AALL0031DOC Very High Risk ALL With Glivec

AALL0031 Page 1
Open to Entry: October 14, 2002
CHILDREN'S ONCOLOGY GROUP
AALL0031
A CHILDREN’S ONCOLOGY GROUP PILOT STUDY FOR THE TREATMENT OF VERY

HIGH RISK ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AND ADOLESCENTS
(STI571 (GLEEVEC) NSC#716051/IND#61135)
A PHASE III GROUP-WIDE PILOT STUDY
This protocol is for research purposes only and should not be copied, redistributed or used for any
other purpose. The procedures in this protocol are intended only for use by clinical oncologists in
carefully structured settings and may not prove to be more effective than standard treatment. A
responsible investigator associated with this clinical trial should be consulted before using or
attempting any procedure in this protocol.
STUDY CHAIR
Kirk R. Schultz, M.D.

British Columbia's Children's Hospital
Div of Pediatric Hem-Onc
4480 Oak St, Rm A119D
Vancouver, BC V6H 3V4
Canada
Phone: (604) 875-2316
Pager: (604) 875-2161
Fax: (604) 875-2911
E-mail: kschultz@interchange.ubc.ca
For Group Operations and Research Data Center Contacts See: http://members.childrensoncologygroup.org/
AALL0031 Page 2
NOTE REQUIREMENT FOR

CENTRAL REVIEW BEFORE
STUDY ENTRY
Eligibility for entry onto AALL0031 for Very High Risk ALL requires a central
confirmation of a) Ph+ ALL and b) hypodiploidy. This should be done as soon as the
institutional laboratory has identified one of these criteria. Lack of compliance will
result in the patients being ineligible for study entry. RDE of the patient on this study
will not be allowed if the necessary central review(s) hasn’t/haven’t been completed to
document the patient eligibility. RDE of the patient on this study will not be allowed if
the necessary central review(s) hasn’t/haven’t been completed to document the patient
eligibility group (i.e., Ph+ status or low hypodiploidy).
FORMER POG INSTITUTIONS – Central review is required for:
a) BCR/ABL by FISH or RT-PCR (not performed by former POG reference laboratory)
b) t(9;22) by cytogenetics
c) Chromosomes ≤ 44 by cytogenetics
d) DNA index < 0.81 by flow cytometry (not performed by former POG reference laboratory)
FORMER CCG INSTITUTIONS - Central review is required for:

e) BCR/ABL by FISH or RT-PCR
f) t(9;22) by cytogenetics
g) Chromosomes ≤ 44 by cytogenetics
h) DNA index < 0.81 by flow cytometry
Central review and confirmation will occur within 3 working days of receipt of the report.
Central review and confirmation of only one of the 4 criteria is required for study entry.
Send submissions for Central review to Dr. Andrew Carroll or Dr. Nyla Heerema. In addition
contact the Study Chair (Kirk Schultz) by e-mail: kschultz@interchange.ubc.ca or telephone (604)
875-2316 when a diagnostic sample has been submitted for confirmation.
FORMER POG INSTITUTIONS FORMER CCG INSTITUTIONS

Andrew Carroll, PhD Nyla Heerema, PhD
University of Alabama Childrens Hospital of Columbus
Department of Human Genetics Director of Cytogenetics
1530 3rd Ave. South 1645 Neil Avenue
Kaul Bldg., Room 314B Hamilton Hall, Room 167
Birmingham, AL 35294-2050 Columbus, OH 43210-1228
Phone: 205-934-4968 Phone: 614-292-7815
Fax: 205-934-1078 Fax: 614-292-7072
E-mail: acarroll@uabmc.edu E-mail: heerema-1@medctr.osu.edu
AALL0031 Page 3
SHORT ABSTRACT
The intensive, risk-adjusted chemotherapy regimens employed by the Children’s Cancer Group (CCG)
and the Pediatric Oncology Group (POG) for treatment of children ≥ 1 year of age with acute
lymphoblastic leukemia (ALL) have resulted in an overall EFS of approximately 70 - 80%. Subgroups
of these children, however, still have a poor prognosis with an expected 5 year EFS of < 45% utilizing
such regimens. The proposed pilot study represents the first attempt by the combined Children’s
Oncology Group (COG) to develop a treatment strategy aimed at the subgroup of patients with very high
risk (VHR) of treatment failure on current protocols. There are four subgroups with VHR ALL who will
be evaluated on this study. They include: 1) patients with Ph+ ALL; 2) hypodiploid patients with ≤ 44
chromosomes; 3) patients who had an M3 (> 25% blasts) bone marrow at the end of induction therapy
and who later achieved remission either with chemotherapy or a bone marrow transplant; 4) patients
who have M2 (5–25% blasts) marrows at the end of induction therapy and do not achieve an M1 (<5%
blasts) marrow by the end of an extended induction period (POG studies) or by the end of consolidation
(CCG studies). This pilot study will utilize a novel intensified chemotherapeutic regimen for VHR
patients based on 1) the use of ifosfamide and etoposide in POG ALL relapse studies; 2) the use of high
dose methotrexate for children and infants; and 3) the intensive CCG New York (NY) II regimen used
for patients with lymphomatous ALL. The BCR-ABL-specific tyrosine kinase inhibitor STI571 will be
used for Ph+ patients and hematopoietic stem cell transplant (HSCT) will be offered to patients with
appropriate donors. The study will determine whether an adequate number of VHR patients will be
accrued to form the basis for development of a future phase III trial within the COG. The presence or
absence of minimal residual disease (MRD) in patients in remission also will be determined. If the
intensive treatment is found to have acceptable toxicity and shows potential, either alone, or with
transplant, for improving outcome of the VHR patient population, it will be the first promising strategy
identified for this group.
AALL0031 Page 4
TABLE OF CONTENTS
Section Page
1.0 SPECIFIC AIMS AND HYPOTHESES 7
1.1 Specific Aims 7
1.2 Hypotheses 7
2.0 OVERVIEW OF STUDY DESIGN 8
2.1 Abstract 8
2.2 Experimental Design 9
3.0 BACKGROUND AND RATIONALE 13
3.1 Introduction 13
3.2 Rationale for Chemotherapy 13
3.3 Rationale for Use of HSCT for VHR Patients 16
3.4 Rationale for Use of STI571 for Ph+ Patients 17
3.5 Rationale for Studies of Minimal Residual Disease (MRD) in ALL 18
3.6 Identification of a VHR Subset of Patients with ALL 19
3.7 Chemotherapy: NYII Induction 19
3.8 Chemotherapy: CCG-1953/POG-9407 20
3.9 Chemotherapy: STI571 Phase I trial 20
3.10 MRD Using Multiparameter Flow Cytometry 21
4.0 ELIGIBILITY CRITERIA, STUDY ENTRY, AND DEFINITIONS 22
4.1 Eligibility Criteria 22
4.2 Patient Registration and study enrollment 24
4.3 Definitions 24
5.0 TREATMENT PLAN 25
5.1 Frontline Induction 25
5.2 Consolidation Block 1 (3 weeks) 25
5.3 Consolidation Block 2 (3 weeks) 27
5.4 Reinduction Block 1 (3 weeks) 29
5.5 Intensification Block 1 (8 weeks) 30
5.6 Reinduction Block 2 (3 weeks) 33
5.7 Intensification Block 2 (8 weeks - identical to Intensification 1 in section 5.5) 34
5.8 Maintenance – Cycles 1-4 (8 week cycles) 34
5.9 Maintenance – Cycles 5-12 (8 week cycles) 38
6.0 HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) 40
6.1 Preparative Regimen 40
6.2 Donors Acceptable for Entry Onto Study 40
6.3 Non-Random Assignment to HSCT Therapy 41
7.0 DOSE ESCALATION OF STI571 41
7.1 Stratum For Treatment 41
7.2 STI571 41
7.3 STI571 dose escalation schedule for chemotherapy and pre HSCT arm 43
7.4 STI571 dose escalation schedule for HSCT arm 43
7.5 Dosage of STI571 44
8.0 THERAPY MODIFICATIONS FOR TOXICITY (ALL PHASES) 45
8.1 Asparaginase (E. coli; Erwinia; PEG) 45
8.2 Cyclophosphamide 46
8.3 Cytarabine (Ara-C), Intravenous or Subcutaneous 46
8.4 Daunorubicin 46
8.5 Dexamethasone 47
8.6 Mercaptopurine 47
8.7 Methotrexate, Intrathecal 48
AALL0031 Page 5
8.8 Methotrexate, Intravenous 49
8.9 Methotrexate, Oral 49
8.10 Vincristine 50
8.11 STI571 (Gleevec) 50
8.12 VP-16 (etoposide, VePesid) 52
8.13 Ifosfamide 52
8.14 Toxicity of TBI 52
9.0 GUIDELINES FOR HEMATOPOIETIC STEM CELL TRANSPLANT 53
9.1 Transplant Guidelines 53
9.2 GVHD Prophylaxis 54
9.3 Supportive care 54
10.0 REQUIRED OBSERVATIONS 56
10.1 Observations from time of initial diagnosis for all patients enrolled on study 56
10.2 Evaluations at time of entry onto COG AALL0031 57
10.3 Evaluations during Treatment on COG AALL0031 57
10.4 End of Therapy 59
10.5 Follow-up Phase (Off Protocol Therapy-Chemotherapy) 60
10.6 Observation before start of HSCT 60
10.7 Follow-Up Phase (Off Protocol Therapy - HSCT) 61
10.8 At Relapse (On or Off Therapy) – Contact the study chair as soon as is possible. 62
10.9 Rapid Reporting of Toxicity 63
11.0 MINIMAL RESIDUAL DISEASE EVALUATIONS 64
11.1 Quantitative evaluations for MRD 64
11.2 Immunophenotypic Analysis 65
11.3 Molecular Evaluations 65
11.4 MicroArray Evaluations 65
12.0 DRUG INFORMATION 66
12.1 ASPARAGINASE 66
12.2 CYCLOPHOSPHAMIDE (CTX, Cytoxan) 69
12.3 CYTARABINE (cytosine arabinoside, AraC, Cytosar) 70
12.4 DAUNORUBICIN (Daunorubicin, DNR, Cerubidine) 71
12.5 DEXAMETHASONE (Decadron) 72
12.6 6-MERCAPTOPURINE (6-MP, Purinethol) 73
12.7 METHOTREXATE (MTX, amethopterin) 74
12.8 MESNA (sodium 2-mercaptoethane sulfonate, MESNA) 77
12.9 VINCRISTINE SULFATE (VCR, Oncovin ) 78
12.10 IMATINIB MESYLATE (STI-571, Gleevec® ), (formerly CGP 57148) 79
12.11 ETOPOSIDE (VP-16, VePesid ) 81
12.12 IFOSFAMIDE (IFX, IFOS) 83
12.13 GRANULOCYTE COLONY-STIMULATING FACTOR, 84
12.14 LEUCOVORIN CALCIUM (LCV, Wellcovorin, citrovorum factor, folinic acid) 85
12.15 CYCLOSPORIN. 87
13.0 SUPPORTIVE CARE GUIDELINES 88
13.1 Blood Products 88
13.2 Infection Prophylaxis 89
13.3 Varicella Exposure 89
13.4 Fever with Neutropenia (F and N) 90
13.5 Use of Growth Factors 90
13.6 Nausea and Vomiting 90
13.7 Nutrition 90
13.8 Venous Access 90
13.9 Hepatic Veno-Occlusive Disease (VOD) 91
13.10 Bleeding disorders associated with STI571 91
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14.0 REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 91
14.1 Criteria for Removal from Protocol Therapy 91
15.0 SURGICAL GUIDELINES 92
15.1 Biopsy Of The Clinically Enlarged Testis 92
16.0 RADIATION THERAPY GUIDELINES 92
16.1 Indications for Radiation 92
16.2 Cranial Irradiation 93
16.3 Testes 96
16.4 Total Body Irradiation Section 98
17.0 PATHOLOGY AND SPECIMEN GUIDELINES (APPLIES TO FORMER CCG
INSTITUTIONS) 103
17.1 FAB Morphology 103
17.2 Diagnostic CSF Cytospin Samples for Morphology 103
17.3 Cytogenetics Studies 103
17.4 Specimens to the COG ALL Biology Reference Laboratory 104
18.0 STATISTICAL CONSIDERATIONS 104
18.1 Accrual and Disease Outcome 104
18.2 Statistical Design and Toxicity Monitoring 105
18.3 Statistical Power to Detect Differences 106
19.0 ADVERSE EVENT REPORTING REQUIREMENTS 107
19.1 Expedited Reporting Requirements for Protocols Utilizing Investigational Agents
Supplied by the National Cancer Institute (NCI) 107
19.2 Expedited Reporting For Investigational Agent(S) Used In A Clinical Trial Involving A
Commercial Agent(S) 109
19.3 Adverse Event Reporting For Commercial Agents 109
19.4 Reporting Secondary AML/MDS 110
20.0 RECORDS AND REPORTING 111
20.1 Categories or Research Records 111
20.2 CDUS 111
20.3 Clinical Trials Agreement 111
21.0 STUDY COMMITTEE 113
22.0 REFERENCES 115
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 121
(#1) SAMPLE INFORMED CONSENT DOCUMENT FOR PATIENTS ENROLLED ON A FRONT
LINE CCG, POG, OR COG STUDY. 122
(#2) SAMPLE INFORMED CONSENT DOCUMENT FOR PATIENTS NOT ENROLLED ON A
FRONT LINE CCG, POG, OR COG STUDY. 138
(#3) SAMPLE CONSENT DOCUMENT FOR MINIMUM RESIDUAL DISEASE SPECIMENS 154
(#4) SAMPLE INFORMED CONSENT DOCUMENT FOR STEM CELL TRANSPLANT 158
AALL0031 This protocol is for research purposes only, see page 1 for usage policy. Page 7
1.0 SPECIFIC AIMS AND HYPOTHESES
1.1 Specific Aims
1.1.1 Primary
1. To determine the feasibility in terms of patient accrual and toxicity of an intensified
chemotherapeutic regimen incorporating novel agents for treatment of children and adolescents with
very high risk (VHR) ALL
1.1.2 Secondary
1. To determine if the BCR-ABL-specific tyrosine kinase inhibitor STI571 can be incorporated into
this regimen with acceptable toxicity for patients with Ph+ ALL.
2. To compare EFS for VHR patients treated with the intensive chemotherapy with that of historical
controls.
3. To conduct a preliminary evaluation of the feasibility and efficacy of following intensive

