerebrospinal fluid levels are < 1% of plasma levels. 
 
Erwinia L-asparaginase is immunologically distinct from E. coli L-asparaginase and may allow 

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continued asparaginase therapy when a hypersensitivity reaction occurs to the Escherichia coli 
source of  asparaginase. Patients may still sustain a hypersensitivity reaction to the substitute; 
however, most (more than 75%) do not and can complete the planned therapy. 
 
Formulation and Stability: Erwinaze is supplied as a sterile, white lyophilized powder for 
reconstitution.  Each single vial contains 10,000 International Units (IU) of asparaginase Erwinia 
chrysanthemi in Type 1 clear neutral glass vials of 3 mL nominal capacity, closed with 13 mm 
halobutyl freeze-drying stoppers and aluminum over seals. Unopened vials should be protected 
from light and stored between 2°C and 8°C (36°-46ºF). The product is stable for 4 hours after 
reconstitution either into a syringe for IM administration or in an IV bag. 
 
Guidelines for Administration:  The contents of each vial should be reconstituted by adding 1 
mL or 2 mL of preservative free 0.9% sodium chloride to the vial containing 10,000 IU of 
asparaginase Erwinia chrysanthemi for Injection.  The contents of the vial should be dissolved by 
gentle mixing or swirling. When the 10,000 International Unit vial is reconstituted with 1 mL of 
0.9% sodium chloride, the resulting solution concentration is 10,000 International Units per mL.  
When the 10,000 International Unit vial is reconstituted with 2 mL of 0.9% sodium chloride the 
resulting solution concentration is 5,000 International Units per mL.   
 
The calculated dose of solution should be withdrawn from the vial into a polypropylene syringe 
within 15 minutes of vial reconstitution. The reconstituted solution should not be refrigerated or 
frozen. The dose must be administered to the patient within 4 hours of initial reconstitution. For 
intravenous use, slowly inject the reconstituted asparaginase Erwinia chrysanthemi into an IV 
infusion bag containing 100 mL of normal saline acclimatized to room temperature. Do not 
shake or squeeze the IV bag.  
 
Asparaginase Erwinia chrysanthemi when administered intramuscularly,no more than 2 mL 
should be given at any one injection site. For intravenous use, infuse asparaginase Erwinia 
chrysanthemi in 100 mL of normal saline over 1 hour. Do not infuse other intravenous drugs 
through the same intravenous line while infusing asparaginase Erwinia chrysanthemi.  
 
Drug Ordering: Erwinaze (asparaginase Erwinia chrysanthemi) is a commercially available 
product manufactured by EUSA Pharma (USA), INC.  Erwinaze is approved by the 
U.S. Food and Drug Administration (FDA) to treat patients with acute lymphoblastic leukemia, 
who have developed hypersensitivity to E.coli derived L-asparaginase and pegaspargase. 
8.4 
Cyclophosphamide (Cytoxan) NSC #26271  
Source and Pharmacology: Cyclophosphamide is an alkylating agent related to nitrogen 
mustard.  Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes (CYP2B6, 
CYP2C9, and CYP3A4) in the liver to active compounds. The initial product is 4-
hydroxycyclophosphamide (4-HC) which is in equilibrium with aldophosphamide which 
spontaneously releases acrolein to produce phosphoramide mustard. Phosphoramide mustard, 
which is an active bifunctional alkylating species, is 10 times more potent in vitro than is 4-HC 
and has been shown to produce interstrand DNA cross-link analogous to those produced by 
mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the urine as 

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the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges 
from 4.1 to 16 hours after IV administration. 
Formulation and Stability: 
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 gm and 2 gm vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25°C (77°F) is recommended. The 
product will withstand brief exposures to temperatures up to 30°C (86°F). 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Cyclophosphamide for Injection: Reconstitute with Sterile Water or Bacteriostatic Water for 
Injection (paraben preserved only) to a concentration of 20 mg/mL. Solutions reconstituted with 
preservative should be used within 24 hours if stored at room temperature or within 6 days if 
stored under refrigeration. If administered as undiluted drug at the 20 mg/mL concentration, 
reconstitute with NS only to avoid a hypotonic solution. Cyclophosphamide may be further 
diluted in dextrose or saline containing solutions for IV use. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information 
8.5 
Cytarabine (cytosine arabinoside, Ara-C, Cytosar®) NSC # 63878  
Source and Pharmacology: Cytarabine appears to act through the inhibition of DNA 
polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has 
also been reported. It exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 
phase to the S-phase. Cytarabine is metabolized by deoxycytidine kinase and other nucleotide 
kinases to the nucleotide triphosphate (Ara-CTP), an effective inhibitor of DNA polymerase. 
Ara-CTP is inactivated by a pyrimidine nucleoside deaminase, which converts it to the nontoxic 
uracil derivative (Ara-U). It appears that the balance of kinase and deaminase levels may be an 
important factor in determining sensitivity or resistance of the cell to cytarabine. It has an initial 
distributive phase t½ of about 10 minutes, with a secondary elimination phase t½ of about 1 to 3 
hours. Peak levels after intramuscular or subcutaneous administration of cytarabine occur about 
20 to 60 minutes after injection and are lower than IV administration. Intrathecally administered 
doses are metabolized and eliminated more slowly with a t½ of about 2 hours. 
Formulation and Stability: Cytarabine for Injection, USP, is available in vials of 100 mg, 500 
mg, 1 g, and 2 g containing a sterile powder for reconstitution. It is also available at a 20 mg/mL 
concentration with benzyl alcohol or as a preservative free solution, and at a 100 mg/mL 
concentration as preservative free solution. Hydrochloric acid and/or sodium hydroxide may be 
added to adjust the pH. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). 
Cytarabine solutions should be protected from light. 
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 
hours at room temperature. Solutions reconstituted without a preservative should be used 
immediately. Discard if solution appears hazy. Diluted solutions in dextrose 5% in water or 0.9% 
sodium chloride are stable for 8 days at room temperature; however, the diluted cytarabine 
should be used within 24 hours for sterility concerns 
Guidelines for Administration:  See Treatment and Dose Modification sections of the protocol. 
Intrathecal Administration: For intrathecal administration, dilute with 5-10 mL preservative free 
0.9% sodium chloride injection,lactated Ringer’s injection or Elliot’s B solution or as per 

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institutional standard of practice. The volume of CSF removed should be equal to at least ½ the 
volume delivered.  Intrathecal cytarabine mixed in 0.9% sodium chloride injection, lactated 
Ringer’s injection, or Elliot’s B solution is stable for 24 hours at 25ºC but contains no 
preservative and should be administered as soon as possible after preparation. 
IV Infusion: Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or 0.9% 
sodium chloride injection. Solution containing a bacteriostatic agent should not be used for the 
preparation of doses > 200 mg/m2. May be further diluted with dextrose or sodium chloride 
containing solutions. May give by IV push injection, by IV infusion, or by continuous infusion. 
High Dose (>1000 mg/m²/dose)  IV Infusion: Dilute in D5W or NS to a convenient volume and 
infuse over 3 hours. Administer steroid eye drops (dexamethasone or prednisolone), 2 drops each 
eye q6h beginning immediately before the first dose and continuing 24 hours after the last dose. 
If patient does not tolerate steroid eye drops may administer artificial tears on the same schedule. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
8.6 
Dexamethasone  
(Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521  
Source and Pharmacology: Dexamethasone is a synthetic fluorinated glucocorticoid devoid of 
mineralocorticoid effects. Dexamethasone 0.75 mg has potent anti-inflammatory activity 
equivalent to approximately 5 mg of prednisone. Glucocorticoids produce widespread and 
diverse physiologic effects on carbohydrate, protein, and lipid metabolism, electrolyte and water 
balance, functions of the cardiovascular system, kidney, skeletal muscle, and the nervous 
systems. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes (T-
lymphocytes), monocytes, and eosinophils. Glucocorticoids selectively bind to the cortisol 
receptors on human lymphoid cells which are found in larger numbers on leukemic 
lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors and 
inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose 
transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Elimination half-lives for the following age groups have been reported to be: infants and children 
under 2 years of age: 2.3 to 9.5 hours; 8 to 16 years: 2.82 to 7.5 hours; and adults (age not 
specified): 3 to 6 hours. The biologic half-life is 36- 72 hours. It is primarily metabolized in the 
liver and excreted by the kidneys. 
Formulation and Stability: Available in 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 
and 6 mg tablets; liquid formulations are available in 0.5 mg/5 mL and 0.5 mg/0.5 mL 
concentration. Inactive ingredients vary depending on manufacturer but tablet formulations may 
include: calcium or magnesium stearate, corn starch, lactose, and various dyes. Liquid 
formulations may include: 5%-30% alcohol, benzoic acid, sorbitol, sodium saccharin, glycerin, 
purified water, and various dyes. 
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL, 10 mg/mL, 20 
mg/mL, and 24 mg/mL. Four milligrams of dexamethasone sodium phosphate is equivalent to 
3.33 mg of dexamethasone. Vial sizes include 1 mL, 5 mL, 10 mL, 25 mL, and 30 mL and are 
available in multi-dose vials as well as unit of use vials and syringes. Inactive ingredients vary 
depending on manufacturer but include creatinine, sodium citrate, sodium hydroxide to adjust 

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pH, Water for Injection, sodium sulfite, bisulfite and metabisulfite, methyl and propyl paraben, 
benzyl alcohol, and EDTA. 
Guidelines for Administration: See Treatment and Dose Modifications section of the protocol. 
In general, all doses to be given orally using tablets or liquid formulations.  If IV administration 
is used, Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For 
IV use, it may be further diluted in dextrose or saline containing solutions. Avoid benzyl alcohol 
containing dexamethasone solutions for use in neonates. Diluted solutions that contain no 
preservatives should be used within 24 hours, but maintain stability for at least 14 days in PVC 
bags at room temperature protected from light. If taken orally, repeat oral dose if vomiting 
occurs within 30 minutes.   If one dose is missed, this dose can be made up at the end of a cycle 
at the discretion of the treating physician.  If more than one dose is missed, those doses should be 
skipped and not be made up.   
Supplier: Commercially available from various manufacturers. See package insert for further 
information 
8.7 
Dexrazoxane (Zinecard®), NSC# 169780 
Source and Pharmacology: Dexrazoxane is a synthetic chemical, a cyclic derivative of EDTA 
that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is 
converted intracellularly to a ring opened chelating agent that interferes with iron mediated free 
radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. 
The disposition kinetics of dexrazoxane are dose-dependent with administered doses from 60 to 
900 mg/m2. The plasma half-life is 2 to 2.5 hours. Qualitative metabolism studies have 
confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two 
monoacid-monoamide ring products in the urine of animals and man. Metabolite levels were not 
measured in the pharmacokinetics studies. Urinary excretion plays an important role in the 
elimination of dexrazoxane: 42% of the drug (500 mg/m2) was excreted in the urine. In vitro 
studies have shown that dexrazoxane is not bound to plasma proteins. The pharmacokinetics of 
dexrazoxane have not been evaluated in patients with hepatic or renal insufficiency. There was 
no significant effect of dexrazoxane on the pharmacokinetics of doxorubicin (50 mg/m2) or its 
predominant metabolite, doxorubicinol, in a crossover study in cancer patients. 
Formulation and Stability: Dexrazoxane for Injection is available as a sterile, pyrogen-free 
lyophilized powder in the following strengths: 250 mg single dose vial packaged with a 25 mL 
vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP, and 500 mg single dose vial packaged 
with a 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP. Store at 25°C (77°F); 
excursions permitted to 15°-30°C (59°-86°F). Dexrazoxane must be reconstituted with 0.167 
Molar (M/6) Sodium Lactate Injection, USP, to give a concentration of 10 mg dexrazoxane for 
each mL of sodium lactate. Reconstituted dexrazoxane, when transferred to an empty infusion 
bag, is stable for 6 hours from the time of reconstitution when stored at controlled room 
temperature, 15°-30°C (59°-86°F), or under refrigeration, 2°- 8°C (36°-46°F). The reconstituted 
dexrazoxane solution may be further diluted with either 0.9% Sodium Chloride Injection, USP or 
5.0% Dextrose Injection, USP, to a concentration range of 1.3 to 5.0 mg/mL in intravenous 
infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room 
temperature, 15°-30°C (59°-86°F), or under refrigeration, 2°-8°C (36°-46°F). 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 

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Administer IV push immediately prior to anthracycline dose (the elapsed time from the 
beginning of the dexrazoxane dose to the end of the anthracycline infusion should be 30 minutes 
or less). 
Supplier: Commercially available. See package insert for further information. 
8.8 
Doxorubicin (Adriamycin®) NSC #123127 
Source and Pharmacology: An anthracycline antibiotic isolated from cultures of Streptomyces 
peucetius. The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various 
organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding 
activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and 
RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin 
cellular membrane binding may affect a variety of cellular functions. Enzymatic electron 
reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generate 
highly reactive species including the hydroxyl free radical (OH•). Free radical formation has 
been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the 
cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic 
morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced 
apoptosis may be an integral component of the cellular mechanism of action relating to 
therapeutic effects, toxicities, or both. Doxorubicin serum decay pattern is multiphasic. The 
initial distributive t½ is approximately 5 minutes, suggesting rapid tissue uptake of doxorubicin. 
The terminal t½ of 20 to 48 hours reflects a slow elimination from tissues. Steady-state 
distribution volumes exceed 20 to 30 L/kg and are indicative of extensive drug uptake into 
tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is predominately by 
metabolism and biliary excretion. The P450 cytochromes which appear to be involved 
with doxorubicin metabolism are CYP2D6 and CYP3A4. Approximately 40% of the dose 
appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the 
urine during the same time period. Binding of doxorubicin and its major metabolite, 
doxorubicinol to plasma proteins is about 74-76% and is independent of plasma concentration of 
doxorubicinHydrocortisone sodium succinate. 
Formulation and Stability: Doxorubicin is available as red-orange lyophilized powder for 
injection in 10 mg¹, 20 mg¹, 50 mg¹, 150 mg² vials and a preservative free 2 mg/mL solution in 
10 mg¹, 20 mg¹, 50 mg¹, 75 mg¹, 200 mg² vials. 
¹ Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF˜ (rapid 
dissolution formula) 
also contains methylparaben 1 mg per each 10 mg of Doxorubicin to enhance dissolution. 
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
Aqueous Solution: Store refrigerated 2°-8°C (36°-46°F). Protect from light. Retain in carton until 
contents are used. 
Powder for injection: Store unreconstituted vial at room temperature 15°-30°C (59°-86°F). 
Retain in carton until contents are used. Reconstitute with preservative-free normal saline to a 
final concentration of 2 mg/mL. After adding the diluent, the vial should be shaken and the 
contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature 
under normal room light (100 footcandles) and 15 days under refrigeration 2°-8°C (36°-46°F). 
Protect from exposure to sunlight. Doxorubicin may be further diluted in 0.9% NaCl or dextrose 
containing solutions and administered by infusion. 

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Guidelines for Administration: Administer IV through the tubing of rapidly infusing solution 
of D5W or 0.9% NaCl preferable into a large vein. Protect final preparation from light. To avoid 
extravasation, the use of a central line is suggested. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
8.9 
Etoposide (VePesid®, Etopophos®, VP-16) NSC #141540  
Source and Pharmacology: A semisynthetic derivative of podophyllotoxin that forms a 
complex with topoisomerase II and DNA which results in single and double strand DNA breaks. 
Its main effect appears to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours 
and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, 
approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal 
clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a 
dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non renal 
processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide 
clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. 
Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism 
accounts for most of the non renal clearance of etoposide. The maximum plasma concentration 
and area under the concentration time curve (AUC) exhibit a high degree of patient variability. 
Etoposide is highly bound to plasma proteins (~94%), primarily serum albumin. 
Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. 
Preliminary data suggests that systemic exposure for unbound etoposide correlates better than 
total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. Etoposide 
phosphate is a water soluble ester of etoposide which is rapidly and completely converted to 
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide 
phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses. 
Formulation and Stability: Etoposide for Injection is available in sterile multiple dose vials. 
The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg 
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 
mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. 
Unopened vials of etoposide are stable until expiration date on package at controlled room 
temperature (20°-25°C or 68°-77°F ). 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 
mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under 
refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide phosphate are stable until the 
expiration date on the package. 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
Etoposide: Dilute Etoposide to a final concentration < 0.4 mg/mL in 5% Dextrose Injection, USP 
or 0.9% Sodium Chloride Injection, USP. Etoposide infusions are stable at room temperature for 
96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours at room temperature 
with concentrations of 0.4 mg/mL. The time to precipitation is highly unpredictable at 
concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to precipitate formation 
risk. However, the use of an in-line filter is not mandatory since etoposide precipitation is 
unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous 

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injection. Slow rate of administration if hypotension occurs. Leaching of diethylhexyl phthalate 
(DEHP) from polyvinyl chloride (PVC) bags occurred with etoposide 0.4mg/mL in 0.9% sodium 
chloride solution. To avoid leaching, prepare the etoposide solution as close as possible, 
preferably within 4 hours, to the time of administration or alternatively as per institutional policy, 
glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be used. 
 
Etoposide Phosphate: Dilute the 100 mg vial with 5 or l0 mL of Sterile Water for Injection, USP; 
5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for 
Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injection with Benzyl 
Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 
11.4 mg/mL etoposide phosphate) respectively. Use sterile water for injection without benzyl 
alcohol for neonates and infants < 2 years of age or patients with hypersensitivity to benzyl 
alcohol. When reconstituted as directed, etoposide phosphate solutions can be stored in glass or 
plastic containers under refrigeration for 7 days. When reconstituted with a diluent containing a 
bacteriostat, store at controlled room temperature for up to 48 hours. Following reconstitution 
with Sterile Water for Injection, USP, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection 
store at controlled room temperature for up to 24 hours. Following reconstitution, etoposide 
phosphate may be further diluted to concentrations as low as 0.1 mg/mL etoposide with 5% 
Dextrose Injection or 0.9% Sodium Chloride Injection. The diluted solution can be stored under 
refrigeration or at controlled room temperature for 24 hours. 
Supplier: Commercially available from various manufactures. See package insert for more 
detailed information. 
8.10 Hydrocortisone 
Commercially available for injection in vials containing 100 mg of the drug in powdered form.  To 
prepare for intrathecal use, reconstitute each vial with 2 mL of preservative-free 0.9% sodium 
chloride injection to yield a solution containing 50 mg of hydrocortisone/mL.  Prepare just prior to 
use, and discard unused solution to avoid the risk of bacterial contamination.  Commercial 
hydrocortisone injections which contain paraben or benzyl alcohol should not be used to prepare 
intrathecal dose forms. 
 