consolidation by Hematopoietic Stem Cell Transplantation (HSCT) as therapy for patients with
HLA-matched related donors.
4. To determine if MRD assessed at the end of induction and prior to reinductioin and prior to HSCT
therapy by PCR and flow cytometry can predict relapse.
5. To evaluate whether MRD detected by PCR at post-intensification time points is prognostically

significant.
6. To evaluate whether gene expression patterns can be identified by microarray evaluations to predict
disease recurrence or response to STI571.
1.2 Hypotheses
1. Accrual of VHR patients to all treatment arms (chemotherapy; STI571; HSCT) will be adequate to
form the basis for development of a future phase III VHR trial within the COG.
2. The chemotherapy regimen will have acceptable toxicity.

3. Inclusion of the BCR-ABL-specific tyrosine kinase inhibitor, STI571, for Ph+/BCR-ABL patients
will have acceptable toxicity when given in combination with the chemotherapy regimen.
4. EFS for VHR patients on the chemotherapy regimen will be improved compared with that of
historical controls.
5. A short intensive consolidation followed by HLA-matched related donor HSCT will be feasible for
VHR ALL patients with available donors.
6. At early time points, MRD assessed by PCR and/or flow cytometry will predict outcome.
7. At late time points, MRD detected by PCR will be highly predictive of treatment failure.
8. Gene expression patterns can be identified by microarray evaluations to predict relapse or resistance
to STI571.
2.0 OVERVIEW OF STUDY DESIGN
2.1 Abstract
The intensive, risk-adjusted chemotherapy regimens employed by the Children’s Cancer Group (CCG)
and the Pediatric Oncology Group (POG) for treatment of children ≥ 1 year of age with acute
lymphoblastic leukemia (ALL) have resulted in an overall EFS of approximately 70 - 80% (Sather, HN,
personal communication; Shuster J. personal communication). Subgroups of these children, however,
still have a poor prognosis. For example, the recent CCG-1882 trial for NCI poor risk patients
demonstrated that an augmented intensive regimen was effective for the majority of those with an
unfavorable slow early response (≥ 25% marrow blasts at day 7 of induction therapy), yet the subset of
patients with a t(9;22)(q34;q11), also called the Philadelphia chromosome (Ph), still had very poor
outcome, with 5 of 7 patients having events.1 The overall group of Ph+ patients treated on CCG studies
conducted between 1989 and 1995 had a 4-year EFS of 20%.2 Other patients, such as those with a
balanced t(1;19)(q23;p13),3,4 or near-haploidy5-7 have also been reported to have poor outcomes on
recent intensive protocols. The prognostic significance of t(4;11)(q21;q23) among non-infant patients is
controversial: Behm et al. have reported poor outcome for such patients. Pui et al. reported favorable
outcome.8,9 Uckun et al. found that non-infants who lacked cytogenetic evidence of a t(4;11) but who
were positive for expression of the MLL-AF4 fusion transcript had favorable outcome.10 Other patients
presumed to have a poor outcome are those who fail induction or consolidation therapy and are typically
taken off study.
The proposed pilot study represents the first attempt by the combined Children’s Oncology Group
(COG) to develop a treatment strategy aimed at the subgroup of patients with very high risk (VHR) of
treatment failure on current protocols. To define a subset of patients with a very high risk (VHR) of
treatment failure who warrant intervention with a novel multi-agent intensive treatment strategy, we
have re-evaluated outcome among clinically- and biologically-defined subsets of the large cohort of
patients ≥ 1 year of age that had been enrolled on CCG risk-adjusted trials conducted between 1989 and
1995. The VHR group was defined as those patients who have an expected 5-year EFS of < 45%. Four
subgroups with VHR ALL were identified: 1) patients with Ph+ ALL; 2) hypodiploid patients with ≤
44 chromosomes; 3) patients who had an M3 (>25% blasts) bone marrow at the end of induction therapy
and who later achieved remission either with chemotherapy or a bone marrow transplant; 4) patients
who have M2 (5–25% blasts) marrows at the end of induction therapy and do not achieve an M1 (<5%
blasts) marrow by the end of an extended induction period (POG studies) or by the end of consolidation
(CCG studies).
This pilot study will utilize a novel intensified chemotherapeutic regimen for VHR patients based on 1)
the use of ifosfamide and etoposide in POG ALL relapse studies;11,12 2) the use of high dose
methotrexate for children13-16 and infants;17 and 3) the intensive CCG New York (NY) II regimen used
for patients with lymphomatous ALL.18 The BCR-ABL-specific tyrosine kinase inhibitor STI57119-22
will be used for Ph+ patients and hematopoietic stem cell transplant (HSCT) will be offered to patients
with appropriate donors. The study will determine whether an adequate number of VHR patients will be
accrued to form the basis for development of a future phase III trial within the COG. The presence or
absence of minimal residual disease (MRD) in patients in remission also will be determined. If the
intensive treatment is found to have acceptable toxicity and shows potential, either alone, or with
transplant, for improving outcome of the VHR patient population, it will be the first promising strategy
identified for this group.
2.2 Experimental Design
2.2.1 Overall Design
Experimental Design: An Overview
Frontline Induction/Consolidation (4-15 weeks)
MRD
Consolidation Block 1 (3 weeks)

IV Ifosfamide, IV Etoposide, IT Methotrexate, STI571 for Ph+
ALL, and Radiation to Testes (if indicated)
MRD

HD Methotrexate, IT Methotrexate, HD Cytarabine
Patients Meeting Transplant Criteria* Patients Not Receiving Transplants
MRD MRD
Preparative Regimen (1 week) Reinduction Block 1 (3 weeks)

TBI, Etoposide, IV Cyclophosphamide IV Daunorubicin, IV Cyclophosphamide, IV
Vincristine, IM L-asparaginase, PO
Dexamethasone, IT Methotrexate, STI571 for
Ph+ ALL
Hematopoietic Stem Cell Transplant (HSCT)
MRD Intensification Block 1 (8 weeks)

IV Methotrexate, IT Methotrexate, IV Etoposide,
At week 24 or at the beginning of STI571
IV Cyclophosphamide, HD Cytarabine, IM
L-asparaginase, STI571 for Ph+ ALL
MRD
At week 48 or end of STI571 MRD
Post Transplant Phase Reinduction Block 2 (3 weeks)
STI571 for Ph+ ALL beginning at week 16-24 See Reinduction 1
Intensification Block 2 (8 weeks)

See Intensification 1
MRD
Maintenance (8-week cycles) Maintenance (8-week cycles)

Cycles 1-4 Cycles 5 - 12
MRD= Minimum Residual Disease HD Methotrexate, IT Methotrexate, PO Radiation to Brain (if indicated),
Evaluation Methotrexate, IV Vincristine, PO IV Vincristine, PO
*There is an HLA-matched sibling Dexamethasone, PO 6-Mercaptopurine, Dexamethasone, PO 6-
or relative or 1 antigen mismatched IV Etoposide, IV Cyclophosphamide, Mercaptopurine, IT Methotrexate,
sibling or relative (excluding HLA- STI571 for Ph+ ALL PO Methotrexate, STI571 for Ph+
DR mismatch). ALL
2.2.2 Treatment Schema
2.2.2.1 Frontline Induction

All patients are to receive 3-4 drug induction for 4-6 weeks either on or identical to a frontline CCG or
POG trial for ALL. Eligible VHR patients who are Ph+, hypodiploid with ≤ 44 chromosomes or DNA
index <0.81, or M3 at the end of frontline induction will enter the VHR trial within 14 days of the end of
frontline induction. Patients who are M3 at the end of frontline induction and remain M2 or M3 at the
end of extended induction (POG) or consolidation (CCG) will enter the VHR trial within 14 days of the
marrow response assessment.
2.2.2.2. VHR Therapy

VP-16 (100 mg/m2/day, IV ): days 1-5
Ifosfamide (1.8 g/m2/day, IV ): days 1-5
MESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5
G-CSF (5 µg/kg, SC): days 6-15
Methotrexate (age-adjusted, IT): day 1, 8*, 15*
STI571ii (Ph+ only): in dose escalation days 1 -21
If Testis + ve – testis RT (24 Gy in 8 fractions)
* Patients classified as CNS 2 or those with traumatic taps who did not receive 2 additional intrathecal
methotrexate doses in induction will receive 2 additional intrathecal methotrexate doses in
consolidation block 1 on days 8 and 15.

Methotrexate (5 g/m2 over 24 hours, IV ): day 1
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3
Methotrexate (age-adjusted, IT): day 1
ARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3
Reinduction Block 1 (3 weeks)

*Patients with HLA-matched related donors will be moved to the HSCT
arm at this point.
VCR (1.5 mg/m2/day, IV ): days 1, 8, and 15
DAUN (45 mg/m2/day bolus, IV): days 1 and 2
CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4
PEG-ASP (2500 IUnits/m2, IM): day 4
Methotrexate (age-adjusted, IT): days 1 and 15
DEX (6 mg/m2/day, PO): days 1-7 and 15-21
For CNS 3 patients a boost of 600 cGy for those receiving HSCT
STI571ii (Ph+ only): in dose escalation days 1 - 21
Methotrexate (5 g/m2 over 24 hours, IV ): days 1 and 8
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 9, and 10
Methotrexate (age-adjusted, IT): days 1 and 15
VP-16 (100 mg/m2/day, IV ):days 15-19
CPM (300 mg/m2/day, IV ):days 15-19
MESNA (150 mg/m2/day, IV): days 15-19
ARA-C (3 g/m2, q12h, IV): days 36, 37
L-ASP (6000 IUnits/m2, IM): days 37
STI571ii (Ph+ only): in dose escalation STI571 days 36 - 56
Reinduction Block 2 (3 weeks)

VCR (1.5 mg/m2/day, IV ): days 1, 8 and 15
DAUN (45 mg/m2/day bolus, IV): days 1 and 2
CPM (250 mg/m2/dose q12h x 4 doses, iv): days 3 and 4
PEG-ASP (2500 IUnits/m2, IM): day 4
Methotrexate (age-adjusted, IT): day 1
DEX (6 mg/m2/day, PO): days 1- 7 and 15 - 21
STI571ii (Ph+ only) iv: in dose escalation days 1 - 21

Methotrexate (5 g/m2 over 24 hours, IV ): days 1 and 8
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 9, and 10
MTX (age-adjusted, IT): days 1 and 15
VP-16 (100 mg/m2/day, IV ):days 15-19
CPM (300 mg/m2/day, IV ):days 15-19
MESNA (150 mg/m2/day, IV): days 15-19
ARA-C (3 g/m2, q12h, IV): days 36, 37
L-ASP (6000 IUnits/m2, IM): days 37
STI571ii (Ph+ only): in dose escalation days 36 - 56
Maintenance (8-week cycles): Cycles 1-4
MTX (5 g/m2 over 24 hours, IV ): day 1
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3
Methotrexate (age-adjusted, IT): days 1, 29
VCR (1.5 mg/m2, IV): days 1, 29
DEX (6 mg/m2/day PO): days 1-5; 29-33
6-MP (75 mg/m2/day, PO): days 8-28
Methotrexate (20 mg/m2/wk, PO): days 8, 15, 22
VP-16 (100 mg/m2, IV): days 29-33
CPM (300 mg/m2, IV): days 29-33
STI571ii (Ph+ only): in dose escalation days 29 – 49
Chemotherapy on day 29 will only start if ANC>1000, platelets >100,000 and normal
LFTs
Maintenance (8-week cycles): Cycles 5-12

Methotrexate (age-adjusted, IT): day 1 of each cycle
VCR (1.5 mg/m2, IV): days 1, 29
DEX (6 mg/m2/day, PO): days 1-5; 29-33
6-MP (75 mg/m2/day, PO): days 1-56
Methotrexate (20 mg/m2/wk, PO): days 8, 15, 22, 29, 36, 43, 50
STI571ii (Ph+ only): in dose escalation days 1 – 21 and days 29 - 49
If CNS + ve at diagnosis – cranial irradiation 18 Gy in 10Rx
i
Abbreviations:
G-CSF = Granulocyte Colony Stimulating Factor
VP-16 = Etoposide
MTX = Methotrexate
IV = Intravenous
SC = Subcutaneous
IT = Intrathecal
PO = Oral
IM = Intramuscular
ARA-C = Cytarabine
CPM = Cyclophosphamide
VCR = Vincristine
DEX = Dexamethasone
DAUN = Daunorubicin
6-MP = 6-mercaptopurine
E.Coli L-ASP = L-asparaginase
ii
Dose to be given 4-12 hours before the initial dose of each cycle of chemotherapy
iii
or until Methotrexate level is < 0.1 µM
3.0 BACKGROUND AND RATIONALE
3.1 Introduction
Little progress has been realized toward successful application of chemotherapy for the children who
constitute the VHR group. These patients share the common feature of early treatment failure. Those
who do not achieve a complete remission within four to six weeks of diagnosis have a very grave
prognosis.23 Similarly, poor outcome is observed for patients who are Ph+ or have ≤ 44 chromosomes at
diagnosis, although the majority of these two subsets do achieve an initial remission.2,6,24 Our strategy
in designing the chemotherapy for the current trial is to build upon a recent model (POG-9407/CCG-
1953) developed for infants (< 1 year of age) with ALL.17 Because infants also tend to have recurrent
leukemia early in their clinical course, the principle of the infant trial is to introduce intensive
combinations of anti-leukemic agents given in a novel schedule very early in the treatment course. We
will use this model in the current trial, but with some adaptations that are necessary given the fact that
some of the registrants on the VHR trial will come to the study as primary failures of initial induction
therapy. We also will employ strategies utilized successfully in the treatment of relapsed and
lymphomatous ALL.11,12,18 In addition, bone marrow transplant appears to be a potentially effective
therapy for VHR patients with suitable donors, and will be employed as a component of this pilot
study.25,26 Finally, the experimental agent STI571, a BCR-ABL tyrosine kinase inhibitor, will be
incorporated into the chemotherapy regimen for Ph+ ALL patients as described below.
The study schema is shown in section 2.2.1. VHR patients who have initially been enrolled on and
completed 4-6 weeks of 3 or 4 drug induction therapy on a frontline CCG or POG study for childhood
ALL, or who have received an induction identical to a POG or CCG induction therapy will be eligible to
participate in this study. CCG patients identified later as failing to achieve remission will have received
additional consolidation therapy prior to study entry. Upon entry on the VHR study, all patients will
receive a minimum of two consolidation chemotherapy “blocks” that are designed to be applicable for
both those who are and those who are not yet in complete remission. Patients with suitable donors will
be offered transplant after the initial two consolidation blocks.
3.2 Rationale for Chemotherapy