8.11 Leucovorin Calcium (LCV, Wellcovorin®, citrovorum factor, folinic acid), NSC 
#003590  
Source and Pharmacology: Leucovorin is a mixture of the diastereoisomers of the 5-formyl 
derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)- 
l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require reduction by 
the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of 
“one-carbon” moieties. Administration of leucovorin can counteract the therapeutic and toxic 
effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate 
reductase. In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines 
used in cancer therapy, such as 5- fluorouracil. Leucovorin is readily converted to another reduced 
folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic 
acid (an active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition of 
this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at 
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life of total 

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reduced folates was approximately 6.2 hours. Following oral administration, leucovorin is rapidly 
absorbed and expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-
isomer (the biologically active form) but only 20% of the d-isomer is absorbed. Oral absorption of 
leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% 
for 25 mg, 75% for 50 mg, and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the 
CSF folate levels. 
Formulation and Stability: Leucovorin calcium for injection is supplied as a sterile ready to use 
liquid and a sterile powder for injection. The 10 mg/mL preservative free liquid is available in 50 
mL vials containing sodium chloride 400 mg/vial. Store preservative free liquid in the 
refrigerator at 2°-8°C (36°-46°F) protected from light. The powder for injection is available in 50 
mg, 100 mg, 200 mg, 350 mg and 500 mg vials. Store at room temperature 15° to 25°C (59° to 
77°F) protected from light. Reconstitute the sterile powder with sterile water for injection or 
bacteriostatic water for injection to a concentration of 10 mg/mL leucovorin calcium. Do not use 
diluents containing benzyl alcohol for doses > 10mg/m² or in infants < 2 years of age or patients 
with allergy to benzyl alcohol. When Bacteriostatic Water is used, the reconstituted solution is 
good for 7 days. If reconstituted with sterile water, use solution immediately as it contains no 
preservative. One milligram of leucovorin calcium contains 0.004 mEq of leucovorin and 0.004 
mEq of calcium. The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg 
tablets. Inactive ingredients vary depending on manufacturer but tablet formulations may 
include: corn starch, dibasic calcium phosphate, magnesium stearate, pregelatinized starch, 
lactose, microcrystalline cellulose, and sodium starch glycolate. 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin 
should be injected intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV 
leucovorin and sodium bicarbonate are incompatible. Oral leucovorin should be spaced evenly 
(e.g. every six hours) throughout the day and may be taken without regard to meals. Doses > 25 
mg should be given IV due to the saturation of absorption. Leucovorin should not be 
administered < 24 hours after intrathecal injections which contain methotrexate unless there are 
special circumstances. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
8.12 Mercaptopurine (6-MP, Purinethol®, 6-mercaptopurine, Purixan®) NSC #000755  
Source and Pharmacology: Mercaptopurine is an analogue of the purine bases adenine and 
hypoxanthine. The main intracellular pathway for 6-MP activation is catalyzed by the enzyme 
hypoxanthine-guanine phosphoribosyl transferase (HGPRT) which catalyzes the conversion of 
6-MP to several active nucleotide metabolites including thioinosinic acid, a ribonucleotide which 
can interfere with various metabolic reactions necessary for nucleic acid (RNA and DNA) 
biosynthesis. It can also cause pseudofeedback inhibition of the first step in de novo purine 
biosynthesis or convert to another ribonucleotide which can cause feedback inhibition. 
Mercaptopurine can be incorporated into DNA in the form of 6-TG nucleotides as well and thus 
produce toxicity. The absorption of an oral dose of 6-MP is incomplete and variable, with only 
about 16%-50% of an administered dose reaching the systemiccirculation secondary to a first 
pass metabolism in the liver. Food intake and co-administration with cotrimoxazole (TMP/SMX) 
significantly reduces absorption of 6-MP. After IV administration, 6-MP has a plasma half-life 
of 21 minutes in children and 47 minutes in adults. Approximately 19% is bound to protein. 

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Mercaptopurine is well distributed into most body compartments except the CSF (with high dose 
IV 6-MP the CSF to plasma ratio is 0.15). Mercaptopurine is metabolized by xanthine oxidase in 
the liver to 6-Thiouric acid an inactive metabolite. In patients receiving both 6-MP and 
allopurinol (a xanthine oxidase inhibitor) the dose of 6-MP must be reduced by 50-75%. Since 
TPMT, 6-thiopurine methyltransferase, is also one of the enzymes involved in the metabolism of 
6-MP, those individuals who have an inherited deficiency of the enzyme may be unusually 
sensitive to the myelosuppressive effects of 6-MP and prone to developing rapid bone marrow 
suppression following the initiation of treatment. 6-MP is excreted in urine as metabolites and 
some unchanged drug; about half an oral dose has been recovered in 24 hours. A small 
proportion is excreted over several weeks. 
Formulation and Stability: Available as a 50 mg tablet containing the inactive ingredients corn 
and potato starch, lactose, magnesium stearate, and stearic acid. Store at 15°-25°C (59°-77°F) in 
a dry place. 
 
PURIXAN® (mercaptopurine) oral suspension is supplied as a commercially available 2000 
mg/100 mL (20 mg/mL) pink to brown viscous liquid in amber glass multiple-dose bottles.  The 
suspension contains the following inactive ingredients: xanthan gum, aspartame, concentrated 
raspberry juice, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate and purified 
water.  Once opened, PURIXAN® should be used within 6 weeks. Store between 15 to 25ºC (59º 
to 77ºF) in a dry place. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
Do not give oral mercaptopurine with food or milk. Concurrent milk products can decrease 
absorption and mercaptopurine’s effect is enhanced if given at bedtime on an empty stomach. 
Oral mercaptopurine should be given, if possible, at least two hours after and at least one hour 
before food or milk. If allopurinol is also given, the oral dose of mercaptopurine should be 
reduced by 65-75%. Patients with severe myelosuppression should have their thiopurine S-
methyltransferase (TPMT) status and/or their thiopurine metabolite concentrations evaluated, so 
that the dose of mercaptopurine can be reduced in patients with a TPMT defect. Patients with the 
rare homozygous deficient TPMT phenotype may tolerate only 1/10th to 1/20th the average 
mercaptopurine dose. TPMT testing and thiopurine metabolite measurements are commercially 
available. 
 
For children unable to swallow the tablets whole, a 10mg/mL oral suspension can be 
compounded. Suspensions prepared in this manner are stable at room temperature or refrigerated 
(preferred) for at least 14 days following compounding.  The suspension should be shaken well 
before each use. Procedures for proper handling and disposal of cytotoxic drugs should be used 
when preparing the suspension. (Aliabadi HM, Romanick M, Desai S et al. Effect of buffer and 
antioxidant on stability of mercaptopurine suspension. Am J Heath-Syst Pharm. 65:441-7, 2008).   
 
 
PURIXAN® suspension (20 mg/mL) may also be used for patients unable to swallow tablets.  
Prior to each administration of PURIXAN®, the bottle should be shaken vigorously for at least 
30 seconds to ensure the oral suspension is well mixed.   
 

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Repeat oral dose if vomiting occurs within 30 minutes.  If one dose is missed, this dose can be 
made up at the end of a cycle at the discretion of the treating physician.  If more than one dose is 
missed, those doses should be skipped and not be made up.  
 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
 
8.13 Methotrexate (MTX, amethopterin, Trexall®) NSC #000740 
Source and Pharmacology: A folate analogue which reversibly inhibits dihydrofolate reductase, 
the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate 
formation limits the availability of one carbon fragments necessary for the synthesis of purines 
and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell 
reproduction. The polyglutamated metabolites of MTX also contribute to the cytotoxic effect of 
MTX on DNA repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute 
drug concentration and the duration of drug exposure. MTX is actively transported across cell 
membranes. At serum methotrexate concentrations exceeding 0.1 μmol/mL, passive diffusion 
becomes a major means of intracellular transport of MTX. The drug is widely distributed 
throughout the body with the highest concentration in the kidney, liver, spleen, gallbladder and 
skin. Plasma concentrations following high dose IV MTX decline in a biphasic manner with an 
initial half-life of 1.5-3.5 hours, and a terminal half life of 8-15 hours. About 50% is bound to 
protein. After oral administration, approximately 60% of a 30 mg/m2 dose is rapidly absorbed 
from the GI tract, with peak blood levels at 1 hour. At doses >30 mg/m² absorption decreases 
significantly. Even at low doses absorption may be very erratic, varying between 23% and 95%. 
The elimination of MTX from the CSF after an intrathecal dose is characterized by a biphasic 
curve with half-lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the 
lumbar concentration of MTX is ~ 100 x’s higher than in plasma. (Ventricular concentration is ~ 
10% of lumbar concentration). MTX is excreted primarily by the kidneys via glomerular 
filtration and active secretion into the proximal tubules. Renal clearance usually equals or 
exceeds creatinine clearance. Small amounts are excreted in the feces. There is significant 
entero-hepatic circulation of MTX. The distribution of MTX into third-space fluid collections, 
such as pleural effusions and ascitic fluid, can substantially alter MTX pharmacokinetics. The 
slow release of accumulated MTX from these third spaces over time prolongs the terminal half-
life of the drug, leading to potentially increased clinical toxicity. 
Formulation and Stability: Methotrexate for Injection is available as a lyophilized powder for 
injection in 20 mg and 1 g vials. The powder for injection contains approximately 0.14 mEq 
sodium in the 20 mg vial; 7 mEq sodium in the 1 g vial. Methotrexate for Injection is also 
available as a 25 mg/mL solution in 2, 4, 8, 10, 20 and 40 mL preservative free vials and 2 and 
10 mL vials with preservative. The 2, 4, 8, 10, 20, and 40 mL solutions contain approximately 
0.43, 0.86, 1.72, 2.15, 4.3, and 8.6 mEq sodium per vial, respectively. The preserved vials 
contain 0.9% benzyl alcohol as a preservative. Sterile methotrexate powder or solution is stable 
at 20 to 25ºC (68 to 77ºF); excursions permitted to 15°-30ºC (59°-86ºF). Protect from light. 
Guidelines For Administration: 
Intravenous Administration: Powder for injection: Dilute 1 g vial with 19.4 mL of non-preserved 
SWFI, Dextrose 5% in water or 0.9% Sodium Chloride Injection for a 50 mg/mL concentration. 

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Dilute the 20 mg vial to a concentration ≤ 25 mg/mL with above diluents. The powder for 
injection may be further diluted in 0.9% Sodium Chloride or dextrose containing solutions to a 
concentration of ≤ 25 mg/mL for IV use. The 25 mg/mL solution may be further diluted in Saline 
or Dextrose containing solutions for IV use. Do not use the preserved solution due to the risk of 
benzyl alcohol toxicity. Methotrexate dilutions are chemically stable for at least 7 days at room 
temperature but contain no preservative and should be used within 24 hours. Diluted solutions 
especially those containing bicarbonate exposed to direct sunlight for periods exceeding 4 hours 
should be protected from light. 
High dose Methotrexate requires alkalinization of the urine, adequate hydration and leucovorin 
rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, and NSAIDS as renal excretion of 
MTX is inhibited by these agents. 
Intrathecal Administration: Use preservative free 25 mg/mL solution or 20 mg lyophilized 
powder for injection.  For intrathecal administration, dilute with 5-10 mL preservative free 0.9% 
Sodium Chloride Injection, lactated Ringer’s, or Elliot’s B solution, or as per institutional 
standard of practice. The volume of CSF removed should be equal to at least half the volume 
delivered. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information 
 
8.14  Prednisone (Deltasone, Meticorten, Orasone®, Liquid Pred, Pediapred®, 
Sterapred®) NSC #010023 
Source and Pharmacology: Prednisone is a synthetic compound closely related to 
hydrocortisone. Glucocorticoids produce widespread and diverse physiologic effects on 
carbohydrate, protein, and lipid metabolism, electrolyte and water balance, functions of the 
cardiovascular system, kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce 
the concentration of thymus-dependent lymphocytes (Tlymphocytes), monocytes, and 
eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human lymphoid cells 
which are found in larger numbers on leukemic lymphoblasts. They also decrease binding of 
immunoglobulin to cell surface receptors and inhibit the synthesis and/or release of interleukins, 
thereby decreasing T-lymphocyte blastogenesis and reducing expansion of the primary immune 
response. The specific cellular mechanisms that act to halt DNA synthesis are thought to be 
related to inhibition of glucose transport or phosphorylation, retardation of mitosis, and 
inhibition of protein synthesis. Peak blood levels occur within 2 hours of oral intake. Prednisone 
is approximately 75% protein bound with a plasma t½ of 3.2 to 4 hours. (Biologic half-life is 12-
36 hours.) 
Formulation and Stability:Available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 50 mg 
tablets; liquid, 5 mg/5 mL or 5 mg/mL. Inactive ingredients vary depending on manufacturer but 
tablet formulations may include: calcium or magnesium stearate, corn starch, lactose, erythrosine 
sodium, mineral oil, sorbic acid, sucrose, talc and various dyes. Liquid formulations may 
include: 5-30% alcohol, fructose, sucrose, saccharin, and sorbitol. 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
If taken orally, repeat oral dose if vomiting occurs within 30 minutes.   If one dose is missed, this 
dose can be made up at the end of a cycle at the discretion of the treating physician.  If more than 
one dose is missed, those doses should be skipped and not be made up.   

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Supplier: Commercially available from various sources. See package insert for further 
information 
8.15 Vincristine (Oncovin®, VCR, LCR) NSC #67574 
Source and Pharmacology: Vincristine is an alkaloid isolated from Vinca rosea Linn 
(periwinkle). It binds to tubulin, disrupting mircotubules and inducing metaphase arrest. Its 
serum decay pattern is triphasic. The initial, middle, and terminal half-lives are 5 minutes, 2.3 
hours, and 85 hours respectively; however, the range of the terminal half-life in humans is from 
19 to 155 hours. The liver is the major excretory organ in humans and animals; about 80% of an 
injected dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the 
urine. The P450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to 30 
minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it 
remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There is poor CSF 
penetration. 
Formulation and Stability: Vincristine is supplied in a vial each mL of which contains 
vincristine sulfate, 1 mg (1.08 μmol); mannitol, 100 mg; sterile water for injection; Acetic acid 
and sodium acetate are added for pH control. The pH of Vincristine Sulfate Injection, USP 
ranges from 3.5 to 5.5. This product is a sterile solution. Store refrigerated at 2°-8°C or 36°-
46°F. Protect from light and retain in carton until time of use. Do not mix with any IV solutions 
other than those containing dextrose or saline. 
Guidelines for Administration:  The delivery of vincristine via either IV slow push or minibag 
is acceptable. Injection of vincristine sulfate should be accomplished within 1 minute. 
Vincristine sulfate must be administered via an intact, free-flowing intravenous needle or 
catheter. Care should be taken to ensure that the needle or catheter is securely within the vein to 
avoid extravasation during administration. The solution may be injected either directly into a 
vein or into the tubing of a running intravenous infusion. When dispensed the container or 
syringe containing vincristine must be enclosed in an overwrap with warnings that it is for 
intravenous use only and is fatal if given intrathecally or similar wording per institutional 
standard. 
Supplier: Commercially available from various manufacturers. See package insert for more 
detailed 
9. CORRELATIVE/SPECIAL STUDIES  
9.1 
Asparaginase Enzyme Activity/Pharmacokinetic (PK) Samples (Required of all 
participants) 
9.1.1 Asparaginase PK Sample Acquisition and Handling 
 
1. Draw 3 mL of blood into a red top Vacutainer tube (no anticoagulant).  
Record the date and time that the sample was collected.   
 
2. Allow the tube to stand at room temperature for 30 min to clot (do not place 
the tube in ice).   
 
3. Centrifuge the clotted blood sample at 1,100-1,300 x g for 10 minutes at 25º C.  
Record the time that the sample was centrifuged.   

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9.1.3 Schedule 
Obtain Asparaginase PK Samples at the Following Time Points: 
  Induction Phase: Days 7 (two samples: one prior to IV asparaginase dose and 
one 5-10 minutes after completion of infusion), 11, 18, 25 and 32  
  Post-Induction:  Just prior to each dose of asparaginase administered during 
post-induction treatment phases (ie, every 3-weeks for patients randomized to 
SC-PEG asparaginase and every 2-weeks for patients randomized to 
Oncaspar) 
 For patients switched to Erwinia: Just prior to first dose of Erwinia  
 
Note: Induction Day 7 sample should be obtained 5-10 minutes after completion 
of IV asparaginase infusion.  
 
Note: If Day 7 asparaginase is delayed in induction, shift the days that PK 
samples are collected accordingly.  For example: If asparaginase is given on 
Day 10 instead of Day 7, the PKs should be collected on Days 14, 21, 28 and 
35 instead of Days 11, 18, 25 and 32. 
 
Note: Post-induction asparaginase samples will be run in real time. These samples 
should be shipped to MGH at least once per week.  
 
Note: PK samples should be obtained on the day the asparaginase is scheduled to 
be administered (pre-dose) even if the asparaginase ends up being held.  If the 
asparaginase dose is held and is not given within 3 days, then a repeat PK 
sample should be drawn just prior to the actual dose. 
 
9.2 
Antibody Samples (Required of all participants) 
9.2.1 Antibody Sample Acquisition and Handling 
 
1. Draw at least 2 mL of venous blood into a dark green-top (sodium 
heparinized) collection tube.  Invert the tube gently 4 times to mix the blood 
with the heparin then place tube immediately on ice (no longer than one 
minute after mixing). 
 
2. Record the sample date and time of collection.  
 
3. Centrifuge the blood sample immediately (within 30 minutes of collection) in a 
refrigerated centrifuge, at approximately 3,000 rpm for 5 minutes. 
 
4. Using a disposable pipette, transfer the plasma fraction (within 5 minutes of 
centrifugation) into each of three specimen shipping tubes.  At least 0.25 mL 
(250 µL) of plasma should be in each tube. Sample tubes should be labeled 
with the pre-printed bar coded sample labels provided in the specimen kits.  

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9.2.3 Schedule 
 
Obtain Antibody Samples at the Following FIVE Time Points: 
 
 Day 7: Prior to first dose of asparaginase 
 Day 32/End of Induction 
 CNS Phase (or Consolidation I for VHR): Just prior to 1st post-induction dose 
of asparaginase  
 Mid-Consolidation II: Week 13 of post-induction asparaginase (SC-Peg dose 
#5 or Oncaspar dose #7) 
 End of Consolidation II: Just prior to last dose of asparaginase 
 
Note: Antibody samples should be obtained at the same time as the PK samples 
(just prior to dose of asparaginase).  Allowable deviations in timing of 
Induction Day 7 and Day 32 samples are +/- 3 days; for CNS Phase (or 
Consol I for VHR),  Mid-Consolidation II and End of Consolidation II it is +/- 
7 days. If asparaginase is held or delayed, the antibody sample should be 
collected prior to the correct corresponding asparaginase dose number (not by 
the week number).   
9.3 
Note: If Day 7 asparaginase is delayed in induction, shift the days that antibody 
samples are collected accordingly. For example: If asparaginase was given on Day 
10 instead of Day 7, the antibody should be collected on Day 10 instead of Day 
7.Minimal Residual Disease (MRD) Samples (Leukemia patients only) 
9.3.1 Sample Acquisition and Handling 
 Obtain  
o Marrow: One purple top (EDTA) tubes, with 2-3 mL of bone 
marrow aspirate  
o Blood: One purple top (EDTA) tubes, with 2-3 mL of peripheral 
blood  
9.3.2 Shipment 
o Outside Sites: Send with a cold pack (not on dry ice), same day 
overnight to DFCI (see section 9.6) 
o DFCI: Place in dirty utility refrigerator on 6 North and page Study 
 
 
9.3.3 Schedule 
 At time of study entry (pre-treatment): Required of all leukemia 
patients 
 Induction Phase, Day 18 optional (Marrow: collect if consent is obtained 
for Day 18 bone marrow study; Blood: collect if consent is obtained to 
collect additional research specimens) 
 Induction Phase, Day 32: Required of all leukemia patients 

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 End of Treatment optional bone marrow (collect only if consent is 
obtained for end of treatment marrow); Must be completed within 30 
days before or 60 days after the off treatment date. 
 VHR patients only: 
o Conslidation IB, Day 1: Peripheral blood 
o Consolidation IC, Day 1: Peripheral blood 
o CNS Phase, Day 1 (coincide with 1st LP): Bone Marrow and 
Peripheral blood 
o Consolidation II, Day 1 (ETP patients only): Peripheral blood 
 T-ALL patients: 
o CNS Phase, Day 1 (coincide with 1st LP): Bone Marrow (if 
consent is obtained for CNS phase bone marrow study) and 
Peripheral blood 
o Consolidation II, Day 1: Peripheral blood 
 At time of suspected relapse 
 
9.4 
Biology Research Samples—Peripheral Blood and Marrow (Optional) 
9.4.1 Sample Acquisition and Handling 
 Obtain  
o Marrow: 1-2 purple top (EDTA) tubes each with 2-3 mL of bone 
marrow aspirate in purple top (EDTA) tube 
o Peripheral Blood: 1-2 purple top (EDTA) tubes, each with 2-3 mL 
of blood 
9.4.2 Shipping 
 Outside Sites: Send with a cold pack (not on dry ice), same day overnight to 
DFCI (see section 9.6) 
 DFCI: Place in dirty utility refrigerator on 6 North and page Study Team 
Sample 
 
9.4.3 Schedule 
 At time of study entry (pre-treatment) 
 At time of suspected relapse 
 
9.5 
CSF Research Samples (Optional) 
9.5.1 Sample Acquisition and Handling 
     Obtain 1-3 mL of leftover CSF (collected at the time of a therapeutic 
lumbar puncture, just prior to the administration of intracthecal 
chemotherapy) and immediately place specimen on ice. 

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10. STUDY CALENDAR 
Baseline evaluations, including radiographic imaging, are to be conducted within 7-
days prior to start of protocol therapy. All study assessments should be performed within 
+ 3 days of the timepoints indicated below during the induction phase and within + 7 
days of the timepoints during post-induction phases, unless otherwise noted.  
10.1 Study Assessements: Study Entry and Induction Phase 
 
Study 
Entry 
Day 
1 
Day
4 
Day    
7 
Day 
11 
Day 
18 
Day 
25 
Day 
32 
Physical Exam 
X 
 
 
 
 
 
 
X 
CBC w/differential and platelets 
X 
X 
X 
 
 
 
 
X 
Serum chemistry a 
 
X 
 
 
 
 
 
 
 
X 
Bone Marrow aspirate/biopsy for 
morphology 
 
X 
 
 
 
 
 
 
Xb
 
Bone Marrow for 
Immunophenotype 
 
Xq
 
 
 
 
 
 
 
 
Bone Marrow for Cytogenetics, 
FISH and/or PCR 
Xc 
 
 
 
 
 
 
 
MRD (Marrow/Blood) 
 
X 
 
 
 
 
 
Xd
 
 
 
Xb
 
Biology Research Studies 
(Marrow/Blood) 
Xe
 
 
 
 
 
 
 
 
Asparaginase PK samples 
(blood)m 
 
 
 
 
 
Xn
 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
Asparaginase Antibody samples 
(blood) 
 
 
 
 
Xp 
 
 
 
X 
Vitamin D 25 OH level (blood) 
 
 
Xf
 
 
 
 
 
 
 
Xf
 
CSF for cell count, cytospin 
 
 
 
 
 
 
 
 
Xk
 
 
 
Xk
 
Chest x-ray 
X 
 
 
 
 
 
 
Xg
 
CT scans (Neck, chest, abdomen, 
pelvis) 
Xh
 
 
 
 
 
 
 
Xi
 
Echocardiogram (recommended, 
not required) 
 
X 
 
 
 
 
 
 
 

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B-HCG (urine or serum) 
Xj 
 
 
 
 
 
 
 
AE/Toxicity Assessment L 
X 
X 
X 
 
X 
X 
X 
X 
a Chemistries should include BUN, Creatinine, AST, direct bilirubin 
b Required only if marrow involvement documented at diagnosis; Day 32 
MRD studies from marrow/blood only for leukemia patients. 
c FISH and/or PCR should be sent in for all patients at diagnosis to screen for 
TEL/AML1, BCR-ABL and MLL rearrangements (Note: when possible, FISH is 
preferred over PCR as screening test for TEL/AML1).  Additional FISH/PCR tests 
(to screen for trisomies, E2A/PBX1, 9p deletions and other abnormalities) may be 
sent at discretion of treating clinician and are encouraged in patients with normal 
or uninterpretable karyotype. Reports from all karyotype, FISH and PCR studies 
should be sent to DFCI and will be reviewed by Principal Investigator or designee 
to determine final risk group status. 
d Marrow specimen only for leukemia patients who have consented to optional Day 
18 marrow; peripheral blood to be sent for any leukemia patient who has consented 
to optional additional research specimens 
e Only for patients who have consented to optional research specimens 
f Obtain Vitamin D level at study entry and at the end of the induction phase for 
patients who have consented to collection of these research specimens. The first 
Vitamin D sample may be collected within 3 days of beginning treatment. 
gRequired only if chest x-ray was positive at diagnosis 
h Required only for lymphoblastic lymphoma patients.  A chest CT for leukemia 
patients with mediastinal mass on pre-study chest x-ray is suggested but not 
required. 
iCT of involved sites required for remission assessment only for lymphoblastic 
lymphoma patients.  A chest CT scan is suggested for leukemia patients with 
mediastinal mass at diagnosis, but is not required.  
jOnly for female patients of childbearing potential prior to initiation of therapy. 
k Day 18 and Day 32: CSF is collected for clinical purposes.  Leftover CSF obtained 
at these timepoints may be sent for research purposes if patient has consented to 
optional research studies. If end-induction LP is delayed, should still collect CSF 
even if LP occurs more than 3 days past Day 32.  
LAE assessment should be performed on an ongoing basis (at least once per month) 
throughout the time a participant is on study.  Note: SAE’s need be reported in real 
time. 
mDays 25 and 32 Asparaginase PK samples will be run in real time.  These samples 
should be shipped to laboratory within one week of the Day 32 sample being drawn.  
nDay 7 Asparaginase PK samples should be collected prior to first dose of 
Asparaginase and 5-10 minutes after completion of Asparaginase infusion. 
o Day 11, 18, 25 and 32 PK samples can be drawn +  3 days from timepoint 
p Day 7 asparaginase antibody sample should be collected prior to first dose of 
asparaginase (at same time first PK sample is drawn)   

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q Copies of flow histograms for all patients with T-ALL or T-lymphoblastic 
lymphoma should be sent to DFCI for central review. 
Note: For lymphoblastic lymphoma patients without marrow involvement, MRD samples 
(bone marrow/blood) are not required.  

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10.2 Study Assessments: Post-Induction Treatment Phases 
 
Consolidation I 
CNS Phase
Consolidation II 
Continuation 
End of 
Therapy 
Physical Exam 
 
X 
 
X 
 
CBC w/differential and platelets 
 
Xl 
X 
Xa 
Xa 
 
Serum chemistryb 
 
Xl 
 
X 
                   Xa 
           
Xa 
 
 
Bone Marrow aspirate for 
morphology 
 
 
Xc 
 
 
 
MRD (Marrow/Blood) 
 
            Xc 
 
Xc 
 
Xk 
 
 
Xn 
Asparaginase PK samples 
(blood) 
 
Xm 
 
 
Xd 
 
Xd 
 
 
 
 
 
 
Asparaginase Antibody samples 
(blood) 
 
Xm 
 
Xe 
Xf 
 
 
Vitamin D 25 OH level (blood) 
 
 
 
 
 
Xg 
 
Xg 
Echocardiogram 
 
 
 
 
 
 
Xh 
CSF  
 
 
Xi 
 
Xi 
 
 
AE/Toxicity Assessmentj 
 
X 
X 
X 
X 
X 
a Obtain CBC and chemistries at the start of each 3-week chemotherapy cycle 
b Chemistries prior to each 3-week cycle should include AST and direct bilirubin.  
c VHR Leukemia & T-ALL patients only.  Blood for MRD should be obtained at the 
start of Consolidation IB and IC (for VHR leukemia patients only). Marrow should 
be performed at time of 1st LP of CNS phase.  Marrow is required of all VHR 
leukemia patients and is optional for non-VHR T-ALL (should be performed only 
in T-ALL patients who have consented to marrow at this timepoint).  Blood for 
MRD should be obtained at the start ofthe CNS phase (for VHR leukemia patients 
& T-ALL). 
d Asparaginase PK samples should be obtained just prior to each post-induction dose 
of asparaginase (during CNS and Consolidation II phases, and Consolidation IC 
phase for VHR patients). All post-induction asparaginase PK samples will be run 
in real time.  Samples should be shipped to laboratory for analysis as soon as they 
are obtained. PK samples should be obtained on the day the asparaginase is 

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scheduled to be administered (pre-dose) even if the asparaginase ends up being 
held.  If the asparaginase dose is held and is not given within 3 days, then a repeat 
PK sample should be drawn just prior to the actual dose. If patient is switched to 
IM Erwinia, PK sample should be obtained just prior to first dose of Erwinia then 
every 3 weeks through Consolidation II, just prior to an Erwinia dose.  
e Draw antibody sample just prior to 1st dose of post-induction asparaginase (CNS 
Phase for SR/HR; Consolidation IC for VHR) 
f Draw 2 antibody samples: 1) Mid-Consolidation II-just prior to Week 13 dose of 
post-induction asparaginase (SC-Peg dose #5 or Oncaspar dose #7); 2) End of 
Consolidation II-just prior to last dose of asparaginase 
gObtain Vitamin D level at the start of the 1st or 2nd cycle of Continuation phase and 
at the 1st day of the last continuation cycle or the 1st off treatment visit  for patients 
who have consented to collection of these research specimens. 
h Echocardiogram is suggested for all patients, but is not required. 
i Optional collection of leftover CSF during lumbar puncture performed as part of 
treatment.  CSF is collected during the 4th Lumbar puncture during the CNS phase 
and 1st Lumbar puncture performed during the Consolidation II phase.  Leftover CSF 
is only collected with consent.  
jAE assessment should be performed on an ongoing basis throughout the time a 
participant is on study  (at least once per month through the end of the 
Consolidation II phase and at least once very 3 months during the Continuation 
phase). Note: SAE’s need be reported in real time. 
  k T-ALL patients only: obtain a blood sample at the start of their first cycle of 
Consolidation II 
lDay 32 labs can be used if Consolidation I begins within 3 days of Day 32 
mOnly for VHR patients, on Day 8 of Consolidation IC 
n Marrow specimen only for leukemia patients who have consented to optional End 
of Treatment marrow; must be collected within 30 days before or 60 days after the 
off treatment date.Peripheral blood not necessary at this timepoint.  
Note: For lymphoblastic lymphoma patients without marrow involvement, MRD samples 
(bone marrow/blood) are not required at any time points. 
 
10.3 Assessment Schedule after Completion of Therapy 
Suggested: 
 Physical exam/history and CBC with differential/platelets  
o Monthly x 6 months, then  
o Every 2 months x 6 months, then 
o Every 4 month x 1 year, then 
o Every 6 months x 1 year, then 
o Annually. 
 Echocardiograms 
o SR patients: At the completion of therapy, and then 3-5 years after  
completion of therapy.  May by obtained more frequently as 
clinically indicated 

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o HR/VHR patients: Annually x 5 years, then every other year x 5 
years, or as clinically indicated. 
 Ophthalmologic Evaluation 
o At the completion of therapy and 1-year post-therapy (to rule out 
steroid-associated cataracts) 
 Dental Evaluation 
o At the completion of therapy, then every 6 months, or as clinically 
indicated. 
 
 

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11. CLINICAL RESPONSE CRITERIA 
 
11.1 Definition of CNS Status  
 
 
 
CNS-1 = CSF without blasts on cytospin, regardless of CSF WBC count  
 
 
 
CNS-2 = CSF WBC <5 with blasts present on cytospin     
 
 
 
CNS-3 = CSF WBC >5 with blasts present on cytospin 
 
Steinherz/Bleyer Algorithm to Interpret Traumatic LP’s (>10 RBC per high 
power field) with > 5 WBC/hpf: 
 
 CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf  should be treated as 
CNS-3 if : (CSF WBC/CSF RBC) > 2x (Blood WBC/Blood RBC).   
 All other CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf in CSF 
specimen should be treated as CNS2. 
 
 
11.2 Definition of Complete Remission 
11.2.1  Leukemia:  
 An interpretable bone marrow (a specimen with normal marrow elements present) with fewer than 
1% malignant lymphoblasts by microscopic examination and peripheral blood without 
lymphoblasts, and an APC > 1000/mm3 and platelets > 100,000/mm3, and no evidence of 
extramedullary leukemia (no blasts in spinal fluid, at least 70% reduction in size of masses noted on 
imaging at diagnosis, as defined below for patients with lymphoblastic lymphoma).  Note: Patients 
are allowed to have > 1% normal myeloid or lymphoid blasts (hematogones) in their marrow 
consistent with recovery and still meet the definition of complete remission.   Normal recovery 
blasts may be distinguished from persistent malignant lymphoblasts by flow cytometry, 
immunohistochemistry or other studies.  Consult principal investigator with any questions. 
11.2.2 Lymphoblastic Lymphoma:  
At least a 70% reduction in size of largest nodes or masses noted at diagnosis.  Reduction may be 
measured as a decrease in a sum of the products of the two greatest diameters (SPD) of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected according to 
the following features: 
a) they should be clearly measurable in at least two perpendicular dimensions, 
b) they should include mediastinal masses whenever this site was initially involved. 
In addition to this radiographic criterion, there should also be complete disappearance of all 
clinical evidence of disease by physical examination and no morphologic evidence of disease in 
bone marrow (if involved at initial diagnosis) and spinal fluid. 
 
11.3 Failure to Achieve Remission (Induction Failure) 
11.3.1 Leukemia:  
If >1% blasts (confirmed to be leukemic lymphoblasts by flow cytometry, 
immunohistochemistry or other studies) are identified in the marrow on Days 32, 
or on any marrow performed up through Day 53 (without a preceding marrow 
consistent with complete remission), the patient will be classified as an Induction 

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Failure and removed from protocol (contact Principal Investigator or designee prior 
to removing from protocol if patient is induction failure).  Any patient with 
evidence of extramedullary leukemia on exam, in the spinal fluid or by 
radiographic imaging (<70% reduction in size of largest nodes or masses noted at 
diagnosis, or any new biopsy-proven masses) will also be considered an induction 
failure, regardless of marrow findings. 
11.3.2 Lymphoblastic Lymphoma: 
If end-induction imaging reveals persistent nodal involvement or masses (< 70% 
reduction in size of largest nodes or masses noted at diagnosis), the patient will be 
classified as an Induction Failure and removed from protocol (Notify Principal 
Investigator or designee if patient is an induction failure).   Any patient with new, 
biopsy-proved sites of disease will also be considered an induction failure.  In 
addition, any patient with evidence of persistent disease in bone marrow (>5% 
blasts confirmed by flow cytometry, FISH or other studies) or spinal fluid (CNS-
3) will also be considered an induction failure. 
    