Consolidation block 1 consists of combination therapy with etoposide (100 mg/m2) and ifosfamide (1.8
g/m2) each for 5 days, with MESNA uroprotection and Granulocyte-colony stimulating factor support.
Recent evidence from 2 studies indicates that this combination may be effective in producing complete
responses among children with recurrent or refractory ALL. 11,12 In the first of these studies 8 of 20
patients achieved complete remission with acceptable toxicity, largely related to bone marrow
suppression.11 In the second study, Pediatric Oncology Group investigators escalated the daily dose of
ifosfamide to a maximum of 4 g/m2 per day for 5 days.12 Dose escalation appeared to enhance the
complete remission rate, with a total of 7 of 16 children with recurrent and/or refractory ALL achieving
complete response. However, at the higher dose levels, the incidences of severe infections were greater,
although tolerable. The combination has also been evaluated in consolidation therapy and periodic
maintenance in 2 recent POG trials (POG 9411 and POG 9412) for children with hematologic and CNS
relapse respectively. For purposes of this study we have decided to begin at the standard dose of 1.8
g/m2 per day to try to prevent potential renal or CNS complications which could otherwise interfere with
protocol tolerance and timely delivery. Consideration to dose escalation may be given during the course
of study conduct depending upon toxicities and response. The background information thus makes the
combination of etoposide and ifosfamide a logical choice for a study that will include patients for whom
frontline induction therapy failed.
2
Consolidation block 2 will use high dose intravenous methotrexate (5 g/m ) and high dose intravenous
cytarabine (3 g/m2). Intravenous methotrexate doses ranging from 1g/m2 to 5 g/m2 with Leucovorin rescue
have been used by POG, CCG, and European investigators.13,14,27-33 High dose methotrexate (5 g/m2)
with Leucovorin rescue was pioneered by the BFM group and has resulted in improved outcomes for
children with ALL.27 In general, with appropriate alkaline hydration and Leucovorin rescue, serious
adverse events appear to be largely avoidable, and problems of mucositis and renal dysfunction have not
been an issue.
High dose intravenous cytarabine has proven useful for treatment of refractory ALL.34,35 Moreover, the
combination of high dose methotrexate and high dose cytarabine may be synergistic, as suggested by the
improved outcome observed for patients with B-cell leukemia and Burkitt’s lymphoma.32 Furthermore, the
recent POG-9517 study35 has established the safety of the combination of high dose intravenous
methotrexate (5 g/m2) followed by cytarabine (3 g/m2) for treatment of B-cell leukemia and non-Hodgkin’s
lymphoma. Based on these considerations, early administration of high dose intravenous methotrexate
followed by high dose intravenous cytarabine is feasible and may contribute to improvement in outcome
without undue morbidity.
Following consolidation blocks 1 and 2, patients who have a suitable family donor for allogeneic HSCT
(expected to comprise 20% of all VHR patients) will then be assigned to transplant. Patients who do not
have a suitable donor will continue on chemotherapy consisting of alternating reinduction and
intensification blocks, and twelve 8-week cycles of continuation therapy. Rationale for HSCT is given
below, following the completion of the discussion of the chemotherapy regimen.
On the chemotherapy arm, reinduction blocks 1 and 2 are based on the NYII induction regimen that was
developed by Steinherz et al 18 and was used on the CCG-1901 trial for lymphomatous ALL (Steinherz,
PG, CCG, unpublished data). NYII induction is also currently being used on the CCG-1953/POG-9407
infant ALL trial. NYII induction as originally described employed continuous infusion daunorubicin on
days 0 and 1 followed by a single dose of cyclophosphamide on day 2, as well as weekly vincristine,
daily prednisone, 9 doses of L-asparaginase and 2 doses of intrathecal methotrexate. The identical
regimen will be used for reinduction blocks 1 and 2 on the VHR trial, except that dexamethasone will be
used in place of prednisone, based upon the recent information that it may be efficacious in preventing
relapse of ALL, although this information is currently limited to those at standard risk for treatment
failure. In both phases the dexamethasone will be given in two 7-day courses separated by a 7 day no
steroid interval. This is being done in an effort to reduce the risks of avascular necrosis, which have
been observed on recent CCG high-risk trials involving adolescent patients. Further, for purposes of this
study the cyclophosphamide will be given in a fractionated schedule of 250 mg/m2 every 12 hours for 4
doses as has been piloted successfully in the infant ALL trial. PEG asparaginase will be substituted as a
single dose of 2500 u/m2 for the multiple dose historic regimen of L-asparaginase.
The intensification phases are modeled closely after those used on the current CCG-1953/POG-9407
infant ALL protocol. Patients will receive two 9-week courses of intensification chemotherapy separated
by reinduction block 2. During each intensification phase, patients will receive high dose methotrexate
(5 g/m2) on two consecutive weeks. Intrathecal methotrexate will be given during the first week only.
Treatment during the third week will consist of a five-day course of cyclophosphamide and etoposide.
Cyclophosphamide will be substituted for ifosfamide during these repetitive courses to eliminate the
likelihood of cumulative nephrotoxicity,39 which could potentially compromise the delivery of other
chemotherapy agents or marrow transplantation should the patient subsequently relapse and require this
strategy. Following a two-week rest to allow hematopoietic recovery, patients will receive two weeks of
high dose cytarabine followed by L-asparaginase as utilized in the POG version (POG-9407) of the
infant ALL trial, which also has documented effectiveness in patients with refractory ALL and myeloid
leukemia.34
The traditional combination of mercaptopurine and methotrexate 13,27,29,36,40-42 will serve as the
backbone for maintenance therapy. The therapy will be reinforced at monthly intervals with pulses of
vincristine and dexamethasone. As described for the reinduction blocks, dexamethasone will be
substituted for prednisone.37,38. There will be a total of twelve 8-week cycles of maintenance therapy.
The first four cycles will differ from the later cycles in providing an intensified intrathecal therapy at 4-
week intervals, as well as a single courses of high dose methotrexate (5 g/m2) at the beginning and a 5-
day course of cyclophosphamide and etoposide at week 6. Once again, this strategy and sequence is
modeled after the CCG-1953/POG-9407 infant all trial.
It is the intent of this treatment design that all chemotherapy will be delivered without omission, but
with modifications in schedule as dictated by guidelines for administration. Only during the last eight
cycles of continuation therapy will omissions of mercaptopurine and methotrexate be recommended, if
necessary, to keep the cycles on schedule. Total duration of chemotherapy on the chemotherapy arm is
anticipated to be 119 weeks or 2.3 years.
For patients completing chemotherapy on the VHR trial, the total cumulative dose of anthracycline
delivered during reinduction blocks 1 and 2 will be 180 mg/m2. In addition, patients will have received
doses ranging from 0 to 150 mg/m2 during the initial induction on POG and CCG frontline trials. The
total cumulative dose of etoposide delivered for patients completing therapy will be 3500 mg/m2. The
etoposide schedule of 100 mg/m2 per day for 5 days delivered at intervals of two or more months may
increase the hazard of secondary leukemogenesis, but this complication is expected to occur at a low
rate.43
Treatment of the Central Nervous System (CNS)

Patients on the VHR study will receive intrathecal methotrexate once during each of the two consolidation
phases, twice during each of the two reinduction blocks, twice during each of the two intensification phases,
and once per cycle during the maintenance phase. Intrathecal therapy will not be given, however, during
the weeks of intensification with high dose cytarabine since the combination of intrathecal drugs and high
dose cytarabine has been associated with adverse CNS toxicity.32 The high dose cytarabine administered
during consolidation, however, is expected to be effective in treating occult CNS disease.
With the exception of those who present with CNS-3 (≥ 5 WBC/µL with definable blasts in the
cerebrospinal fluid or the presence of cranial nerve palsy) at diagnosis, patients will not routinely receive
cranial radiation. Patients who are CNS-3 at diagnosis and achieve remission by the end of frontline
induction will receive whole brain radiotherapy (18 Gy) in conjunction with cycle 5 of maintenance
therapy. Intrathecal methotrexate frequency will decrease to intervals of 8 weeks during cycles 5 through
12 of continuation therapy.
Traumatic Spinal Taps and CNS-2 at diagnosis

Determining with certainty that a patient who underwent a traumatic spinal tap had a pre-existing CNS-3
disease is an impossible task. The Steinherz-Bleyer formula is used as an attempt to assess such a
situation. However, the diagnosis of CNS-3, results in patients receiving irradiation and treatment
intensification, as a result of a marginal difference in the ratios proposed by the formula. Because of
these important implications the ALL Definitions Committee met at the April 2002 COG meeting and
developed modified criteria. Because this determination is arbitrary due to the lack of an exact scientific
methodology, the criteria were developed to have enough of a safety margin to be applied in these
situations.
As can be seen from the tables below, analysis of previous CCG ALL studies show that patients with
traumatic taps and CNS-2 disease had inferior EFS to those who were CNS-1. The group hypothesized
that introducing blasts into the CNS sanctuary and failing to give adequate intrathecal therapy is a least
one important factor causing the increased incidence of events in these patients.
CCG 1800’s std, CCG 1922 # of pts 2896

CNS relapse BM relapse EFS
CNS 1 4% 14.4% 75%
CNS 2 7.4% 19% 66%
CNS 3 5.8% 25% 57%
TST 0.0 22.4% 63%
CCG 1952, CCG 1962 # of pts 2035