 
11.4 Criteria for relapse 
 
11.4.1  Greater than 5% lymphoblasts identified morphologically in bone marrow 
aspirate/biopsy identified to be leukemic by flow cytometry, cytogenetics, FISH, 
immunohistochemistry, or other tests. 
 
11.4.2  Development of biopsy-proven extramedullary site of disease (eg, CSF, 
testicle, lymph node) 
 
11.4.2.1 
CNS relapse: CSF sample with > 5 WBC per high power 
field and lymphoblasts on cytospin, or 2 consecutive CSF 
specimens meeting the definition of CNS-2 (< 5 WBC/hpf 
with lymphoblasts seen) obtained at least 3 weeks apart.  
 

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12. ADVERSE EVENT REPORTING REQUIREMENTS 
12.1 Definitions 
12.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
 
By protocol definition, the following expected toxicities related to the diagnosis 
and treatment of ALL and considered to be unrelated to asparaginase do not need 
to be recorded as AEs, unless they meet definition of an SAE in section 12.1.2: 
 Blood count abnormalities (any grade) 
 Electrolyte abnormalities (any grade) 
 Uric Acid (any grade) 
 Transaminitis without clinical symptoms 
 Mucositis (grade 2 or below) 
 Nausea (any grade) 
 Vomiting (any grade) 
 Fatigue (any grade) 
 Anorexia (any grade) 
 Fever (any grade) 
 Constipation (any grade) 
 Diarrhea (any grade) 
 Hypertension thought to be related to steroids (grade 1) 
 Hyperglycemia related to steroids that does not require the use of insulin 
 Neuropathy – sensory, motor, or cranial (grade 3 or below and thought to 
be related to Vincristine) 
 Vascular access complications (grade 2) 
 Allergic reactions that are not related to asparaginase (grade 2 or below) 
(Note: All asparaginase-related allergic reactions must be reported, 
regardless of grade.) 
 Any grade 1 or grade 2 expected toxicities that are not related to 
asparaginase 
 
**Following approval of DFCI IRB amendment number 31, additional 
adverse events related to asparginase will be collected retrospectively on all 
participants through 30 days after their final dose of asparaginase.  Additional 
events being retrospectively collected will not be considered new SAEs and 

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will not require reporting to the DFCI IRB, unless they are events which meet 
the protocol definition of SAE (Section 12.1.2). These additional adverse 
events are as follows:  
 Febrile Neutropenia (grade 3 and 4 only) 
 Seizure (grades 1 – 2) 
 Intracranial Hemorrhage (grades 1 – 2) 
 Injection site reactions related to Erwinia (all grades) 
 The following abnormal laboratory values (only if  ≥ grade 2): 
o Serum Amylase Increased 
o Lipase Increased 
o Alanine Aminotransferase Increased 
o Aspartate Aminotransferase Increased 
o Creatinine Increased 
o Blood Bilirubin Increased 
o Alkaline Phosphatase Increased 
o Hypoalbuminemia (low blood albumin levels) 
o Hypertriglyceridemia 
o Abnormal Sodium Levels (hypernatremia & hyponatremia) 
o Abnormal Potassium Levels (hyperkalemia & hypokalemia) 
o Abnormal Glucose Levels (hyperglycemia & hypoglycemia) 
o Activated Partial Thromboplastin Time Prolonged 
o INR Increased  
o Fibrinogen Decreased 
 
12.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, regardless of causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 Requires intensive inpatient medical interventions, including mechanical 
ventilation, pressor support, and/or fluid resuscitation, or emergent 
surgical operations.   Unplanned hospital admissions for febrile 
neutropenia, bacteremia or other documented infections, seizure, 
pancreatitis, thrombosis, nausea/vomiting, diarrhea, and other expected 
toxicities from the study treatment will not be considered a serious adverse 
event unless the severity of the condition is considered life-threatening 
and/or lead to intensive medical interventions or surgical procedures. 
 Hospital admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered SAEs 
if the illness or disease existed before the person was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the 
trial (e.g., surgery performed earlier than planned).    

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 Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. An example of 
such a medical events is allergic bronchospasm requiring intensive 
treatment in an emergency room or in the hospital. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 toxicities that are expected from the study treatment and are not 
considered life-threatening (ie, do not require intensive medical or surgical 
management, as defined above). 
 emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 respite care 
 
12.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
 
12.1.3.1 
Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent(s). For the purposes of this 
study, an adverse event is considered expected when it appears in the 
current adverse event list, the Investigator’s Brochure, the package insert 
or is included in the informed consent document as a potential risk.   
 
Refer to Section 7.1 for a listing of expected adverse events associated 
with the study agent(s). 
12.1.3.2 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   

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12.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment.  
 Unlikely - The AE is doubtfully related to the study treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 
12.2  Serious Adverse Event Reporting Requirements and Criteria 
 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance 
with national regulations, local safety reporting requirements, and reporting 
requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that 
institution to their respective IRB. It is the responsibility of each participating 
investigator to report serious adverse events to the study sponsor and/or others as 
described below.  
 
 
 
12.2.1 Reporting to the Sponsor 
 
All serious adverse events that occur after the time of enrollment, during 
treatment, or within 60 days of the first day of the last cycle of chemotherapy 
must be reported to the DF/HCC Overall Principal Investigator, Lewis Silverman, 
MD, within 24 business hours of learning of the occurrence.  This includes 
events meeting the criteria outlined in section 12.1.2 as well as the following:  
 
Reporting requirements: 
 
 Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and 
possibly, probably or definitely related to or associated with the study 
intervention 
 
 All Grade 4 (life-threatening or disabling) events, except those that are 
expected AND specifically listed in the protocol as not requiring reporting   
 

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 All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 60 days of the 
first day of the last cycle of chemotherapy. 
 
Note: If the participant is in long term follow up, report the death at the 
time of continuing review.  
 
Investigative sites within DF/HCC will report all serious adverse events directly 
to the DFCI Office for Human Research Studies (OHRS). 
 
Outside investigative sites should report serious adverse events to their respective 
IRB according to the local IRB’s policies and procedures in reporting adverse 
events.   
 
The DF/HCC Study Team will submit SAE reports from outside institutions to the 
DFCI Office for Human Research Studies (OHRS) according to DFCI IRB 
policies and procedures in reporting adverse events.  
 
12.2.2 Reporting to Regulatory Agencies 
 
All SAEs must be reported to the Overall PI, Lewis Silverman, MD, per the 
reporting process outlined in 12.3. The DF/HCC Overall Principal Investigator, 
Lewis Silverman, MD, as holder of the IND and CTA, will be responsible for all 
communication with the FDA and with Health Canada. The Overall Principal 
Investigator will report to the FDA and Health Canada, regardless of the site of 
occurrence, any adverse event that is serious, unexpected and reasonably related 
(i.e., possible, probable, definite) to the investigational agent. All events will be 
reported on a DFCI Adverse Event form and/or MedWatch 3500 or 3500A form. 
 
Unexpected fatal or life-threatening experiences associated with the use of the 
investigational agent will be reported to FDA and Health Canada as soon as 
possible but in no event later than 7 calendar days after initial receipt of the 
information. 
 
All other serious unexpected experiences associated with the use of the 
investigational agent will be reported to the FDA and Health Canada as soon as 
possible but in no event later than 15 calendar days after initial receipt of the 
information. 
 
12.2.3 Reporting to Baxalta US Inc.  
 
The DF/HCC Overall Principal Investigator, Lewis Silverman, MD, will be 
responsible for all communication with Baxalta. The DF/HCC Overall Principal 
Investigator will report Baxalta, regardless of the site of occurrence, all serious 

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12.4 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
12.5 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 60 days of the first day 
of the last cycle of chemotherapy should be followed to their resolution, or until the 
participating investigator assesses them as stable, or the participating investigator 
determines the event to be irreversible, or the participant is lost to follow-up. The 
presence and resolution of AEs and SAEs (with dates) should be documented on the 
appropriate case report form and recorded in the participant’s medical record to 
facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator, Lewis Silverman, MD, and their 
respective IRB of any unanticipated death or adverse event occurring after a participant 
has discontinued or terminated study participation that may reasonably be related to the 
study.   
 
13. DATA AND SAFETY MONITORING 
 
13.1 Data Reporting 
13.1.1 Method  
The ODQ will collect, manage, and monitor data for this study.  
13.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows: 
 

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Forms 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 
On Study Forms 
Within 14 days of registration 
Induction Data Forms 
Within 14 days of Induction Completion  
Consolidation I Data Forms 
Within 14 days of the end of Consolidation 1 
CNS Data Forms 
Within 14 days of  the end of the CNS phase 
Consolidation II Data Forms 
Every 3 months  
Continuation Data Forms 
Every 3 months 
Adverse Event Data Forms 
Within 14 days of the end of each phase OR during the 3 
month reporting period 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or being taken 
off study for any reason 
Follow up/Survival Forms 
Within 14 days of the protocol defined follow up visit 
date or call 
Serious Adverse Event 
Report Forms 
Within 24 business hours of notification of the event 
 
13.2 Safety Meetings 
 
The existing DFCI/ALL Consortium Data and Safety Monitoring Committee (DMC) 
will review and monitor toxicity and accrual data from this trial. The committee is 
composed of clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about participant 
safety will be addressed with the Principal Investigator and study team. 
 
The DFCI/ALL Consortium DMC will meet every six months and/or more often if 
required to review toxicity and accrual data.  Information to be provided to the 
committee may include:  up-to-date participant accrual; toxicity information as 
specified in Section 16; all grade 3 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring during protocol therapy; any response 
information (response to induction therapy, relapse and second malignant neoplasm 
events); audit results, and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request.  
 
The DFCI/ALL Consortium DMC will supply information to the DF/HCC Data Safety 
Monitoring Committee (DSMC) upon request. 

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13.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator, Lewis Silverman, MD, or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policyand any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
 
14. REGULATORY CONSIDERATIONS 
 
14.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator, Lewis Silverman, 
MD, will disseminate protocol amendment information to all participating 
investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
14.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
14.3 Ethics 

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This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 
State laws 
 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
14.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
14.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
14.6 Multi-center Guidelines 

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This protocol will adhere to the policies and requirements of the Dana-
Farber/Harvard Cancer Center. The specific responsibilities of the DF/HCC 
Overall Principal Investigator, Lewis Silverman, MD, Coordinating Center, and 
Participating Institutions are presented in the Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan (see Appendix III). 
 The DF/HCC Overall Principal Investigator, Lewis Silverman, MD, is 
responsible for distributing all IND Action Letters or Safety Reports to all 
participating institutions for submission to their individual IRBs for action as 
required. 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
 Except in very unusual circumstances, each participating institution will order 
the agent(s) directly from the supplier. A participating site may order the 
agent(s) only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.  

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15. Laboratory Evaluation and Therapy at Outside Affiliate Sites 
Some standard-of-care laboratory studies and treatments may be performed at satellite sites/ 
hospitals that are affiliated with the Lead Insitution or a Participating Site.  It is the 
responsibility of the Lead Institution or Participating Site to which the satellite/affiliate 
hospital is affiliated to monitor all care that is performed at the satellite/affiliate hospital in 
order to ensure protocol compliance and to screen for any adverse events.   
15.1 Laboratory Studies 
15.1.1 Laboratory studies that can be peformed at satellite sites/affiliate hospitals: 
Standard-of care labs (complete blood count, liver function tests, amylase, lipase, 
triglyceride levels) used to determine whether starting criteria for chemotherapy are 
met and/or to monitor for side effects.   
15.1.2 Laboratory Studies that can only be obtained at Lead or Participating Instution:  
 All Research Laboratories, including asparaginase enzyme levels 
 Methotrexate levels (Consolidation I)  
15.2 Therapy 
15.2.1 Chemotherapy that may be administered at satellite sites/affiliate hospitals or at 
home:  
  Standard-of-care chemotherapy agents (eg, vincristine, 
doxorubicin/dexrazoxane) administed during Consolidation II or Continuation 
phases may be administered at a satellite site/affiliate hospital.   
  Intramuscular Erwinia asparaginase (for patients who develop allergy to PEG 
asparaginase) may be administered at a satellite site/affiliate hospital.  
 
Intravenous Erwinia asparaginase (for patients who is unable to 
tolerate IM Erwinia) may not be administered at a satellite 
site/affiliate hospital.          
 Oral agents (eg, prednisone, dexamethasone, 6-mercaptopurine) may be 
administered in the home or at a satellite site/affiliate hospital.  
 Intravenous/Intramuscular methotrexate (Consolidation II or Continuation phase 
only) may be administered in the home or at a satellite site/affiliate hospital.   
 Low-dose intravenous cytarabine during the Consolidation IB phase may be 
administered the home or at a satellite site/affiliate hospital.    
15.2.2 Therapy that can only be administered at Lead or Participating Instution:  
 All doses of Oncaspar or Calaspargase Pegol (SC-PEG)  
 All intravenous chemotherapy administered during the Steroid Prophase, 
Remission Induction, Consolidation I, and CNS phases (exception: low-dose 
cytarabine during Consolidation IB for VHR patients) 
 All intrathecal chemotherapy 
 

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15.2.3 Procedures and Radiographic Studies 
 Diagnostic bone marrow, nodal and/or mass biopsies and radiographic studies 
that have already been performed at an outside institution do not have to be 
repeated prior to study entry, but the pathologic/radiographic interpretation of 
these studies confirming protocol eligibility must be performed at Lead 
Institution or Participating Institution. 
 All subsequent protocol-required or optional bone marrow tests (eg, end-
induction, Day 18 or end-of-therapy), restaging radiographic studies (to assess 
remission status) and lumbar punctures with intrathecal chemotherapy may only 
be performed at Lead Institution or Participating Institution  
 

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16. STATISTICAL CONSIDERATIONS  
 
Patients will be randomized to receive either IV Calaspargase Pegol (SC-PEG) 2500 IU/m2 (arm 
A) or IV Oncaspar 2500 IU/m2 (arm B), both administered as a single dose during induction and 
then for 30 weeks during post-induction treatment phases (IV SC-PEG given every 3 weeks and 
IV Oncaspar every 2 weeks).  Samples to assess serum asparaginase enzyme activity will be 
obtained weekly (for 4 weeks) after the induction dose (days 4, 11, 18, and 25 post-asparaginase 
dose). In the post-induction treatment phases, IV SC-PEG 2500 IU/m2 will be administered 
every 3 for 30 weeks (weeks 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28, a total of 10 doses in 30 
weeks) with samples obtained prior to every dose.  IV Oncaspar 2500 IU/m2 will be administered 
every two weeks on weeks 1,3,5,…29 (a total of 15 doses in 30 weeks) and asparaginase enzyme 
samples will be obtained prior to every dose.   Both IV Oncaspar and IV SC-PEG asparaginase 
enzyme level samples will be taken at the same time point on weeks 7, 13, 19 and 25.  
 
Safety data will be monitored on each arm and compared to that of the historical control rate 
observed on DFCI protocol 05-001. On DFCI Protocol 05-001, 7% of enrolled subjects were not 
randomized due to ineligibility, induction failure, induction death, early toxicity, early 
withdrawal, and the presence of the Philadelphia chromosome.  Additionally, some patients will 
be unable to complete 30 weeks of post-induction therapy. Therefore, we assume that 
approximately 7% of patients who enroll on this randomized pilot trial will not be evaluable for 
post-induction toxicity assessment and the post-induction pharmacokinetic analyses.  
16.1 Primary Objectives: Safety and Feasibility of SC-PEG asparaginase 
 
A total of 240 patients will be enrolled on this trial to evaluate the primary endpoint. We plan to 
enroll 120 patients on each arm to have 112 patients on each arm evaluable for the monitoring of 
asparaginase toxicity in Consolidation I, CNS and Consolidation II phases of treatment and the 
pharmacokinetic secondary endpoint. The randomization will be stratified into four groups based 
on disease type, age and risk group classification: ALL patients under 10 years of age and SR, 
ALL patients under 10 years of age and HR, ALL patients 10 years and older (and by definition 
HR), and patients with lymphoblastic lymphoma. We estimate that of the 240 patients enrolled, 
34 will have lymphoblastic lymphoma.  
 
16.1.1 Safety 
 
 
16.1.1.1 Safety Monitoring 
One primary objective of this study is to compare the asparaginase-related toxicity rate of IV SC-
PEG with that of IV Oncaspar on Protocol 05-001.  The toxicity data from the IV Oncaspar arm 
of this study will be monitored to ensure that the rate of asparaginase-related toxicities with IV 
Oncaspar is not dissimilar between Protocol 05-001 and Protocol 11-001, thus allowing for the 
toxicity comparison between 11-001 IV SC-PEG- and 05-001 IV Oncaspar-treated patients .  
Toxicity rates from the induction phase and post-induction phases of treatment for both arms will 
be monitored. 

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We will carefully monitor and prospectively collect data relating to asparaginase-related 
toxicities of any grade.   On DFCI Protocol 05-001, the three most common asparaginase-related 
toxicities were pancreatitis, hypersensitivity and thrombotic complications.  The rates of these 
toxicities on each arm will be compared at the DMC meeting approximately every six months. 
We will also monitor other severe toxicities, defined as any grade 4 or higher toxicity (excluding 
asymptomatic laboratory abnormalities, and noting that elevations of amylase and lipase are 
markers of pancreatitis and will be included in the rate of asparaginase-related toxicity) 
occurring during the induction phase and  during the 30 weeks of post-induction treatment 
including asparaginase.  Severe pancreatitis will be defined as an elevation in serum amylase 
greater than three times normal with clinical signs and symptoms consistent with that diagnosis 
persisting for more than 72 hours.  Mild to moderate pancreatitis will be defined as above with 
signs and symptoms lasting for less than 72 hours.  All other toxicity grading will be per CTC 
version 4.0.  
 
On DFCI Protocol 05-001, the overall asparaginase-related toxicity rate for patients randomized 
to IV Oncaspar was 27% for the Consolidation I, CNS and Consolidation II phases of treatment.  
Safety data will be subsequently monitored approximately every 6 months by the DMC.  The 
safety analysis will not be a comparison of randomized arms, but each arm will be monitored by 
comparing toxicity rates to the historical control arm of IV Oncaspar on 05-001. We will monitor 
the proportion of patients experiencing asparaginase-related toxicity to ensure that this rate does 
not significantly differ from the 27%, observed on 05-001 in either arm. Assuming we have 
approximately 30 patients enrolled on each arm (60 total), who have adequate toxicity data 
(Consolidation I-Consolidation II phases of treatment) at the time of the first interim analysis, if 
12 or more of the 30 (40%; exact two-sided 80% CI: 28%-53%) patients experience 
asparaginase-related toxicity, we would consider this unacceptable, as the expected rate of 27% 
is excluded from the lower bound of the exact one-sided binomial 90% confidence interval (or 
exact two-sided 80% CI). The trial would stop accrual and the safety data would be carefully 
reviewed by the DMC. Similar assessments will be made at each interim analysis for each arm. 
Based on an accrual rate of 10 patients per month and a DMC meeting occurring every six 
months we plan on three interim looks at the data and a final analysis at 100% information when 
all patients are enrolled have adequate toxicity follow-up data (approximately 10 months post 
consolidation I). We assume that the asparaginase-related toxicity rate will be similar for 
lymphoblastic lymphoma patients.  With 112 evaluable patients on each arm at the final analysis, 
if 38 or more (34%; exact two-sided 80% CI: 28%-40%) patients experience asparaginase-
related toxicity, we would consider this unacceptable. The upper bound of the exact one-sided 
90% CI (or exact two-sided 80% CI) for the true unknown rate of asparaginase-related toxicity 
would be no more than 40%.   
 
At each DMC meeting, we will also consider asparaginase-related toxicities separately and 
consider stopping if the incidence of pancreatitis, allergy, and/or thrombosis for the SC-PEG arm 
are significantly higher than that of IV-Oncaspar. Similarly, the induction toxicity rate for 
pancreatitis, allergy, thrombosis, bacterial and fungal infection and the rate of excessive toxicity 
(all other grade 4 or higher toxicities) will also be compared to that of the historical control rate 
and monitored at each DMC meeting.  Since the study is not powered to detect differences in 
toxicity rates between arms, only to monitor rates versus historical controls, comparison of the 

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toxicity rates between arms will only be made at the request of the DMC at each interim analysis. 
The rate of asparaginase-related toxicity will be reported for each arm along with the exact 
binomial 90% confidence intervals with a maximum width no wider than 16%. 
 
Toxicity grading using CTC version 4.0 will also be reported for all patients who received 
therapy. The number and proportion of patients with each toxicity type will be reported. The 
worst grade toxicity will be determined for each patient and the proportions will be reported with 
the 90% confidence intervals for each arm.  
 
16.1.1.2 Minimum Residual Disease (MRD) Monitoring 
COG Protocol AALL07P4 tested SC-PEG asparaginase during the induction phase.  Patients 
were initially randomized to receive either SC-PEG or Oncaspar at 2500 IU/m2.  After a protocol 
amendment, patients randomized to SC-PEG received a dose of 2100 IU/m2.  The study was 
suspended on December 22, 2010 based on a higher rate of Day 29 end-induction MRD- 
positivity (MRD+) for patients treated with SC-PEG 2100 IU/m²/dose compared with SC-PEG 
2500 IU/m²/dose or Oncaspar 2500 IU/m²/dose.  The difference in frequency of MRD-positivity 
was statistically significant and crossed pre-defined safety monitoring boundaries. 
 
Based on this finding, we will monitor the frequency of high end-induction MRD (defined as > 
0.001 by PCR assay) in patients with B-precursor ALL at each interim analysis.  Of the first 432 
B-ALL patients treated on Protocol 05-001, end-induction MRD was successfully assayed in 
92% of patients and 12.5% were found to be MRD-high.  We will monitor the proportion of 
patients with MRD levels >0.001 in each arm at the end of remission induction to ensure that this 
rate does not significantly differ from 12.5%. Assuming we have 30 patients per arm (60 in total) 
at the first interim analysis and 92% have informative end-induction samples (N=28), if 7 or 
more of the 28 (25%; two-sided 80% CI: 14%-38%) patients have high MRD samples, we would 
consider this unacceptable, as the expected rate of 12% is excluded from the lower bound of the 
exact one-sided 90% confidence interval. The trial would stop accrual and the data would be 
reviewed by the DMC. Similar assessments will be made at each interim analysis. Comparisons 
between arms will be made at the request of the DMC at each interim analysis. The rate of high 
end-induction MRD will also be reported for each arm along with the 90% confidence intervals 
with a maximum width no wider than 16%.  
 
16.1.2 Feasibility and Pharmacokinetic Endpoints 
16.1.2.1 Feasibility of Every 3-Week Dosing of IV SC-PEG  
The feasibility of administering IV SC-PEG at a dose of 2500 IU/m2 every 3-weeks will be 
assessed by calculating the proportion patients who achieve a nadir serum asparaginase activity 
(NSAA) level ≥0.10 IU/mL (considered therapeutic) at any post-induction time point in each 
arm. We will compare the proportion of patients who have at least 1 NSAA measure ≥0.10 
IU/mL between arms.  In the first 114 analyzed on DFCI Protocol 05-001, 100% of patients 
treated with IV Oncaspar had at least 1 NSAA level ≥ 0.10 IU/mL during the post-induction 
asparaginase consolidation. With 112 evaluable patients on each arm and assuming 99% of 
patients on the IV Oncaspar arm have at least 1 NSAA level ≥ 0.10 IU/mL during the post-
induction asparaginase consolidation, we will have 89% power to detect a 10% reduction in the 
proportion of patients who have at least 1 NSAA level ≥ 0.10 IU/mL during the post-induction 

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asparaginase consolidation, using a one-sided Fisher exact test at the 0.025 significance level. If 
there is no difference in the proportion of patients who have at least 1 NSAA level ≥ 0.10 IU/mL 
during the post-induction asparaginase consolidation, we will consider the administration of 
every 3-week IV SC-PEG feasible.     
16.1.2.2 Asparaginase Enzyme Activity: Induction Phase – Early Stopping 
 
We will also compare the proportion of patients with serum asparaginase enzyme activity of at 
least 0.10 IU/mL at 4, 11, 18 and 25 days after a single dose of either IV Oncaspar (2500 IU/m2) 
or IV SC-PEG (2500 IU/m2) is administered during the induction phase.  
 
At the Day 25 time point (18 days after the dose of IV Oncaspar) on Protocol 05-001, 88% 
patients in induction had a serum asparaginase enzyme activity level ≥0.10 IU/mL, however only 
7% achieved this level at the Day 32 time point (Table 2.4 of the Background section).  On the 
COG Protocol AALL07P4, 100% of patients had a serum asparaginase enzyme activity level 
≥0.10 IU/mL at both 22 and 29 days after the dose of IV SC-PEG (Table 2.5 of the Background 
section).  Asparaginase enzyme activity will be run in real time from samples obtained at 
Induction Days 25 and 32 (18 and 25 days after asparaginase dose) for all patients enrolled on 
Protocol 11-001. Assuming we have approximately 30 evaluable patients enrolled on each arm 
(60 total) at the time of the first interim analysis, if 23 or fewer of the 30 (77%; exact two-sided 
80% CI: 64%-87%) patients have an asparaginase enzyme activity level ≥0.10 IU/mL, at the Day 
25 time point (on either arm),  we would consider this unacceptable, as the expected rate of 88% 
is excluded from the upper bound of the exact one-sided binomial 90% confidence interval.  
Similarly, at the Day 32 time point (25 days after the dose of IV SC-PEG) if 23 or fewer of the 
30 patients (77%; exact two-sided 80% CI: 64%-87%) on the IV SC-PEG arm have an 
asparaginase enzyme activity level ≥0.10 IU/mL, we would also consider this unacceptable. This 
stopping rule will ensure that the proportion of patients who achieve a target therapeutic level 
with IV SC-PEG is comparable to that of IV Oncaspar at Day 25 (18-days post-dose) and is 
maintained at Day 32 (25-days post-dose), which will justify the every 3-week dosing schedule 
during Consolidation for patients randomized to received IV SC-PEG. Similar comparisons will 
be made at each interim analysis and at the final analysis.  
 
Descriptive statistics including the median, range, mean and standard deviation of asparaginase 
enzyme level will be reported and compared as appropriate at each induction day that samples 
are collected for each arm. We will analyze and compare the data between arms longitudinally as 
described for the post-induction time points.   
 
16.1.2.3 Asparaginase Enzyme Activity – Consolidation Phase (post-Induction) 
 
Both IV Oncaspar and IV SC-PEG asparaginase enzyme level samples will be collected in real 
time at the same post-induction time points on weeks 7, 13, 19 and 25.  Descriptive statistics 
including the median, range, mean and standard deviation of serum asparaginase activity will be 
reported for each post-induction week that samples are collected for each arm. To ensure that 
asparaginase levels are being maintained at the ≥0.10 level, the proportion of samples with levels 

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> 0.025, ≥ 0.10, ≥ 0.20, and ≥ 0.40 IU/mL at each time point for both arms will also be reported 
and reviewed at each DMC meeting. 
 
We will directly compare asparaginase enzyme activity levels between the two arms.  With a 
total of 224 evaluable patients (112 on each arm), we would have  96% power to detect a mean 
difference of 0.15 in asparaginase enzyme activity level at the week 7 time point (estimated to be  
steady-state based on data from Protocol 05-001) using a two-sided t-test and assuming a 
standard deviation of 0.30.  This is equivalent to an effect size (δ=∆/σ) of 0.5.  
 
In addition to week 7 post-induction, we will also collect asparaginase enzyme levels at weeks 
13, 19, and 25 for every 2-week IV Oncaspar and compare them to every 3-week IV SC-PEG.  
We will compare the asparaginase enzyme levels between arms longitudinally with a random 
effects mixed model as appropriate. A log-10 transformation will be used for the asparaginase 
levels if the distribution of asparaginase enzyme levels warrant.  These models will consider 
additional baseline patient characteristics including age sex, as well as the stratification factors of 
risk group and disease type, while testing for a difference in asparaginase enzyme activity 
between arms. Generalized estimating equation (GEE) models will be explored using cut-offs 
including > 0.025, ≥ 0.10, ≥ 0.20, and ≥ 0.40 IU/mL. Tables 2.1, 2.2 and 2.3 in the Background 
section provide descriptive statistics for the induction and post-induction time-points in for IV 
Oncaspar on Protocol 05-001.  
 
 
16.2 Secondary Objectives 
16.2.1 Antibiotic Prophylaxis during Induction Phase 
Based on historical rate of bacterial infection in the induction phase of treatment on 05-001 of 
25%, we will also test the hypothesis that antibiotic prophylaxis will significantly reduce the rate 
of bacterial infection.  We will compare the rate of infection during the induction phase in 
patients with ALL enrolled on Protocol 11-001 with those who were treated on Protocol 05-001.  
The induction regimen of the two protocols is nearly identical, with the following exceptions: 1) 
patients on Protocol 11-001 will receive either a single dose of IV SC-PEG or IV Oncaspar while 
all patients on Protocol 05001 received a single dose of IV Oncaspar and 2) patients on 11-001 
will receive antibiotic prophylaxis while those on Protocol 05-001 did not.  For the 11-001 
patient cohort, we will only consider the infections of patients with ALL (not lymphoblastic 
lymphoma) in this comparison, because only patients with ALL were treated on Protocol 05001 
and the frequency and severity of infections may be different in patients with lymphoblastic 
lymphoma who do not have marrow involvement at diagnosis (and thus may have a higher 
neutrophil count for longer during the induction phase).   
 
Because of potential interaction between asparaginase type and risk of infection, we will analyze 
infection rates separately in each randomized arm.  With approximately 103 patients on each arm 
(excluding lymphoma patients), we would have 82% power to detect a 12% reduction in the rate 
of bacterial infection in the induction phase of treatment based on a one-sample, 1-sided exact 
binomial test with a significance level of 0.025. Each arm will be compared to that of the 
historical control rate of 25%.  

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16.2.2 Efficacy 
Although not sufficiently powered to detect difference between the arms, event-free survival 
(EFS) and overall survival (OS) will be calculated using the method of Kaplan and Meier for 
each arm. Event-free survival will be defined as the time from achievement of complete 
remission to the time of relapse, death or second malignancy. Patients not achieving complete 
remission will be considered events at time zero. Overall survival will defined as the time from 
diagnosis until death.  Five-year estimates of EFS and OS will be provided for each arm along 
with the 90% confidence intervals estimated using the formula of Greenwood once sufficient 
follow-up data is obtained. Additionally, we will report EFS and OS estimates for children (<10 
years) and adolescents (≥10 years) and for lymphoblastic lymphoma patients separately for each 
arm along with the appropriate confidence intervals.  
 
Since 2005, we have treated patients with VHR ALL (B-precursor patients with high end-
induction MRD and/or high-risk cytogenetics) with a novel chemotherapy regimen 
including two additional cycles of consolidation therapy.  Treatment for VHR patients on 
Protocol 11-001 will be identical to that on Protocol 05-001, except for the asparaginase 
preparation in some patients.  We will combine outcome data for the VHR cohort on 
Protocol 11-001 with those treated on Protocol 05-001 to describe the outcome of this 
patient subset with the intensified VHR treatment. We estimate that approximately 70 
patients will have been treated on the VHR arm on Protocol 05-001 at the time of its closure 
and anticipate that approximately 20 ALL patients on Protocol 11-001 will be classified as 
VHR for a total of 90 patients combined. Preliminary estimates of EFS and OSwill be 
reported for this cohort of patients.  
 
16.2.3 Vitamin D Screening 
Patients will have vitamin D levels will be prospectively screened (to determine the frequency of 
vitamin D deficiency) and patients will begin vitamin D supplementation at any time point after 
completion of the induction phase when low vitamin D levels are identified. The time points of 
assessment will include pre-treatment, end of induction therapy, the start of continuation phase, 
and at the conclusion of therapy. At each of these time points, patients will be classified based on 
the measurement of 25-hydroxy vitamin D level as:  deficient <20 ng/mL, insufficient 20-29 
ng/mL, sufficient 30-79 ng/mL, or having possible toxicity ≥80 ng/mL.  Based on these 
assessments, patients will be assigned a recommended dose of vitamin supplementation if 
deemed deficient or insufficient. At each time point we will record the level of 25-hydroxy 
vitamin D and the classification of each patient (determines the age-adjusted recommended daily 
allowance or RDA).  At each time point, we will calculate descriptive statistics including 95% 
confidence intervals based on these measures. Pre- and post-measurements will be compared at 
the end of induction and the start of Continuation using a two-sided paired t-test at the 0.05 level. 
For example, if we estimate the 10% of the 240 patients have insufficient or deficient levels at 
baseline, we have at 94% power to detect a difference (a potential increase) in these levels 
assuming an effect size (δ=|μ1- μ2|/σ) of 0.75 or >99% power assuming an effect size of 1.0. 
Similar assessments will be made at subsequent time points.      
16.2.4 Prospective Screening of TCRγ Deletions in T-ALL Patients and Abnormalities of 
IKZF1, CRLF2 and JAK 1/2 in B-ALL Patients 

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Because these abnormalities will be screened only in diagnostic marrow samples, only patients 
with leukemia will be included in these analyses.  The proportion of these abnormalities will be 
recorded along with 90% confidence intervals of these estimates. The association of early T-ALL 
precursor phenotype and ABGD status will be tested. The association of each B-ALL abnormality 
with end-induction MRD both categorized as high (>0.001) and as a continuous measurement. It is 
understood that the proportion of these patients with deletions or abnormalities may be small, and 
thus we would be underpowered to detect differences, so this testing will be considered as 
exploratory. It is estimated that approximately 10% of ALL patients will be T-cell and 90% of 
patients will be B-cell. Assuming we have successful screening results on 206 patients (excluding 
lymphoma patients), the exact two-sided 90% confidence interval will be no wider than 40% for 
proportion of T-ALL patients with ABGD and no wider than 13% for the proportion of patients 
with each abnormality screened for B-ALL patients.   
16.2.5 BH3-Profiling to Identify Patients at High Risk of Treatment Failure 
The loss of mitochondrial membrane potential will be measured in lymphoblasts taken at the 
time of diagnosis to identify which anti-apoptotic BCL-2 family members are present and 
potentially primed for death. We will test for an association between the loss of membrane 
potential and chemotherapy response as measured by induction response, end-induction MRD 
level and EFS. Because BH3-profiling studies will be performed using diagnostic marrow 
samples, only patients with leukemia will be included in these analyses.  Assuming we have 206 
patients (excluding lymphoma patients) and approximately 90% enter complete remission, we 
would have 90% power to detect a difference in the loss of membrane potential between those 
who did not enter a complete remission versus those who entered a complete remission assuming 
an effect size of 0.75 using a two-sided t-test with a significance level of 0.05 and >99% power 
assuming an effect size of 1.0. The correlation of the loss of mitochondrial potential with end-
induction MRD levels will also be explored. Preliminary estimates of EFS categorized based on 
the loss of mitochondrial membrane potential will be recorded using recursive partitioning based 
on the rpart package in R. 
 
16.3 Accrual Rate 
Based on accrual rates from Protocol 05-001, we expect to accrue approximately 10 patients per 
month to this trial. Assuming 240 patients are enrolled on the trial (120 per arm), accrual will be 
completed in approximately 2 years (24 months).  
 
 
17. PUBLICATION PLAN 
The results will be made public within 24 months of the end of data collection. The initial plan 
for release would be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors.  Once analyses are completed, results will be submitted to a peer-
reviewed journal. 