CNS relapse BM relapse EFS
CNS 1 2.5% 3% 92.5%
CNS 2 8.4% 5.6% 83%
CNS 3 0.0 11% 83%
TST 6% 6% 87.5%
Also, Gajjar et al revealed in their article in Blood the results from St Jude’s studies that patients with
traumatic taps with blasts had an inferior EFS compared to those who were CNS-1(60 ± 6% vs 77 ±
2%). Patients who had two consecutive traumatic taps with blasts had a significantly worse EFS, in fact
their outcome was comparable to patients with CNS-3 disease, with a hazard ratio of 2.39 for adverse
events. This adverse effect was present even after stratifying for the treatment protocol and NCI risk
groups. As in the CCG data, patients with CNS-2 fared worse than those who were CNS-1, 5-year EFS
55 ± 6% vs 77 ± 2%. The subsequent treatment protocol intensified intrathecal therapy for CNS-3, CNS-
2, and traumatic taps with blasts, and virtually eliminated CNS relapse and improved the overall 5-year
EFS to 80% 89. Therefore, management of these patients will be as follows:
In cases of traumatic spinal taps with >5 WBC/uL and presence of blasts at diagnosis, the determination
that the patient has CNS leukemia will still be determined by the Steinherz-Bleyer Formula but with the
following modification: CSF WBC/RBC ratio should be at least more than twice the peripheral blood
WBC/RBC ratio for a patient to be considered as having CNS-3 disease.
Patients classified as CNS 2 or those with traumatic taps will have a recommended additional 2
intrathecal methotrexate doses in induction. Those patients enrolled on AALL0031 that have not
received 2 additional intrathecal methotrexate doses in induction, will receive 2 additional IT
methotrexate doses in consolidation 1 on days 8 and 15.
3.3 Rationale for Use of HSCT for VHR Patients

Numerous reports have been published recently exploring HLA-matched sibling donor bone marrow
transplant (BMT) for adult patients with high risk ALL in first continuous remission.44-48 The overall
disease free survival (DFS) in these studies has ranged from 50% to 72%. CCG employed first
remission matched-related donor BMT for a subset of very high risk patients on CCG-1921.26 Thirty-
seven non-infant patients with family donors were compared to 64 non-infant patients without donors in
aggregate. There was no significant difference in the outcome of the 2 populations. By contrast, BMT
did appear to improve the outcome of children with Ph+ ALL, with 6 of 9 patients remaining disease-
free. An international study of outcome for 267 patients with Ph+ ALL showed improved outcome at 2
years for those who underwent matched related donor BMT (EFS = 71%) compared with that of patients
treated with mismatched related donor BMT(EFS = 56%), unrelated donor for BMT (EFS = 37%), or
chemotherapy (EFS = 44%).25 Although low WBC at diagnosis may identify a low risk population that
does not require HSCT,49 this factor does not appear to result in a long-term EFS that is > 45% in the
larger international analysis.25
Among other VHR patients defined herein, information regarding the impact of BMT is sparse and
incomplete. No CCG or POG data were available for patients with hypodiploidy ≤ 44 chromosomes who
underwent BMT. Patients with an M3 bone marrow at the end of induction therapy had a 4-year EFS of
39%.24 For these patients, no information was available regarding the type of donor, preparative
regimen used, or other details regarding the conditions of the HSCT. A recent abstract from POG
demonstrated that non-Ph+ ALL high risk patients may not benefit more from treatment with HLA-
identical sibling BMT than from aggressive chemotherapy.50 Evaluation of therapeutic approaches for
children with these poor prognostic features will require the comparison of consistent HSCT and
chemotherapeutic regimens. At this time, the best outcome for children with Ph+ appears to be with
HLA-matched or 1 antigen mismatched related donor BMT in first complete remission. The benefits of
using HSCT for other very high risk features is less clear.
On the proposed VHR trial, patients with HLA-matched related donors or 1 antigen mismatched
(excluding HLA-DR mismatch) related donors will be eligible to receive HSCT after the two initial
consolidation chemotherapy blocks. Details of the conditioning regimen and other aspects of HSCT are
given below.
3.4 Rationale for Use of STI571 for Ph+ Patients

STI571 is a tyrosine kinase inhibitor that specifically inhibits the c-ABL and PDGF receptor kinases.21,51
This compound can also inhibit the tyrosine kinase activity of the 2 chimeric fusion proteins associated with
Ph+ CML (p210BCR-ABL) and ALL (p190BCR-ABL), in both cell lines and in tumor-bearing mice.21,22,52,53
Inhibition of proliferation of primary ALL blasts with p190BCR-ABL is comparable to that of primary blasts
from CML patients with p210BCR-ABL.54 Clinical trials with STI571 have been initiated in adults with both
BCR-ABL+ CML and ALL. A phase I trial in adult CML patients who have failed interferon therapy
showed little toxicity at the 300 mg/day dose, with Grade 3 myelosuppression occurring in only 2 of 24
patients.20 Complete hematological responses were observed in 23/24 (96%) patients at this dose;
cytogenetic responses were observed in 33% of patients.20
In another preliminary report, 12 adults with CML in myeloid blast crisis and 10 patients with ALL or CML
in lymphoid blast crisis were treated with STI571 at doses of 300-600 mg/day.19 Eleven of 15 (73%)
evaluable patients had a reduction of 50% or more in the number of marrow or peripheral blasts after 4
weeks of therapy. Four patients achieved a complete remission, but relapses occurred in 3 of the 4 patients
after 2 to 6 months of starting therapy. Toxicity was minimal, although one toxicity of concern is a possible
effect on platelet function leading to an increased bleeding tendency. The currently open phase I COG trial
(P9973) is using STI571 in children with relapsed Ph+ ALL and has been limited only by mild liver toxicity
(see Preliminary Results, below).
On the VHR trial, STI571 will be given on a daily dosing schedule for 21 days during each phase of
chemotherapy, with the exception that no drug will be given on days when high dose methotrexate is given.
The rationale for excluding STI571 in combination with HD methotrexate is that hepatotoxicity appears to
be one of the primary toxicities of the drug on the CCG/POG Phase I study (Bernstein M, Champagne M,
personal communication). Another toxicity that has occurred in both children and adults on Phase I trials is
possible induction of platelet dysfunction leading to increase bleeding episodes (Bernstein M, Champagne,
M., Drucker, B., personal communication). This toxicity is of particular concern when used in combination
with severely myelosuppressive chemotherapy courses. Details of these toxicities on the Phase I trials are
given below in Preliminary results. Maintenance of platelet levels greater than 20,000/µL will be part of the
treatment regimen. Dosage of STI571 will be 340 mg/m2, a dose that has biological activity and minimal
side effects. Escalation will be by increased duration of dosage in 4 levels. Toxicity with each block of
therapy will be monitored and modifications based on the toxicity observed with each drug combination.
3.5 Rationale for Studies of Minimal Residual Disease (MRD) in ALL

Nearly all patients now achieve remission, defined as < 5% blasts in the bone marrow, by the end of the
induction phase of therapy on contemporary intensive CCG or POG regimens. Using molecular
techniques, such as the polymerase chain reaction (PCR),30,55-60 flow cytometry/leukemic cell
progenitor (FACS/LPC) assays,61,62 and multiparameter flow cytometry,63,64 it is now possible to
detect and quantify the leukemic blasts, or “minimal residual disease” (MRD) that remain in the bone
marrow of patients in morphological remission.
MRD detection strategies may provide an opportunity to identify subsets of VHR patients with
substantially different prognoses. Goulden and coworkers,65 Cave and coworkers,66 and van Dongen
and coworkers67 have demonstrated prognostic significance of PCR-based estimates for end-of-
induction disease burden. Coustan-Smith63 and coworkers have demonstrated prognostic significance
for MRD assessed by multidimensional flow cytometry. In contrast, clonotypic cells have been detected
using very sensitive PCR assays several years after cessation of therapy in some children, most of whom
are probably cured.60
Several reports have correlated disease burden measured by PCR before and after allogeneic BMT with
outcome following transplant.62,68-72 Van Dongen et al. 67 quantified residual ALL using competitive
RT-PCR for T cell receptor (TCR) and Ig heavy chain rearrangements. MRD detected at early time
points was able to identify patients who were at high risk of relapse, suggesting that as these evaluations
are validated, modification of therapy based on early quantitative MRD measurements can be used to
modify therapy for improved patient outcome.
Several studies of MRD have been conducted in patients with Ph+ ALL.68,71-73 In the study by
Preudhomme et al.,71 9 of 18 patients who underwent allogeneic or autologous transplants were negative
by PCR for BCR-ABL transcripts in the bone marrow. In all 3 patients who relapsed after 22 to 28
months, relapse was preceded by the development of a positive bone marrow PCR result. In the study by
Stockschlader et al.,72 all patients tested by RT-PCR were negative for the BCR/ABL rearrangement 4
weeks after transplant. Among 3 patients who relapsed, both tested patients became positive by RT-
PCR for BCR-ABL prior to relapse. Interestingly, data from Radich et al.73 suggests that increased risk
of relapse among patients who were MRD+ after transplant was restricted to the subset who expressed
the p190 BCR-ABL chimeric mRNA.
The optimal method for measuring MRD is unclear. Current POG ALL studies (POG-9904; POG-9905;
POG9906; POG-9806) are aiming to determine the optimal method by comparing the incidence and
prognostic significance of MRD determined by multiparameter flow cytometry with those determined
by RT-PCR. MRD data from these studies are not yet available On the VHR trial, we plan to assess
MRD both by multiparameter flow cytometry and by RT-PCR. PCR-based MRD studies will be carried
out in collaboration with Dr. Cheryl Willman at the University of New Mexico School of Medicine,
Albuquerque, NM. Flow cytometry-based MRD studies will be conducted in collaboration with Dr.
Michael Borowitz at the John Hopkins University School of Medicine. Bone marrow samples for MRD
determinations will be collected at five time points: 1) at study entry; 2) before consolidation block 2; 3)
before reinductions block 1 and 2; and 4) before maintenance cycle 1. In HSCT patients they will be
evaluated: 1) at study entry; 2) before consolidation block 2; 3) before HSCT; 4) at 24 weeks, and 48
weeks after HSCT.
3.6 Identification of a VHR Subset of Patients with ALL