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al. Molecular response to treatment redefines all prognostic factors in children and adolescents 
with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM 
ALL 2000 study. Blood. 2010;115(16):3206-14. 
37. 
Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, 
et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell 
ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077-84. 
38. 
Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB. Bony morbidity in 
children treated for acute lymphoblastic leukemia. J Clin Oncol. 2001;19(12):3066-72. 
39. 
Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of 
treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J 
Clin Oncol. 2000;18(18):3262-72. 
40. 
Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium 
and Vitamin D. Washington, D.C.: Institute of Medicine, National Academy of Sciences; 2010. 
41. 
Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, 
and adolescents. Pediatrics. 2008;122(5):1142-52. 
42. 
Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in 
children and its management: review of current knowledge and recommendations. Pediatrics. 
2008;122(2):398-417. 
43. 
Atkinson SA. Vitamin D status and bone biomarkers in childhood cancer. Pediatr Blood 
Cancer. 2008;50(2 Suppl):479-82; discussion 86. 
44. 
Kelly KM, Orjuela M, Ladas EJ, O'Brien J, Belden L, Silverman LB. Low dietary intake of 
calcium associated with increased risk of fracture in males undergoing treatment for acute 
lymphoblastic leukemia. Pediatr Blood Cancer. 2010;55(5):855 (SIOP 2010 Congress abstract 
PA022). 
45. 
Kelly KM, Thornton JC, Hughes D, Osunkwo I, Weiner M, Wang J, et al. Total body bone 
measurements: a cross-sectional study in children with acute lymphoblastic leukemia during and 
following completion of therapy. Pediatr Blood Cancer. 2009;52(1):33-8. 

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46. 
Gutierrez A, Dahlberg SE, Neuberg DS, Zhang J, Grebliunaite R, Sanda T, et al. Absence 
of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute 
lymphoblastic leukemia. J Clin Oncol. 2010;28(24):3816-23. 
47. 
Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al. Early T-
cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet 
Oncol. 2009;10(2):147-56. 
48. 
Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 
and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-80. 
49. 
Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, 
Scheijen B, et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-
ALL. Leukemia. 2010;24(7):1258-64. 
50. 
Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ, et al. 
Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, 
Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic 
leukemia. Blood. 2010;115(26):5312-21. 
51. 
Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down 
syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant 
expression of CRLF2 is associated with mutated JAK2: a report from the International BFM 
Study Group. Blood. 2010;115(5):1006-17. 
52. 
Letai A, Sorcinelli MD, Beard C, Korsmeyer SJ. Antiapoptotic BCL-2 is required for 
maintenance of a model leukemia. Cancer Cell. 2004;6(3):241-9. 
53. 
Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence 
and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood. 2008;111(4):2300-9. 
54. 
Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies 
three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional 
chemotherapeutic agents. Cancer Cell. 2007;12(2):171-85. 
55. 
Zhou J, Goldwasser MA, Li A, Dahlberg SE, Neuberg D, Wang H, et al. Quantitative 
analysis of minimal residual disease predicts relapse in children with B-lineage acute 
lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood. 2007;110(5):1607-11. 
56. 
Inukai T, Kiyokawa N, Campana D, Coustan-Smith E, Kikuchi A, Kobayashi M, et al. 
Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the 
Tokyo Children's Cancer Study Group Study L99-15. Br J Haematol. 2012;156(3):358-65. Epub 
2011/12/02. 
57. 
Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved 
early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic 
leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175-81. 
58. 
Schwartz CL, Thompson EB, Gelber RD, Young ML, Chilton D, Cohen HJ, et al. 
Improved response with higher corticosteroid dose in children with acute lymphoblastic 
leukemia. J Clin Oncol. 2001;19(4):1040-6. 
59. 
Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG, et al. Early 
intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in 
children with acute lymphoblastic leukemia. Blood. 1998;92(2):411-5. 
60. 
Harris MB, Shuster JJ, Pullen DJ, Borowitz MJ, Carroll AJ, Behm FG, et al. Consolidation 
therapy with antimetabolite-based therapy in standard- risk acute lymphocytic leukemia of 
childhood: a Pediatric Oncology Group Study. J Clin Oncol. 1998;16(8):2840-7. 

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61. 
Mahoney DH, Jr., Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, et al. 
Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to 
repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-
risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin 
Oncol. 1998;16(1):246-54. 
62. 
Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating 
childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 
2009;360(26):2730-41. 
63. 
Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bokkerink JP, Bruin MC, et 
al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the 
prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet 
Oncol. 2009;10(10):957-66. 
64. 
Conter V, Arico M, Valsecchi MG, Rizzari C, Testi AM, Messina C, et al. Extended 
intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in 
children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-
Munster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia 
Pediatrica. J Clin Oncol. 1995;13(10):2497-502. 
65. 
Stark B, Sharon R, Rechavi G, Attias D, Ballin A, Cividalli G, et al. Effective preventive 
central nervous system therapy with extended triple intrathecal therapy and the modified ALL-
BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents 
with non-B-cell acute lymphoblastic leukemia: the Israel National Study report. Cancer. 
2000;88(1):205-16. 
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Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M, et al. Risk-
adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve 
survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the 
trial ALL-BFM 95. Blood. 2008;111(9):4477-89. 
67. Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, Pui CH, Campana 
D. Deep-sequencing approach for minimal residual disease assessment in acute lymphoblastic 
leukemia.  Blood 2012; 120 (26):5173-80. 
 
 

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19. APPENDICES  
19.1 Appendix I: Vitamin D and Calcium Supplementation Guidelines 
 
Vitamin D levels will be assessed in all patients at study entry, at the end of induction, at the start 
of continuation phase, and at the end of therapy.  Patients are recommended to begin vitamin D 
supplementation at any time-point when low vitamin D levels are identified, beginning with the 
assessment at the end of the induction phase.  Vitamin D supplementation during the induction phase is 
not recommended, even in patients with low levels identified at the time of diagnosis.   
 
Vitamin D levels will be classified as follows: 
 
Vitamin D deficiency: 25-hydroxy vitamin D level less than 20 ng/mL 
 
Vitamin D insufficiency: 25-hydroxy vitamin D level 20-<30 ng/mL 
 
Vitamin D sufficiency: 25-hydroxy vitamin D level 30-80 ng/mL 
 
Possible toxicity: 25-hydroxy vitamin D level greater than 80 ng/mL 
 
For patients with vitamin D deficiency (especially with levels less than 10 ng/ml) in whom high dose 
vitamin D supplementation is recommended, calcium supplementation is necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin D Deficiency: 
25 (OH) D: < 20 
Vitamin D Insufficiency: 
25 (OH) D: 20- <30 
Supplement 
1-12 years:  600 IU PO of 
Ergocalciferol (D2) daily 
 
≥12 years 1000 IU of 
Ergocalciferol (D2) daily  
 
OR 
 
600 IU PO of cholecalciferol (D3) daily 
 
Recheck in 3 months 
Supplement 
50,000 IU PO of 
Ergocalciferol (D2) weekly for 6 weeks 
(may be preferable if risk of noncompliance) 
 
Recheck 2 weeks after completing 6 week 
course 
 
OR 
 
5,000 IU PO of cholecalciferol (D3) daily 
 
Recheck 2-4 weeks after completing 8-12 
week course 
 
Calcium Supplementation is necessary 
during high dose vitamin D therapy (see 
below)

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Calcium Supplementation Guidelines 
 
In all patients: 
 
Assess dietary calcium intake by estimating whether average intake meets age appropriate RDA 
(table). 
 
If inadequate dietary calcium intake, additional calcium should be administered with the use of 
supplements with the dose adjusted to the age associated RDA.   
 
If vitamin D deficient or insufficient, ensure adequacy of calcium intake. 
 
 
Calcium Guidelines 
Age  
 
 
RDA (mg/day)  
UL Intake (mg/day) 
1-3 years 
 
 
700 mg  
 
 
2500 mg 
4-8 years 
 
 
1000 mg 
 
 
2500 mg 
9-13 years  
 
1300 mg 
 
 
3000 mg 
14-18 years  
 
1300 mg 
 
 
3000 mg 
19-30 years  
 
1000mg  
 
 
2500mg 
31-50 years  
 
1000mg  
 
 
2500mg 
 
Calcium Supplementation Guidelines for Vitamin D Deficient Patients 
In patient with vitamin D deficiency (especially levels less than 10 ng/mL), calcium levels should be 
maintained with oral calcium supplements.  Even for children who are not frankly hypocalcemic, calcium 
supplements are important for avoiding subsequent hypocalcemia from a decrease in bone 
demineralization and an increase in bone mineralization as PTH levels normalize (“hungry-bone” 
syndrome).  Recommended doses of elemental calcium are 30 to 75 mg/kg per day in 3 divided doses.  In 
addition to calcium supplements, calcitriol may be necessary in doses of 20 to 100 ng/kg per day in 2 to 3 
divided doses until calcium levels normalize. High doses of calcium are necessary early in the course of 
No Supplement 
 
Monitor at 
specified 
assessment time-
points 
Vitamin D Sufficiency: 
25 (OH) D: ≥30 

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therapy, after which doses are reduced by half for the next 1 to 2 weeks.  Once vitamin D 
supplementation has been reduced to 600-1000 IU/day, calcium supplementation is usually not necessary. 
 

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19.2 Appendix II: Guidelines for the Management of Thrombosis 
 
 Prevention of VTE:  
o The risk of VTE in similar previous protocols is age-related with a known incidence of 2-
36% based on age (highest risk at oldest age). The peak of this risk is during asparaginase 
therapy from induction through consolidation. 
o In patients with previously identified risk factors for VTE (ex., Factor V Leiden mutation, 
prior VTE, immobilization), consider prophylactic anticoagulation (+/- antithrombin 
infusions) during asparaginase therapy. 
 
 Diagnosis of VTE: 
o All suspected VTE should be diagnosed/confirmed by radiologic imaging before stopping 
asparaginase and initiating anti-coagulation.. 
Thrombosis Type 
Symptoms 
Suggested Imaging 
Non-CNS DVT 
Limb swelling, 
pain, warmth, 
discoloration 
 Doppler Ultrasound (US) 
 Contrast line study (may be 
falsely negative) 
 If high clinical suspicion in upper 
extremity and US is negative, 
consider MRV or contrast CT. 
Pulmonary Embolism 
Chest pain, 
shortness of breath, 
cough/hemoptysis 
 CTA/spiral CT 
 V/Q scan 
Sinus Venous 
Thrombosis 
Headache, seizures, 
vision changes, 
mental status 
changes 
 CTV 
 MRI/MRV (if high clinical 
suspicion and CTV is negative, 
consider MRV). 
 
o At the time of VTE, send a platelet count, antithrombin functional level, PT, PTT, and 
fibrinogen level.   
o Family history of thrombosis should be obtained.  Based on family history and/or 
whether it will impact the decision of length of anticoagulation, consider sending tests of 
inherited thrombophilia1 after completing asparaginase therapy.  Please note:  if these 
tests are sent during asparaginase therapy, the tests measuring protein levels may be 
falsely abnormal due to asparaginase and will need to be repeated when asparaginase is 
complete. The genetic tests (PT, FVL and MTHFR) are not affected by asparaginase. 
 Management of Asparaginase after VTE: 
o Hold Asparaginase and start anticoagulation (see below).   
                                                 
1  Thrombophilias:  Activated Protein C resistance (APCR), Factor V Leiden (send if APCR is positive), 
prothrombin mutation, fasting homocysteine, MTHFR mutation (if homocysteine is positive), Protein C activity 
level, Protein S level, fasting lipoprotein(a), Lupus anticoagulant, Factor VIII activity level, D-Dimer 

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o Central line removal should be considered if the line is nonfunctional or causing 
symptoms, such as extremity swelling or pain, which do not resolve with anticoagulation.  
Consider 2-3 days of anticoagulation prior to line removal.  
o Resume asparaginase when symptoms have resolved and there is evidence of clot 
stabilization and/or recanalization/improvement on repeat imaging.  The typical time to 
stabilization/improvement is 3-4 weeks.  If symptoms are not improved and/or imaging 
has not stabilized after 6-8 weeks, discuss with the study PI or designee.   
o Repeat imaging is necessary before asparaginase is resumed.   
o With adequate anticoagulation, permanent discontinuation of asparaginase due to 
thrombosis is typically not necessary. In cases of significant CNS events or recurrent clot, 
asparaginase may be permanently held only after discussion with the study PI or 
designee.    
 
 Anticoagulation:  Based on the safety and efficacy of LMWH in oncology patients, consider 
using LMWH for all acute thrombotic events.   
 
 Guidelines for Supportive Care to Start and Continue Anticoagulation: 
o Platelet count ≥ 50 kcells/ul or per institutional guidelines.  During anticoagulation, 
transfuse and/or modify anticoagulation based on institutional guidelines.  After 
initial diagnosis of thrombosis, during the first few weeks of anticoagulation, 
consider transfusing platelets to maximize anticoagulation dosing (and anti-Xa 
levels). 
Consider guidelines in table below: 
Platelet count 
(kcells/uL) 
Anti-Xa level (IU/ml) 
Transfuse Platelets 
≥ 50 
0.5-1 
No 
>20 but <50 
Consider lowering goal 
anti-Xa level to 0.1-0.6 OR  
using half LMWH dose 
Consider 
<20 
Hold LMWH 
Consider 
 
o Anti-Xa levels:  Suggested guidelines 
o  Anti-Xa levels should be followed regularly (every 1-2 days) until on a stable 
LMWH dose and dose achieves goal level.  Once on a stable LMWH dose, levels 
should be monitored at least monthly.   
o When asparaginase is restarted, anti-Xa levels will need to be followed at least 
weekly again until levels appear stable on asparaginase (typically takes 4-6 
weeks).   
 
Typical therapeutic range = 0.5 - 1 IU/ml (checked 4 hours after 2nd or 3rd 
dose).  Must be checked by peripheral stick. 
 
Levels may need weekly monitoring with fluctuating renal function. 
 
Please note:  Contact your coagulation laboratory and learn if they add 
antithrombin to samples prior to measuring anti-Xa levels.  If they do 
not, then the anti-Xa level measured in your lab is accurate for patients 
on asparaginase.  If antithrombin is added, the assay is not a good 

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measurement in patients on asparaginase, and you should ask your lab if 
they can run these samples without adding antithrombin.   
 
 
o Antithrombin functional levels: Suggested guidelines 
o At the time of diagnosis of VTE, AT functional levels should be checked and 
repleted for a goal AT nadir > 50% (or per institutional standard).   
o If your lab does not add antithrombin to anti-Xa assays, AT deficiency should be 
suspected if unable to achieve goal anti-Xa levels with reasonable LMWH 
dosing.  
o During asparaginase therapy, AT levels can be followed/repleted as needed for a 
selected goal nadir or can be checked only in those patients with subtherapeutic 
anti-Xa levels.   
 AT units = [(desired AT% - baseline AT %) x weight (kg)] / 1.4 
                                                (ex., where a reasonable AT% = 100 %) 
 Please note: Heparin efficacy requires that the AT functional level is 
adequate.  AT replacement is often required during LMWH therapy 
while on asparaginase.  If AT levels are followed and repleted for a 
selected goal nadir, then check AT levels twice weekly and replete as 
needed.  Once a trend in AT levels is established, the schedule for 
checking AT may be altered. 
o When asparaginase is restarted, either anti-Xa levels or AT levels need to be 
followed at least weekly as AT levels will drop with asparaginase, and LMWH at 
previously adequate doses may not anticoagulate the patient.  4-6 weeks after 
asparaginase has been resumed, anti-Xa or AT levels can be followed less 
frequently depending on the patient’s previous patterns of monitoring. 
 
o Consider transfusing cryoprecipitate to keep fibrinogen > 100 mg/dl while 
anticoagulating during asparaginase therapy 
 
o PT/PTT do not require routine monitoring except if bleeding or prior to surgery  
 
o For invasive procedures (ex. LP), hold anticoagulation at least 24 hours (or per 
institutional standard). 
 
 Anticoagulation Dosing: Suggested Guidelines 
o Treatment anticoagulant dose is based on patient weight/age.   
                       Enoxaparin: 1 mg/kg subcutaneously q12 hrs (recommended in pediatric patients) 
                       Dalteparin: 200 IU/kg/d SC x 4 weeks, then 150 IU/kg/d until complete 
                       Fondaparinux:       <50 kg: 5 mg SC qday 
                                                50-100 kg: 7.5 mg SC qday 
                                                    >100 kg: 10 mg SC qday 
o Prophylactic anticoagulation dose is also based on patient weight/age.   
                       Enoxaparin: 0.5 mg/kg SC q12 hrs or 1 mg/kg SC daily (40 mg maximum) 

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                       Dalteparin: 5000 IU SC daily (based on adult dosing) 
                       Fondaparinux:  2.5 mg SC daily (based on adult dosing) 
 
 Guidelines for Discontinuing Anticoagulation: 
o After receiving a treatment course of anticoagulation (3-6 months), continue treatment 
dose anticoagulation until at least 6 weeks after the final asparaginase dose. 
o A prophylactic dose or treatment dose of anticoagulation can be considered between 
asparaginase and the end of ALL therapy.  Consider prophylactic or treatment dose 
anticoagulation in patients with recurrent thrombosis or with inherited thrombophilias.   
 

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20. 
DANA-FARBER/HARVARD CANCER CENTER MULTI CENTER DATA AND 
SAFETY MONITORING PLAN 
20.1 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
 
20.1.1 Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center 
(DF/HCC) Multi-center protocol will comply with Federal regulationsand Health 
Insurance Portability and Accountability Act (HIPAA) requirements in accordance with 
the CTEP Multi-center Guidelines.        
 
20.1.2 Multi-Center Data and Safety Monitoring Plan Components 
 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with 
Dana-Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead 
Institution. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network 
Clinical Trial Affiliates.  
 
Lead Institution:  Dana-Farber/Children’s Hospital Caner Center will be the Lead 
Institution and will be responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (i.e. the FDA).  The Lead Institution is the home of the 
Overall PI.   
 