As described above, to define a subset of patients with a very high risk (VHR) of treatment failure who
warrant intervention with a novel multi-agent intensive treatment strategy, we have re-evaluated and
updated previous analyses of outcome among clinically- and biologically-defined subsets of the large
cohort of patients ≥ 1 year of age that had been enrolled on CCG risk-adjusted trials conducted between
1989 and 1995. The VHR group was defined as those patients who have an expected 5-year EFS of <
45%. Except where noted, analyses excluded patients who underwent bone marrow transplantation and
only included patients who achieved an initial remission after induction chemotherapy. Three subgroups
with VHR ALL were identified. First, patients with Ph+ ALL detected by conventional cytogenetics
had a 5-year EFS of 9%. Second, hypodiploid patients with 40-44 chromosomes had a 5-year EFS of
33% and those with ≤ 39 chromosomes had a 5-year EFS of 27%. Subsets of patients who did not meet
the VHR definition included hypodiploid patients with 45 chromosomes (5-year EFS of 66%); patients
with a balanced t(1;19)(q23;p13) or an unbalanced der(19)t(1;19)(q23;p13) (5-year EFS of 47% and
81%, respectively); and patients with a t(4;11)(q21;q23) (5-year EFS of 50%).
The third VHR subset comprises patients who had an M3 (>25% blasts) bone marrow at the end of
induction therapy. Outcome data was available only for such patients who later achieved remission
either with chemotherapy or a bone marrow transplant (5-year EFS of 39%). EFS for the entire group of
patients who are M3 at the end of induction therapy is estimated to be similar or inferior to this estimate.
In addition, as described above, we also propose to include patients who have M2 (5–25% blasts)
marrows at the end of induction therapy and do not achieve an M1 (<5% blasts) marrow by the end of
consolidation on CCG studies or by end of the extended induction period on POG studies. Although we
do not have adequate follow-up on induction failure patients, we presume they have a poor outcome.
3.7 Chemotherapy: NYII Induction

The CCG-1901 trial compared NYI vs. NYII therapy. During induction, NYI differs from NYII in the
order of delivery of daunorubicin and cyclophosphamide and in the method for delivering daunorubicin. On
NYI, cyclophosphamide is administered on day 0 and daunorubicin is administered by bolus injection on
days 2 and 3. On NYII, continuous infusion daunorubicin is given on days 0 and 1 followed by
cyclophosphamide on day 2. In the initial study of NYII, the sequential administration of daunorubicin
followed by cyclophosphamide had appeared superior to the reverse ordering in terms of early marrow
response. Similarly, continuous infusion daunorubicin appeared superior to bolus administration.18 NYII
also provided intensified consolidation therapy, and decreased the number of intensive maintenance cycles
relative to NYI. However, only the induction component will be utilized on the proposed VHR trial.
Therefore, on the VHR trial because of concerns regarding ease of administration, we will use the NYI
sequence of bolus infusion daunorubicin followed by cyclophosphamide during reinduction blocks 1 and 2.
However, the dose of daunorubicin used for reinduction on the VHR trial will be 45 mg/m2/day for two
days, whereas NYII induction used 60 mg/m2/day dose used for two days.
3.8 Chemotherapy: CCG-1953/POG-9407
The proposed VHR study uses continuous infusion daunorubicin based on the NYII induction regimen
described above. This induction regimen is also in use on the current CCG-1953/POG-9407 infant ALL
trial. Toxicity due to continuous infusion daunorubicin on CCG-1953 was significant, particularly for
infants < 3 months of age. On the VHR study, however, daunorubicin is expected to be less toxic, since the
dose to be used for reinduction is lower (see above) and the children being treated will be older than 1 year
of age. The most frequent adverse reactions on both CCG-1953 and POG-9407 were hematological,
infectious, and gastrointestinal Grade 3 and 4 toxicities. Liver, pulmonary, and cortical toxicities occurred
less frequently. The 3-year EFS for infants > 91 days on POG-9407 was 65%. Furthermore, as described
above, toxicity with NYII induction on CCG-1901 appeared tolerable.
3.9 Chemotherapy: STI571 Phase I trial

A Phase I study of STI571, P9973, is being conducted by COG to estimate the maximum tolerated dose
(MTD) of STI571 administered orally once daily, without interruption to children with recurrent Ph+
leukemia. The study also proposed to determine dose-limiting toxicities of STI571 given on this
schedule, and will characterize the pharmacokinetic behavior and anti-leukemic activity of STI571 in
these patients.
The POG Phase I trial has now finished accrual. No MTD has been reached up to 570 mg/m2,
equivalent to the adult phase 2 and 3 dose. Grade 3-4 neutropenia was seen in the 23 of 93 courses,
thrombocytopenia in 16 of 93 courses. Some of the hematologic toxicity may be secondary to
underlying leukemia as they were present in 25-30% during the first course of treatment. Grade 3-4
diarrhea was observed in 15/ 93, nausea in 16/93 vomiting in 13/93, abdominal cramping 6/ 93. Grade 3
liver enzyme elevation occurred in 1/93. One intracranial hemorrhage occurred in a patient who was
thrombocytopenic and was receiving enoxaparin.
The most common toxicity was Grade 1 nausea, seen in 7 of 14 patients (50%). Diarrhea, vomiting,
abdominal pain and headaches were each reported in 3 patients (21%). Other toxicities reported in 2
patients each included fatigue, stomatitis, bone pain, and various metabolic alterations (increased
alkaline phosphatase, increased AST, hyperglycemia). Patients accrued on the first 3 treatment levels
cumulate a total of 43 courses of treatment (median 3; range 2-8). The maximum tolerated dose still has
not yet been reached. PK data is not available at this time. Six patients have been accrued at the next
dose level of 570mg/m2. This dose level is roughly comparable to the maximum dose of 1000mg tested
in the adult phase 1 trial. If PK analysis reveals that drug exposure is comparable to what is seen in
adults, this will be the last dose level evaluation in the study. Preliminary evaluation reveals some
clinical antileukemic activity in the phase 1 study.
In adults, STI571 has been generally well tolerated with transient Grade 2-3 elevations of liver
transaminases at doses ranging from 250-1000 mg (approximately 130 – 570 mg/m2). At identical
dosing, Grade 2-3 leukopenia, granulocytopenia and/or thrombocytopenia have also occurred in patients
with chronic phase CML, with the onset varying from Days 14–168. With both side effects neither the
frequency nor the severity have shown any tendency to increase with increasing dose. The blood
cytopenias have generally resolved within a matter of days after temporary breaks in therapy, sometimes
followed by dose reduction. It remains unclear whether myelosuppression represents a side effect of
therapy or is due to a direct anti-leukemic effect.
3.10 MRD Using Multiparameter Flow Cytometry
Dr. Michael Borowitz and colleagues are using multiparameter flow cytometry for detection of MRD as
part of the POG ALinC 17 pilot study, which opened as a limited institution pilot in January 1999.
Samples have been received from 57 patients, 51 of whom have been enrolled on a treatment study.
Forty-five patients with B-precursor ALL were tested at diagnosis with the two-tube B-precursor
antibody panel CD19/CD45/CD20/CD10 and CD19/CD45/CD9/CD34. In 43 cases one or the other (or
both) tubes showed a highly aberrant phenotype and the most informative tube was used for the follow
up study. These 2 cases, as well as 4 additional cases having some areas of overlap with normal B
precursors, were further tested with the antibody KORSA3544 which has been shown to be highly
abnormal in a subset of B precursor ALL cases.74 In 2 of these cases, aberrant expression of
KORSA3544 was a useful parameter to follow. Even in the remaining cases, however, as discussed
below, the failure to find a highly abnormal phenotype did not preclude detection of leukemic cells
because the follow-up samples did not contain any normal B cell precursors that might have been
confused with leukemic cells.
End-of-induction samples have been received for 32 patients. Residual blast cells were detected in 5
patients. The level of positivity ranged from a high of 0.33% of cells to a low of .0054% of cells in a
blood sample. It should be noted that the denominator in these calculations was the total number of
nucleated cells; we employ a whole marrow lysis procedure that retains granulocytes. However, setting
regions on a display containing all cells allows calculation of the mononuclear cell percentage. Thus,
one can correct for the presence of granulocytes and also express our results as a percent of mononuclear
cells, which may be important for correlation with MRD data obtained by molecular techniques in which
Ficoll-purified cells are used. It should be noted, though, that this correction was less than a factor of 2
in all cases examined.
4.0 ELIGIBILITY CRITERIA, STUDY ENTRY, AND DEFINITIONS

Important note: The eligibility criteria listed below are interpreted literally and cannot be waived
(per COG policy posted 5/11/01)
4.1 Eligibility Criteria

NOTE REQUIREMENT FOR CENTRAL REVIEW BEFORE STUDY ENTRY
Eligibility for entry onto AALL0031 for Very High Risk ALL requires a central confirmation of a)
Ph+ALL and b) hypodiploidy. This should be done as soon as the institutional laboratory has identified one
of these criteria. Lack of compliance will result in the patients being ineligible for study entry. Enrollment
of the patient on this study will not be allowed if the necessary central review(s) hasn’t/haven’t been
completed to document the patient eligibility. Enrollment of the patient on this study will not be allowed if
the necessary central review(s) hasn’t/haven’t been completed to document the patient eligibility group (i.e.,
Ph+ status or low hypodiploidy).
FORMER POG INSTITUTIONS – Central review is required for:

a) BCR/ABL by FISH or RT-PCR (not performed by former POG reference laboratory)
b) t(9;22) by cytogenetics
c) Chromosomes ≤ 44 by cytogenetics
d) DNA index < 0.81 by flow cytometry (not performed by former POG reference laboratory)
FORMER CCG INSTITUTIONS - Central review is required for:

e) BCR/ABL by FISH or RT-PCR
f) t(9;22) by cytogenetics
g) Chromosomes ≤ 44 by cytogenetics
h) DNA index < 0.81 by flow cytometry
Central review and confirmation will occur within 3 working days of receipt of the report.
Central review and confirmation of only one of the 4 criteria is required for study entry. In addition
contact the Study Chair (Kirk Schultz) by e-mail: kschultz@interchange.ubc.ca or telephone (604) 875-
2316 when a diagnostic sample has been submitted for confirmation.
FORMER POG INSTITUTIONS FORMER CCG-INSTITUTIONS

Andrew Carroll, PhD Nyla Heerema, PhD
University of Alabama Childrens Hospital of Columbus
Department of Human Genetics Director of Cytogenetics
1530 3rd Ave. South 1645 Neil Avenue
Kaul Bldg., Room 314B Hamilton Hall, Room 167
Birmingham, AL 35294-2050 Columbus, OH 43210-1228
Phone: 205-934-4968 Phone: 614-292-7815
Fax: 205-934-1078 Fax: 614-292-7072
E-mail: acarroll@uabmc.edu E-mail: heerema-1@medctr.osu.edu
4.1.1 Clinical Criteria (Patients must meet one of the three sets of criteria below – criteria 1, 2 or 3)
4.1.1.1 Patients in Remission

Patients 1 to < 22 years of age diagnosed with ALL who achieve remission after frontline induction
therapy, must register within 42 days of initial diagnosis, and must have one of the features listed below:
a. Ph+ ALL: presence of t(9;22)(q34;q11) determined by institutional cytogenetics or FISH; and/or
presence of BCR-ABL fusion transcript identified by RT-PCR
b. Hypodiploid with ≤ 44 chromosomes and/or DNA index <0.81.
c. The diagnosis of Ph+ or hypodiploidy must have been centrally confirmed by central COG
review by either laboratory evaluation of molecular BCR/ABL or DI (DNA Index) or central
confirmation of institutionally performed cytogenetics or FISH.
4.1.1.2 Patients not in Remission
4.1.1.2.1
Patients 1 to < 22 years of age diagnosed with ALL who do not achieve remission after frontline induction
therapy, must enroll within 42 days of initial diagnosis and must have a M3 (> 25% blasts) bone marrow
status at the end of initial induction therapy.
4.1.1.2.2
Patients 1 to < 22 years of age diagnosed with ALL who do not achieve remission after frontline
induction therapy, must enroll within 14 days of their last day of frontline therapy and must be M2
(5-25% blasts) bone marrow status at the end of initial induction therapy and M2 or M3 bone marrow
status at end of consolidation therapy (CCG studies) or at the end of the extended induction phase (POG
studies).
4.12 End of induction Bone Marrow Aspiration sample (day 28 – 35 from diagnosis) or a BM
performed upon entry must be submitted. (See instructions in Section 11.0)
4.1.3 Prior Therapy Restrictions

a) Only those enrolled on the following will be eligible for this study:
1. Frontline POG, CCG or COG studies. OR
2. Induction regimen utilizing vincristine, asparaginase, prednisone/ dexamethasone, and
with or without daunorubicin given the same as CCG, POG or COG protocol.
b) Patients who develop life-threatening complications during frontline therapy are eligible
after approval by the study chair.
4.1.4 Informed Consent

In accordance with institutional policies approved by the U.S. Department of Health and Human
Services, the patient and/or the patient's legally authorized guardian must acknowledge consent for
treatment as a human subject on this study.
a) Consent for COG AALL0031

Signed informed consent for participation must be done before enrollment and
administration of systemic induction therapy. A sample informed consent for the
AALL0031 study may be found at the end of this document.
b) Consent for samples to be collected for MRD evaluations will be a required part of the
initial enrollment onto the study.
c) Non-English Speaking Patients:
To allow non-English speaking patients to participate in the study, health care
services will be provided in the appropriate language.
4.2 Patient Registration and study enrollment
4.2.1 Case Registration (24 hours per day, 7 days per week)
Prior to study enrollment, patients must be registered with the COG Cancer Registry. This will secure
the patient a COG registration number (700000+) that will be used as the identification number.
Patients may be registered on the COG Registration System within the Members' Area of the COG
website. Once in the Members' Area, click on the Applications link to access the Registration
Application.
4.2.2 Recording IRB Approval

Prior to study enrollment, documentation of local IRB approval must be recorded. To record IRB
approval for a COG study, log onto the secured password controlled system within the Members' Area
of the COG website. Once in the Member's Area, click on the Applications link to access the IRB
Application
After recording IRB approval on this website, FAX an officially signed copy of the IRB approval form
(e.g. the 310 form or the CCG IRB form, whichever is more convenient) to the Research Data Center
(352) 392-8162.
4.2.3 Study Enrollment

Treatment start date is Day 1 on this protocol. Information that documents study eligibility and
identifies treatment strata will be required at the time of study enrollment.
Patients must be enrolled between Day 28 and Day 42 from diagnosis. All patients must be enrolled on
study through the COG Registration System within the Members' Area of the COG website. However,
central review should be done as soon as possible. Upon authentication the CRA will enter the
stratification and eligibility information, as provided in the worksheets in the data form packet.
4.2.4 Help
Available 24 Hours per Day, 7 Days per Week
During business hours (8:00 AM - 5:00 PM Eastern Time, Monday - Friday), if you have a technical
problem with patient registration, call the COG helpline at (352) 392-5198, then press 2 as soon as the
auto attendant begins speaking. If a technical problem occurs outside of business hours, call (352) 392-
5198 and follow the instructions given by the auto attendant to page the individual on-call.
4.3 Definitions
4.3.1 Absolute Neutrophil Count (ANC)

The ANC is defined as the WBC/µL times the neutrophil percentage.
4.3.2 Absolute Blast Count

The absolute blast count is defined as the WBC/µL times the blast percentage.
4.3.3 Central Nervous System (CNS ) Disease at Diagnosis

CNS leukemia is defined as an elevated CSF WBC (≥ 5 cells/µL) and a cytocentrifuge preparation
demonstrating lymphoblast cells. CNS leukemia may also be diagnosed when the CSF WBC is normal, but
clinical signs of CNS leukemia such as facial nerve palsy or hypothalamic syndrome are present.
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and contains ≥
5 WBC/µL with blasts, the following algorithm should be used to define CNS disease:
CSF WBC > 2X Blood WBC

CSF RBC Blood RBC
A patient with CSF WBC ≥ 5/µL blasts, whose CSF WBC/RBC is greater than twice the blood WBC/RBC
ratio, has CNS disease at diagnosis. Example: CSF WBC = 60/µL; CSF RBC = 1500/µL; blood WBC =
46000/µL; blood RBC = 3.0 X 106/µL:
60 = 0.04 > 2x 46000 = 0.015

1500 3.0 X 106
CNS-2 disease: is defined as the presence of leukemic blast cells after cytocentrifugation in a non-
traumatic tap containing < 5 WBC/uL.
4.3.4 Overt Testicular Leukemia at Diagnosis

Unilateral or bilateral testiculomegaly with leukemic infiltration confirmed by biopsy. Equivocal findings
on testicular exam warrant biopsy. (See Section 15.0 for biopsy guidelines.)
4.3.5 Bone Marrow Status

M1: < 5% blasts in the bone marrow aspirate regardless of the proportion of mature lymphocytes.
M2 : 5-25% blast cells in the bone marrow aspirate, regardless of the proportion of mature lymphocytes.
M3: > 25% blasts in a bone marrow aspirate.
5.0 TREATMENT PLAN
5.1 Frontline Induction

All patients are to receive 3-4 drug induction for 4-6 weeks on a frontline CCG, POG, or COG trial for
ALL or treated on an Induction regimen given the same as CCG, POG, OR COG. Eligible VHR
patients who are Ph+, hypodiploid with ≤ 44 chromosomes, or M3 at the end of frontline induction will
enter the VHR trial within 14 days of the end of frontline induction. Patients who are M2 at the end of
frontline induction and remain M2 or M3 at the end of extended induction (POG) or consolidation
(CCG) will enter the VHR trial within 14 days of the marrow response assessment.
5.2 Consolidation Block 1 (3 weeks)

Patients will begin block 1 of consolidation provided that the following criteria are met: ANC ≥ 750/ul;
platelets ≥75,000/ul; ALT < 20X the upper limit of normal; direct Bilirubin and creatinine normal for
age. Patients who enter the VHR trial after failing to achieve complete remission, however, may begin
irrespective of hematologic values provided there is no active infection or immediate life-threatening
organ malfunction.
5.2.1 IV Etoposide:
100mg/m2/day in 250 ml/m2 D5W- ½ NS over 1 hour daily x 5 (days 1 - 5). Prehydrate (1st day only)
with D5W/NS at 330 ml/m2/hr X 3 hr.
5.2.1 IV Ifosfamide:
1.8 gm/m2 in 225 ml/m2 D5W-1/2NS over 1 ½ hour daily x 5 (days 1 - 5). Begin immediately upon
completion of Etoposide infusion. Hydrate with 170 ml/m2/hr D5W-1/2NS for first 6 hours followed by
125 ml/m2/hr until ready for next day of therapy.
5.2.2 IV MESNA:
360 mg/m2/dose IV in 10 ml/ D5W-1/2NS over 15 minutes prior to ifosfamide and then every 3 hours (8
doses total/day), days 1-5.
5.2.4 Filgrastim (G-CSF)