DF/HCC Principal Investigator:  Investigator located at the Lead Institution who will 
be charged with the responsibility of the administration of the DF/HCC Project. This 
most often will be the Protocol Chair, but occasionally this may be the overall grant or 
contract holder, as applicable. 
 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC 
protocol submitted as the Lead Institution.  For applicable protocols, the Protocol Chair 
will be the single liaison with any regulatory agencies (i.e. the FDA).  
 
Participating Institution:  A Participating Institution is an institution that desires to 
collaborate with DF/HCC and commits to accruing participants to a DF/HCC protocol.  
The Participating Institution acknowledges the Protocol Chair as having the ultimate 
authority and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 

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Research Organization (CRO), etc) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP 
Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, 
the CRO will be deemed the Coordinating Center.   
 
Clinical Trials Office: The clinical trials offices of the DF/HCC consortium members 
support investigators and their study teams with the coordination, submission and 
ongoing conduct of research protocols involving human subjects.  Specifically, these 
offices support four core service areas including; pre-review of PI initiated protocols; 
assistance in the preparation and management of Investigational New Drug (IND) 
applications and subsequent required reporting to the FDA; regulatory consultation and 
guidance in the interpretation of local, federal, and ICH/GCP guidelines and policies; and 
the orientation and ongoing training support of clinical research personnel.  
 
DF/HCC Office of Data Quality: A group within DF/HCC responsible for registering 
human subjects for trials, ensuring high-quality standards are used for data collection and 
the ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ 
also coordinates quality assurance efforts related to multi-center clinical research. 
 
20.2 GENERAL ROLES AND RESPONSIBILITIES 
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator, Lewis Silverman, MD), Coordinating Center (Dana-Farber Children’s Hospital 
Cancer Center), and the Participating Institutions will all agree to the general responsibilities 
as follows (specific procedures for these general responsibilities are detailed in the DSMP): 
20.2.1 Protocol Chair (DF/HCC Principal Investigator) 
 
The Protocol Chair, Dr. Lewis Silverman, will accept responsibility for all aspects of the 
Multi-Center Data and Safety Monitoring Plan to: 
 Oversee the coordination, development, submission, and approval of the 
protocol as well as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
 Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the 
protocol. 
 Assure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling subjects. 
 For international trials, assure that the protocol is provided to Participating 
Institutions in the primary language spoken at the site.    
 Monitor progress and overall conduct of the study at all Participating 
Institutions.  
 Ensure all DFCI IRB, DF/HCC and other applicable (i.e. FDA) reporting 

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requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with the FDA (investigator-held IND trials), as 
applicable. 
 Identify participating institutions and obtain accrual commitments.  The title 
page of the protocol will include the names and contact information for all 
participating institutions that perform the function of recruiting, enrolling, and 
treating participants for the protocol.  The Coordinating Center (Dana-
Farber/Children’s Hospital Cancer Center) must be designated on the title page.   
 
20.2.2   Coordinating Center (Lead Institution) 
 
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee. The 
DF/HCC Lead Institution, Dana-Farber/Children’s Hospital Cancer Center, will ensure 
that all Participating Institutions within the Multi-Center Protocol demonstrate their intent 
and capability of complying with Federal Regulations, GCPs and HIPAA requirements. 
To assist the Protocol Chair in meeting his/her responsibilities as required by the DSMP, 
the DF/HCC Lead Institution’s study team or designee will assume the following general 
responsibilities: 
 Assist in protocol review. 
 Maintain copies of FWA and Institutional Review Board (IRB) approvals from 
all Participating Institutions. 
 Maintain FDA correspondence, as applicable. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Collect data on protocol specific CRFs. 
 Prepare all submitted data for review by the Protocol Chair. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.   
 Distribute Serious Adverse Event safety reports (both IND Safety reports and 
protocol specific SAEs).  
 Monitor at Participating Institutions either by on-site inspection of selected 
participant records and/or with source documents and research records 
submitted to the Lead Institution.  
    
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical 
Trials provides the following support services to assist the Protocol Chair: 
 Develop protocol specific case report forms (CRF/eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide Central Participant Registration. 
 Verify that eligibility has been confirmed by the investigator and that 
appropriate consent has been obtained.  
 Provide auditing services (funding and ODQ approval required). 
 

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20.2.3   Participating Institution 
 
Each Participating Institution will provide to the Coordinating Center a list of the key 
personnel assigned to the role for oversight of data management at their site. All sites 
must have office space, office equipment, and internet access that meet HIPAA 
standards. 
The general responsibilities for each Participating Institution are as follows: 
 
 Commit to accrual to the Lead Institution’s (Dana-Farber/Children’s Hospital 
Cancer Center) protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain a regulatory binder. 
 Update Coordinating Center (Dana-Farber/Children’s Hospital Cancer Center) 
with research staff changes on a timely basis. 
 Register participants through the Coordinating Center (Dana-Farber/Children’s 
Hospital Cancer Center).  
 Submit source documents, research records, and CRFs per protocol specific 
submission guidelines to the Coordinating Center (Dana-Farber/Children’s 
Hospital Cancer Center). 
 Submit Serious Adverse Event reports to local IRB and directly to the 
Coordinating Center (Dana-Farber/Children’s Hospital Cancer Center).  
 Submit deviations and violations to local IRB and the Coordinating Center 
(Dana-Farber/Children’s Hospital Cancer Center). 
 Secure investigational agents per federal guidelines and protocol requirements. 
 For protocols using investigational agents, the Participating Institution will 
order their own investigational agents regardless of the supplier (i.e. NCI, 
pharmaceutical company) 
Some laboratory studies and treatments are allowed in outside satellite institutions/ 
affiliate hospitals that are affiliated with a Participating institution (Section 15). It is the 
responsibility of the Participating institution to monitor laboratory results, treatment 
and toxicities occurring at its affiliate sites, and to collect all required source 
documentation and data from that site for submission to the Coordinating Center.  
 
 
20.3 PROTOCOL DEVELOPMENT 
 
20.3.1 Activation of a Protocol 
 
The Overall Principal Investigator, Dr. Lewis Silverman, is responsible for the 
coordination, development, and approval of the protocol as well as its subsequent 
amendments, and reporting SAEs, violations and deviations per DFCI IRB guidelines and 
if applicable CTEP Multi-center, FDA or OBA Guidelines.  Further, the Protocol Chair 
will be the single liaison with the FDA. 

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To meet these requirements, the Overall Principal Investigator will be responsible for the 
following minimum standards: 
 
 Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
 Identify, qualify and initiate Participating Institutions and obtain accrual 
commitments.  
 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the Protocol Chair. 
 Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.  
 Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
 
20.3.2 Coordinating Center Support Function 
  
The DF/HCC Lead Institution’s study staff or designee will provide administrative and 
clerical support to the Protocol Chair for the development and distribution of the 
protocol.  
 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee 
include: 
 Maintain Regulatory documents for all Participating Institutions.  
 Review of the protocol and consent to check for logistics, spelling, and 
consistency.   
 Provide the Protocol Chair a list of queries related to any inconsistencies. 
 Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines.  
 Maintenance of contact list of all Participating Institutions in the DF/HCC 
Multi-center Protocol and the distribution of updates to the sites as needed.  
 Derivation of the study calendar, if applicable. 
  Assistance in preparation and maintenance of case report forms. 
 Conduct regular communications with all Participating Institutions (conference 
call, emails, etc)   
 Maintain documentation of all communications.  
 Conduct and maintain documentation of the site initiation training via 
teleconference / webex with all participating sites as a condition and prior to 
study activation at each site.  
 
 
20.4 PROTOCOL MANAGEMENT 
 

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The Coordinating Center (Dana-Farber/Children’s Hospital Cancer Center) is responsible for 
assuring that each Participating Institution has the appropriate assurance on file with the 
Office of Human Research Protection (OHRP).   Additionally, the Coordinating Center 
(Dana-Farber/Children’s Hospital Cancer Center) must maintain copies of all IRB approvals, 
for each Participating Institution.  
 
20.4.1 Protocol Distribution 
 
The Coordinating Center (Dana-Farber/Children’s Hospital Cancer Center) will distribute 
the final approved protocol and any subsequent amended protocols to all Participating 
Institutions.    
 
20.4.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive phone, fax, mail or e-mail notification of 
protocol revisions from the Lead Institution or designee.  It is the individual Participating 
Institution’s responsibility to notify its IRB of these revisions. 
 
Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Lead Institution or 
designee. Non-life-threatening protocol revisions should be IRB approved and 
implemented within 90 days from receipt of the notification. 
 
Revisions for life-threatening Causes: Participating Institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required 
to protect lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions 
will be implemented immediately followed by IRB request for approval 
 
Protocol Closures and Temporary Holds: Participating Institutions will receive fax, e-
mail, or phone notification of protocol closures and temporary holds from the Lead 
Institution or designee. Closures and holds will be effective immediately.  In addition, the 
Lead Institution or designee will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol closures. 
 
20.4.3 Informed Consent Requirements 
 
 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent from participating institutions. As best as possible, the template should 
be followed with the specifications outlined in the DF/HCC guidance document on 
Model Consent Language.   
 

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Participating sites are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Lead Site for their revision prior to 
submission to the participating site's IRB.  
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. It is DF/HCC policy that only attending physicians can 
obtain informed consent and re-consent to drug and/or device trials.   
 
 
20.4.4 IRB Documentation 
 
The following must be on file with the DF/HCC Lead Institution or designee and must be 
submitted and approved by the DFCI IRB prior to participant registration: 
 
 Approval Letter of the institution's IRB  
 Copy of the Informed Consent Form approved by the Participating Institution’s 
IRB  
 IRB approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the DF/HCC Lead 
Institution their IRB approval for Amendments to a protocol.    
 
20.4.5 IRB Re-Approval 
          
Annual IRB re-approval from the Participating Institution is required in order to continue 
research and register participants onto a protocol.  There is no grace period for continuing 
approvals. 
 
Protocol registrations will not be completed if a re-approval letter is not received by the 
DF/HCC Lead Institution from the Participating Institutions on or before the anniversary 
of the previous approval date.   
 
The Coordinating Center (DFCI) will notify the participating institutions when the 
continuing review is due for the DFCI IRB.  The DFCI study team will ask for 
information regarding all subjects participating in the study as well as any subjects that 
may have consented to the study and never started treatment.  Follow up information will 
also be requested on any subject that has come off study.   
 
20.4.6 Participant Confidentiality and Authorization Statement 
 
The HIPPA of 1996 contains, as one of its six major components, the requirement to 
create privacy standards for health care information that is used or disclosed in the course 

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5. The ODQ Registrar will send an email or fax confirmation of the registration 
and randomized treatment assignment to the DFCI Study Team immediately 
following the registration.   
 
6. The DFCI Study Team will email the registration confirmation and 
randomized treatment assignment to the outsite site.  
 
7. Treatment on study should only begin after confirmation of registration is 
received.   
 
The registration procedures outside of business hours, on weekends, and holidays are as 
follows: 
 
1. Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. Complete the protocol-specific eligibility checklist. To be eligible for 
registration to the study, the participant must meet each inclusion and 
exclusion criteria listed on the eligibility checklist. 
 
3. Call the ODQ registration line at 617-632-3761 and follow the instructions for 
registering participants after hours.  Leave detailed contact information for the 
QACT registrar responsible for registering your participant.   
 
4. The ODQ Registrar will (a) validate eligibility and (b) register the participant 
on the study. 
 
5. ODQ will confirm registration by telephone, and email/fax confirmation will 
be sent on the next business day.  Randomized treatment will be assigned and 
communicated on the next business day. 
 
6. Treatment on study should only begin after confirmation of registration is 
received.  On nights, weekends, and holidays, treatment may begin after 
telephone confirmation (prior to communication of randomized treatment 
assignment).   
 
7. Fax or email the eligibility checklist(s) and all pages of the consent form(s) to 
the 
DFCI 
Study 
Team 
at 
Email 
 
 
 
If you have any questions, the ODQ can be reached at telephone 
 
  
 
The following source documents need to be forwarded to the Coordinating Center (Dana-
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classification will only be made once these documents are received by the Coordinating 
Center.   
 Copy of pathology reports confirming diagnosis of leukemia (bone marrow 
aspirate or biopsy indicating > 30% marrow involvement) or lymphoblastic 
lymphoma 
 Copy of marrow pathology (for leukemia) and scan (for lymphoblastic 
lymphoma) reports confirming complete remission at end of remission 
induction phase. 
 Copy of diagnostic flow cytometry reports (leukemia patients only) 
 Copy of results of diagnostic cytogenetics, FISH and PCR (if 
performed)(leukemia patients only) 
 CBC with differential from diagnosis and from end of induction 
 Copy of CSF cell count/cytospin and/or cytopathologic report from diagnosis 
and from end of induction 
 
After receipt of source documents and review of MRD results (if applicable), Lead 
Institution will call or email the participating site to verify final risk group assignment. 
 
20.4.8 DF/HCC Multi-center Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the 
participant is assigned a five digit protocol case number.  This number is unique to the 
participant on this trial and must be used for ODQ CRF/eCRF completion and written on 
all data and ODQ correspondence for the participant. 
 
20.4.9 DF/HCC Multi-center Protocol Registration Policy 
 
20.4.9.1 
Initiation of Therapy:  Participants must be registered 
with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating 
Institution receives a faxed or e-mailed copy of the 
participant’s Registration Confirmation memo from the 
DF/HCC ODQ.  If registration occurs outside of business 
hours, on weekends, or on a holiday, treatment may not be 
initiated until ODQ has confirmed registration by telephone. 
An email/fax confirmation will be sent on the next business 
day.  Therapy must be initiated per protocol guidelines.  The 
Protocol Chair and DFCI IRB must be notified of any 
exceptions to this policy.  
 
20.4.9.2 
Eligibility Exceptions: The DF/HCC ODQ will make no 
exceptions to the eligibility requirements for a protocol 

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without DFCI IRB approval.  The DF/HCC ODQ requires 
each institution to fully comply with this requirement. 
 
20.4.9.3 
Verification of Registration: A registration confirmation 
memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution 
within one working day of the registration. Treatment may 
not be initiated until the site receives a faxed or e-mailed 
copy of the registration confirmation memo. If a participant 
is registered outside of business hours, on weekends, or on a 
holiday, ODQ will confirm registration by telephone, and 
email/fax confirmation will be sent on the next business day.   
 
20.4.9.4 
Confidentiality: All documents, investigative reports, or 
information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant 
specific reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the Lead Institution 
must have the participant’s full name & social security 
number “blacked out” and the assigned DF/HCC ODQ case 
number and protocol number written in (with the exception 
of the signed informed consent document). Participant initials 
may only be included or retained for cross verification of 
identification. 
  
 
20.4.10 Schedule of Data Submission 
An Electronic Data Capture system will be used for this trial.  The DF/HCC ODQ 
develops a set of electronic case report forms, (eCRFs) for use with the DF/HCC Multi-
Center Protocol.  ODQ provides a web based training for eCRF users.  These forms are 
designed to collect data for each study.  
   
Forms 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 
On Study Form 
Within 14 days of registration 
Induction Data Forms 
Within 14 days of Induction Completion  
Consolidation 1 Data 
Forms 
Within 14 days of the end of Consolidation 1 
CNS Data Forms 
Within 14 days of  the end of the CNS phase 

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Consolidation II Data 
Forms 
Every 3 months  
Continuation Data Forms 
Every 3 months 
Adverse Event Data From 
Within 14 days of the end of each phase OR 
during the 3 month reporting period 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Forms 
Within 14 days of the protocol defined follow up 
visit date or call 
Serious Adverse Event 
Report Forms 
Within 24 business hours of notification of the 
event 
 
20.4.10.1 Eligibility Checklist 
 
Purpose - Outlines protocol-specific eligibility criteria and includes the 
following: 
              
Participant Demographics (address, zip code, sex, race, ethnicity, initials, 
date of birth) 
1) Parameters for eligibility 
2) Parameters for exclusion 
3) Parameters for stratifications 
 If a time frame is not specified in the protocol, all test results used to 
confirm eligibility must be completed within 14 days prior to study 
enrollment by the ODQ.  
 
Schedule for Submission – Completed prior to participant registration. The 
Informed Consent/Participant Authorization for the Release of Personal 
Health Information should be submitted with the Eligibility Checklist at the 
time of registration.  
20.4.10.2 On-study Form(s) 
 
Purpose - documents the following items: 
 Demographic data 
 Disease characteristics  
20.4.10.3 Adverse Event Report Form(s) 
 

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Purpose – Documents adverse events that occur while the participant is 
receiving treatment and for up to 60 days following the first day of the last 
cycle of chemotherapy.  All adverse events are to be graded by number 
using the toxicity grading scale required by the protocol. This form is not for 
IRB submission, but for recording the AE in the research database. 
20.4.10.4 Off Treatment and Off Study Form(s) 
 
Purpose - The Off Treatment and Off Study Forms are submitted when the 
participant is removed from the study or has completed all protocol 
treatment.  Participants will complete all protocol treatment and be 
considered “off treatment” Day 21 days after the start of the last cycle 
they receive during the continuation phase of treatment.  Note: If the 
participant dies while on protocol, the Off Study Form is the last form 
submitted. 
20.4.10.5      Follow up / Survival Form 
 
Purpose - Summarizes participant status at a given point in time after being 
removed from treatment.  
 
20.4.11 Data Form Review 
 
When data forms arrive at the DF/HCC ODQ, they are reviewed for: 
   
 
 
Completeness:  
Is all the information provided as required per protocol? 
 
Protocol Treatment Compliance:  
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must be 
within 10% of the calculated protocol dose. 
  
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with 
the treatment? Was the treatment delayed due to the adverse event? What was the most 
severe degree of toxicity experienced by the participant? 
 
Notations concerning adverse events will address relationship to protocol treatment for 
each adverse event grade.  All adverse events encountered during the study will be 
evaluated according to the NCI Common Toxicity Criteria assigned to the protocol and 
all adverse events must be noted on the participant's Adverse Event (Toxicity) Forms. 
 
Response:  
Did the participant achieve a response?  What level of response did they achieve?  On 
what date did the participant achieve the response and how was the response determined? 
 

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Response criteria are defined in the protocol.  A tumor assessment must be performed 
prior to the start of treatment and while the participant is on treatment as specified by the 
protocol.   
 
Objective responses must have documentation such as physical measurements, x-rays, 
scans, or laboratory tests.  
 
20.4.12 Missing and Deficient Memorandum 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in 
accordance with the following policies and procedures: 
 
Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution 
will receive a query within the EDC from the DF/HCC ODQ Data Analyst.  Responses to 
the query should be completed and returned within 14 days.  Responses may be returned 
within the EDC or by updating the data point.  
 
Missing Forms 
 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the DF/HCC ODQ noting the missing forms.  These reports 
are compiled by the DF/HCC QACT and distributed a minimum of three times a year.  
 
20.5 REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent (Calaspargase Pegol) is specified in the protocol 
(Section 8.1).  
 
Participating Institutions should order their own supply from Sigma Tau.  
 
The local IRB should be kept informed of who will supply the agent (i.e., the pharmaceutical 
company) so that any regulatory responsibilities can be met in a timely fashion, and the 
pharmacy will be able to receive and store the investigational agent.  
 
20.6 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
        
 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported to the 

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investigator by participants.  All toxicities encountered during the study will be evaluated 
according to the NCI criteria specified in the protocol (CTCAE version 4.0) and recorded 
prior to each course of therapy.  Life-threatening toxicities should be reported immediately 
to the Protocol Chair and Institutional Review Board (IRB).  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
20.6.1 Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse drug experience at any dose that results in 
any of the following outcomes: death, a life-threatening adverse drug experience, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions in a participant who has 
never had seizure activity in the past that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse.  A serious adverse event will also include 
any adverse drug experience that results in intensive inpatient medical interventions 
(i.e. intensive care unit level of care), including mechanical ventilation, pressor support, 
and/or fluid resuscitation, or emergent surgical operations.   Unplanned hospital 
admissions for febrile neutropenia, bacteremia or other documented infections, seizure, 
pancreatitis, thrombosis, nausea/vomiting, diarrhea, and other expected toxicities from 
the study treatment will not be considered a serious adverse event unless the severity of 
the condition is considered life-threatening and/or lead to intensive medical 
interventions or surgical procedures. 
 
The NCI Common Terminology for Adverse Events (CTCAE), Version 4.0 will be 
utilized for AE reporting.  
 
20.6.2 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is 
delineated in the protocol section 12.  
 
 
 
 
 
The Lead Institution will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating all SAEs to all sites 
conducting the trial. 
 
Participating Institutions must report the AEs to the Protocol Chair and the 
Coordinating Center (Dana-Farber/Children’s Hospital Cancer Center) following the 
DFCI IRB SAE Reporting Requirements.  
 

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 When an event occurs that meets the protocol definition for SAE reporting (refer 
to Section 12 of the protocol), the Overall PI, Lewis Silverman, MD and the DFCI 
study team much be notified within 24 business hours of discovery of the event.  
An SAE report must be completed on a DFCI Adverse Event Form and/or a 
MedWatch 3500 or 3500A form.   
 
 This report must be completed and emailed or faxed to the Overall PI, Lewis 
Silverman, MD, and study coordinator (Samantha Kay-Green, Liza Duble or 
Katharine Majewski).  
 
 SAE reports MUST include the following information within the narrative (which 
can be attached if it does not fit on the Medwatch form): 
 
1. CTCAE V4 Event Name (for every serious event reported) 
2. Grade of Event 
3. Investigator Relationship (not related, unlikely, possibly, probably, definitely) 
4. Expectedness (is the event listed in the consent or IB as risk?) 
5. Date of study team notification of event 
 
Note: SAEs on study will be collected from the time of enrollment to 60 days 
following the first day of the last cycle of chemotherapy.  
 
In addition, all sites are required to track all SAE events in an SAE log.  Prior to each 
monthly telecom (see Section 20.8.1) the study team at DFCI will request that the SAE 
log is updated and signed by the Site PI for tracking and regulatory purposes.  
 
20.6.3 Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical 
studies to notify the FDA and all participating investigators of any serious and 
unexpected adverse experiences that are possibly related to the investigational agent. The 
Protocol Chair will review all IND Safety Reports and is ultimately responsible for 
forwarding the IND Safety Reports to the Participating Institutions.  The Participating 
Institution investigators are to review, send a copy to their IRB according to their local 
IRB’s policies and procedures, and file a copy with their regulatory documents. 
 
20.7 PROTOCOL VIOLATIONS AND DEVIATIONS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or 
“protocol deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the 
DFCI IRB, the definitions for protocol violation and deviation as described by the DFCI 
IRB will be applied for reporting purposes for all Institutions Participating in the DF/HCC 
Multi-center Protocol.  
   

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20.7.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a subject who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
  
Please Note:  
 
If 3 for more minor deviations for the same subject (or of the same type) are 
found on the minor deviation log to impact the safety of participants, 
compromise the integrity of the study data and / or affect subject’s 
willingness to participate in the study the events must be submitted to the 
DFCI IRB as  MAJOR deviation/violation. 
 
***Any questions about a major vs. minor deviation/violation should be reviewed 
with the PI and or study team at the lead institution.   
 
20.7.2 Reporting Procedures 
 
The Protocol Chair: is responsible for ensuring that clear documentation is available 
in the medical record and/or regulatory documents to describe all protocol exceptions, 
deviations and violations.  
The Protocol Chair will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from 
DFCI IRB. The Participating institution must submit the deviation request to the 
Protocol Chair or designee, who will submit the deviation request to the DFCI IRB. 
Upon DFCI IRB approval the deviation should be submitted to the Participating 
Institution’s own IRB, per its institutional policy. 
A copy of the Participating Institution’s IRB report and determination will be forwarded 
to the DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 
business days after the original submission.  
 
All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or 
designee in a timely manner.  
 
All sites are required to keep a minor deviation log.  This is to be completed as minor 
deviations/violations occur (see definition above).  Please submit an updated log to the 
DFCI study team monthly and maintain a copy in the regulatory file.  At each annual 

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continuing review, minor deviation logs from all participating sites will be submitted to 
the DFCI IRB along with local continuing review approval.   
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the DF/HCC Lead Institution or designee will submit the 
report to the Protocol Chair for review. Subsequently, the Participating Institution’s 
IRB violation/deviation report will be submitted to the DFCI IRB for review per DFCI 
IRB reporting guidelines.  
20.8 MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires ongoing monitoring to ensure all 
participating sites are compliant with the most current protocol and that the study is being 
conducted according to all pertinent regulatory requirements.  As the Coordinating Center, the 
DF/HCC Lead Institution or designee provides quality control oversight for the DF/HCC Multi-
center Protocol. 
 
20.8.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the Participating Institution 
will be subject to on-site monitoring conducted by the DF/HCC Lead Institution or 
designee.  
 
The DF/HCC Lead Institution will implement monitoring activities ongoing to ensure 
that Participating Institutions are complying with regulatory and protocol requirements, 
data quality, and subject safety. Additional monitoring practices will include but are not 
limited to; source verification, review and analysis of the following: eligibility 
requirements of all participants , informed consent procedures, adverse events and all 
associated documentation, study drug administration / treatment, regulatory records and 
site trial master files, protocol deviations, pharmacy records, response assessments, and 
data management.   
 
Monitoring will occur before the clinical phase of the protocol begins and will continue 
during protocol performance through study completion.    
 
All data submitted to the DF/HCC ODQ will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Lead Institution or designee and 
if applicable ODQ Data Analysts assigned to the Protocol will perform the ongoing protocol 
data compliance monitoring with the support of the Participating Institution’s Coordinators, 
the Principal Investigators, and the Protocol Chair.  
 
Site Qualification: 
Prior to participating in this trial, all sites must complete a Site Selection and Feasibility 
Questionnaire.  This questionnaire will ask co-investigators to consider DF/HCC 
policies regarding informed consent, serious adverse event reporting and 

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documentation, and pharmacy guidelines.  The questionnaires will also require site 
consideration of IRB procedures, subject enrollment, appropriateness of his/her facility 
for carrying out the proposed protocol, plans for data submission and monitoring, and 
the identification of staff availability and credentials.  Co-investigators will be offered 
opportunity to discuss the questionnaire and accompanying checklist with the DF/HCC 
Lead Institution’s study staff and/or DFCI Overall Principal Investigator, Lewis 
Silverman, MD as appropriate.  
 
The DF/HCC Lead Institution’s study staff will review the Site Selection and 
Feasibility Questionnaire and determine whether the site is qualified to participate.  
Sites believed to be qualified to participate will be invited to submit the protocol to their 
institutional IRB for review.   
  
 
Regulatory Documents:  
Once a proposed Participating Institution receives institutional IRB approval, all 
approval documentation and IRB-approved related documents will be emailed to the 
Coordinating Center study staff and an amendment to add a site will be submitted to the 
DF/HCC IRB.  Once approval is received to add the Participating Institution study 
materials will be sent to the Participating Institution.  Study materials will include, but 
are not limited to, regulatory documents and participant tracking forms.  
 
DFCI will collect all required regulatory documentation prior to study activation.  This 
includes but, is not limited to 1572, Site PI and Co-Investigator CVs, Financial Disclosure 
Forms, IRB approval documentation. The study team will work with all participating sites to 
ensure all updated / revised regulatory documentation is maintained at each site and 
forwarded to DFCI and maintained in the Trials Master File.   
 
All Participating Institutions must maintain and update all essential regulatory 
documents in a regulatory binder.  A designated member of the DF/HCC Lead 
Institution will be responsible for maintaining the Trial Master File which will include 
copied of all regulatory documentation for the Lead Site and all Participating 
Institutions.   
 
All Participating Institutions are required to submit all institutional IRB 
correspondences and approvals to be retained in the Trial Master File at the Lead 
Institution.  The Lead Institution will review all working study documents and ensure 
that most current IRB-approved protocol and study documents are being used by the 
Participating Institutions.  
 
Site Initiation Visit:  
A Site Initiation Visit (SIV) will be conducted with all participating sites via 
teleconference prior to enrolling participants.  The SIV will cover study objectives and 
rationale, history of Calaspargase Pegol (SC-PEG asparaginase), study design, 
eligibility, registration, required data, treatment schedule, side effects/AEs, SAE 
reporting, and dose modification.  It will be lead by the DFCI Overall Principal 

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Investigator, Lewis Silverman, MD.  It is expected that the Site PI and all study staff 
will attend.   
 
Delegation of Authority/Responsibility:  
Participating Institutions will be instructed to complete a Delegation of Responsibility/ 
Authority Log which will be reviewed/approved by the DFCI Overall Principal 
Investigator, Lewis Silverman, MD.  A copy of this document will be retained in the 
Trial Master File.  Participating Institutions will be instructed to inform the DF/HCC 
Lead Institution immediately should there be a change in personnel.  An updated 
training and Delegation of Authority/Responsibility log will need to be completed as 
soon as possible.  
 
Ongoing Communication and Training:  
Regularly scheduled teleconferences will occur between the DF/HCC Lead Institution 
and Participating Institutions every one to two months.  It is expected that Site PIs and 
study staff will attend. This will be a forum to discuss study related issues not limited to 
the following: study accrual, SAE’s/AE’s, clinical response and deviations/violations. 
SAE trackers and minor deviation/violation logs will be requested prior to each monthly 
teleconference.   
 
An agenda will be sent to all sites at the time the teleconference is scheduled.  Minutes 
will be taken and distributed to the participating institutions after each teleconference 
and will maintained in the regulatory file.  Calls will be held more regularly as needed 
based upon study accrual or necessary study updates.  The DF/HCC Lead Institution 
will be available to all Participating Institutions in order to discuss questions and 
concerns on an as-needed basis.  
 
Study related documents and amendment information will be posted on the ALL 
Consortium Website (http://allconsortium.dfci.harvard.edu/) 
 
In addition, the DF/HCC Lead Institution will hold on site consortium meetings at least 
annually.  These meetings will include all site investigators and study staff, as 
necessary. 
 
Source Documentation Submission and Review via Virtual and On-Site Monitoring:  
All data collected on all participants will be monitored for accuracy.  Participating 
institutions will be required to submit source documents to the Lead Institution for virtual 
monitoring.  The required source documentation for virtual monitoring of this study 
includes, but is not limited to:   
 Pathology reports confirming diagnosis 
 All screening laboratory reports and scans. 
 All results of the “Required Assessments”. 
 All results of the “Required Assessments” at study entry and at the date of 
remission assessments 
 Any extra source documentation (i.e., admission notes, scans, culture results) 
pertaining to a serious adverse event (SAE) 

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At the time of registration, all points of eligibility must be found in either source 
documentation or if eligibility points can not be found in source documentation (ie lab 
reports etc.), they must be included in an MD note.  Eligibility source documentation 
must be submitted to DFCI and will be reviewed via virtual monitoring on an on-going 
basis.   
 
Registration documents (consent form and eligibility checklist) will also be reviewed via 
virtual monitoring on an on-going basis.  At the time of registration, the eligibility 
checklist(s) and all pages of the consent form(s) must be faxed or emailed to the DFCI 
Study Team for review (refer to sections 4 and 20.4.7 for participant registration process).  
The DFCI Study Team will review each consent form to ensure 1) it is the most 
appropriate and current version, 2) that the participant information is included on all 
pages of the consent and that all pages of the consent have been submitted, 3) that the 
participant has signed and dated the consent form, 4) that a physician has reviewed and 
signed the consent form on the same day/time as the participant, and that 5) all 
appropriate items have been completed.     
 
In addition, on-site monitoring will occur at each site and will include review of 
regulatory documentation and source documentation.  If sub-standard performance is 
discovered during routine monitoring (virtual or on-site), more frequent on-site 
monitoring visits will be made.  Sub-standard performance includes, but is not limited to, 
data not entered on time, unreported adverse events, or enrolling ineligible participants.   
 
Adverse Event Reporting: 
Documentation of all adverse events must be included as part of source documentation.  
Documentation that a physician determined attribution of each event must also be 
included.  AEs and SAEs must be reported as instructed in the protocol with the log 
serving as record for all events at each Participating Institution.  The DFCI Overall 
Principal Investigator, Lewis Silverman, MD, will be notified/report all AEs SAEs as per 
protocol.  Each Participating Institution will be instructed to keep an SAE log and submit 
it to the DF/HCC Lead Institution prior to each monthly teleconference.  The DF/HCC 
Lead Institution will maintain a master SAE list.   
 
Drug Accountability:  
Participating pharmacies will be required to submit Drug Accountability Logs at the time 
of monitoring documenting receipt and shipment of drug supply, dispensing/ordering of 
supply, and destruction of unused study medication and/or damaged or expired drug.  
Participating Institutional Pharmacies should destroy drug as per their institutional policy.   
 
20.8.2 Evaluation of Participating Institution Performance 
 
20.8.2.1 
Eligibility Checklist:  
 

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Eligibility criteria are checked on a protocol-specific eligibility checklist and 
faxed to the DF/HCC ODQ prior to registration on protocol.  The checklist and 
informed consent document are reviewed by a DF/HCC ODQ Protocol 
Registrar before the participant can be registered on a protocol.  The DF/HCC 
ODQ cannot make exceptions to the eligibility requirements. 
 
20.8.2.2 
Accrual of Eligible Participants:  
 
Annual accrual rates for eligible participants enrolled onto therapeutic clinical 
trials are calculated for each institution.  Participating Institutions are expected 
to maintain the minimum annual average accrual as defined by the protocol 
grant or contract.  
20.9 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. The main focus in auditing is to measure if the 
standards and procedures set are being followed. Auditing is the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and the data were generated, recorded and analyzed, 
and accurately reported per the protocol, Standard Operating Procedures (SOPs) and the 
Code of Federal Regulations. 
 
 
20.9.1 DF/HCC Sponsored Trials 
 
One on-site audit will be schedule by the ODQ at each site after the first 10 subjects are 
accrued and then annually if 10 subjects accrue since the time of the last audit. If a site 
enrolls less than 10 participants, they will undergo one audit over the course of the study.    
Approximately 3-4 subjects would be audited at the site over a 2 day period.  If violations 
which impact subject safety or the integrity of the study are found, more subject records 
may be audited.  
 
20.9.2 Participating Institution Responsibilities 
 
It is the Participating Institution’s responsibility to notify the DF/HCC Lead Institution of 
all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which 
involve the DF/HCC Multi-Center Protocol. All institutions will forward a copy of final 
audit and/or re-audit reports and corrective action plans (if applicable) to the DF/HCC 
Lead Institution or designee within 12 weeks after the audit date.  
 
20.9.3 Coordinating Center (Lead Institution) Responsibilities  
 

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The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports 
and corrective action plans if applicable. The Lead Institution or designee must forward 
these reports to the DF/HCC ODQ per DF/HCC policy for review by the DF/HCC Audit 
Committee. Based upon the audit assessments the DF/HCC Audit Committee could 
accept or conditionally accept the audit rating and final report. Conditional approval 
could require the Protocol Chair to implement recommendations or require further 
follow-up.  For unacceptable audits, the Audit Committee would forward the final audit 
report and corrective action plan to the DFCI IRB as applicable. 
 
20.9.4 Sub-Standard Performance 
 
The Protocol Chair, DFCI IRB and the NCI for CTEP trials, is charged with considering 
the totality of an institution’s performance in considering institutional participation in the 
DF/HCC Multi-Center Protocol. 
 
20.9.4.1 
Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, 
submission of timely accurate data, adherence to protocol requirements, and 
compliance with state and federal guidelines will be recommended for a six- 
month probation period. Such institutions must respond with a corrective 
action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate 
significant improvement will be considered by the Protocol Chair for 
revocation of participation.