5 µg/kg/day S.C., beginning 24 hours after completing chemotherapy and continue for 10 days (day 6-
15), or until ANC > 1500, after the nadir is reached.
5.2.5 Intrathecal Methotrexate:

Age-adjusted doses, as shown below, will be given on day 1.
Age (years) Dose of Intrathecal Methotrexate
1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
Patients classified as CNS 2 or those with traumatic taps will have a recommended additional 2 intrathecal
methotrexate doses in induction. Those patients enrolled on AALL0031 that have not received 2 additional
intrathecal methotrexate doses in induction, will receive 2 additional IT methotrexate doses on days 8 and
15.
For intrathecal administration, dilute with 5-10 ml preservative-free normal saline or lactated Ringer's
solution. The volume of CSF removed should equal at least 1/2 the volume delivered.
5.2.6 Dose Escalation of STI571(Gleevec) (Ph+ ALL patients)

STI571 will be given orally as per section 7.3 for Ph+ patients. 12 Ph+ ALL patients will be entered per
level for a total of 84 patients on the chemotherapy arm and a total of 18 on the HSCT arm. Toxicity
will be monitored as per section 8.11. Withholding of the dose will be as those outlined in section 8.11.
STI571 should be administered each morning and can be given with food. STI571 is a local irritant and
must be taken in a sitting position with a large glass (or bottle, for younger children) of water (250 ml/8
oz; at least 4 oz for children ≤ 3 years of age). The initial dose of STI571 for each cycle of therapy will
begin 4-12 hours before the initial dose of each cycle of therapy. If the patient cannot swallow the
capsule whole, the following guidelines should be used. Prior to administration transfer the contents of
the calculated number of 100 mg capsules to mineral water or apple juice, with each 2 capsules (200
mg) dissolved in approximately 100 mL of fluid. Stir with a spoon and administer the suspension
immediately afterwards.
5.2.7
Platelet count should be maintained by transfusion to platelet count > 20,000/ul while patient is
receiving STI571. Particular caution should be used if the patient is on coumadin.
5.2.8
Medications, which interfere with P-450 metabolism, should be avoided and recommended doses
of acetaminophen, should not be exceeded. The following medications and foods can interfere with
P-450 metabolism: grapefruit juice, erythromycin, azithromycin, clarithromycin, rifampin and its
analogs, fluconazole, ketoconazole, itraconazole, cimetidine, cannabinoids (marijuana or
dronabinol) and the leukotriene inhibitors used in asthma such as zafirlukast and zileuton. In
addition, drug interactions in patients receiving prochlorperazine (Compazine) and coumadin are
possible. Patients who require prochlorperazine during therapy should be monitored for akathisia and
those on coumadin should have weekly prothrombin times while on therapy. These medications should
not be used during STI571 administration unless there is unavoidable medical need and no appropriate
alternative agents are available. Also, acetaminophen should not be taken in greater than the
recommended dose.
5.2.9 Radiation Therapy

All patients with biopsy proven testicular leukemia at diagnosis will receive testicular radiation (24Gy in
8 fractions) during the first consolidation phase. For additional details on testicular radiation, (see
Section 16.3).
5.3 Consolidation Block 2 (3 weeks)

Begin when ANC ≥ 750/ul and platelets ≥ 75,000/ul; ALT < 20X upper limit of normal; direct bilirubin
and creatinine normal for age. Obtain bone marrow aspirate on day 1. For MRD evaluations (see
section 11.1).

(age adjusted, give intrathecal within 1-2 hours of start of I.V. Methotrexate dose) Day 1
1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
5.3.2 IV Cytarabine:
3 gm/m /dose in 300 ml/m2 NS over 3 hours q 12 hr x 4 doses, beginning at end of Methotrexate
2
infusion (day 2 and 3). (Hours 24, 36, 48, and 60). Administer dexamethasone ophthalmic solution 2
drops each eye q.i.d. x 3 days, starting just prior to first dose of cytarabine.
5.3.1 Filgrastim (G-CSF):

5 µg/kg/day SC, at least 24 hours after completion of Cytarabine and daily x 10 days (days 4 – 13) or
until ANC > 1500, post nadir.
5.3.4 High Dose Methotrexate Infusion (HDMTX)

500 mg/m2 IV over 30 minutes , followed by 4500 mg/m2 over 23.5 hr. on day 1.
HDMTX max dose 10 gm/24 hrs **Hold Bactrim on the day of HDMTX infusion and for at least
72 hours after the start of the HDMTX infusion and until the MTX level is less than 0.1 uM.
**Hold any nonsteroidal anti-inflammatory medications or aspirin-containing medications on the day of
HDMTX infusion and for at least 72 hours after the start of the HDMTX infusion and until the MTX
level is less than 0.1 uM.
Prehydrate with D5W 0.25 NS + 60 mEq NaHCO3/L at 125mL/m2/hour for ≥ 6 hours and until urine
specific gravity is ≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. HDMTX should be mixed in 2350 mL/m2 of
D5W/0.25 NS + 60 mEq NaHCO3/L to run at 100 mL/m2/hour. Adjust fluid volume and sodium bicarb
to maintain urine sg and pH at above parameters. Additional fluids may be given piggyback if required
to maintain the sg < 1.010. If urine pH drops below 7.0 give bicarb at 25 mEq/m2 over 15 minutes.
Continue hydration and alkalinization throughout HDMTX infusion, and until the MTX level is less
than 0.18 µM at a minimum.
Hour 0 MTX 0.5 gm/m2 IV over 30 minutes followed by MTX 4.5 gm/m2 continuous IV
infusion over 23.5 hours. Be certain that the HDMTX infusion is completed in the 24 hour period.
Unintentional prolongation to as long as 26 hours is not encouraged but is acceptable.
Hour 24 MTX level, BUN, creatinine (immediately at end of infusion) have lab run levels STAT
if possible. Blood samples can be drawn from intravenous access devices. If MTX level ≥ 100 µM:
increase hydration to 200 mL/m2/hour, start leucovorin at 100 mg/m2 every 3 hours, monitor MTX level,
BUN, creatinine every 12 hours and call study chair.
Hour 36 Leucovorin 75 mg/m2 as a single IV dose should be given exactly 36 hours after the
START of HDMTX infusion. Hour 42, 48, 54, 60, 66, 72: Leucovorin 15mg/m2 IV or PO as tolerated
x 6 doses and until MTX level < 0.1 µM. Discontinue leucovorin only when MTX level < 0.1 µM.
Hour 48 MTX level, BUN, creatinine have lab run levels STAT if possible. May discharge after
hour 48 if MTX level ≤ 0.18 µM and patient able to hydrate orally and take remaining doses of
leucovorin. If level > 0.18 but < 5 µM; increase hydration to 200 mL/m2/hour with alkalinization, and
continue leucovorin. If level > 5 µM; increase hydration fluids to 200 mL/m2/hour, increase leucovorin
to 15 mg/m2 every 3 hours, and repeat MTX level, BUN, creatinine every 12 hours and call study chair.
Hour 72 MTX level. Discontinue leucovorin if MTX level < 0.1 µM. If level > 0.1 but < 0.18 µM
then give leucovorin 15 mg/m2 every 6 hours x 4 doses, until 96 hour level available and < 0.1 µM. If
level > 0.18 but < 0.5 µM; continue increased hydration and leucovorin 15 mg/m2 every 6 hours until
level < 0.1 µM. If level > 0.5 µM, then continue increased hydration; give leucovorin 15 mg/m2 every 3
hours, repeat MTX level, BUN, creatinine every 12 hours, and call the study chair.
5.3.4.1 Management of the patient with delayed MTX clearance:

As above increase hydration, alkalinization, and leucovorin based on MTX levels obtained at 24, 48, 72
hours from the START of HDMTX infusion.
For subsequent courses:

• DO NOT EXTEND leucovorin or modify subsequent courses if patient did not experience >
Grade II mucositis or > 1 week delay in administration of chemotherapy. If patient again has
delayed clearance follow guidelines and monitor for toxicity.
• If patient experienced Grade II clinical toxicity and 48 hour MTX level was > 0.18 but <5
uM then increase hydration to a rate of 200 mL/m2/hour prior to, during, and for at least 24
hours immediately following HDMTX for next course.
• If patient experienced Grade III or IV clinical toxicity and 48 hour MTX level was > 0.18 but
< 5 uM then reduce dose of MTX by 25% of the original dose (i.e. 3.75 gm/m2/dose; with
10% dose as bolus and 90% dose as infusion) for next course maintaining hydration at 200
mL/m2/hour and following leucovorin rescue schedule as above. If patient has delayed
clearance and Grade III or IV toxicity after reduced dose, then decrease next course to 50%
of original dose. If patient has adequate clearance or ≤ Grade II toxicity escalate dose in 25%
increments back to the original doses as able with subsequent courses.
Management of the patient with markedly delayed MTX clearance:

If 24 hour MTX level > 100 µM OR 48 hour level > 5 µM OR 72 hour level > 0.5 µM increase
hydration, increase leucovorin, monitor BUN, creatinine (Cr) and call study chair, as above. For
subsequent courses:
• If patient experienced Grade II clinical toxicity then increase hydration to a rate of 200
mL/m2/hour prior to, during, and for 24 hours immediately following HDMTX for next
course and dose reduce HDMTX by 25% of the original dose (i.e. 3.75 gm/m2/dose; with
10% dose as bolus and 90% dose as infusion) with leucovorin as above. If tolerated without
delayed excretion, increase MTX dose by 25% for each course until full dose achieved.
• If patient experienced Grade III or IV clinical toxicity then reduce dose of MTX by 50% of
the original dose (i.e. 2.5 gm/m2/dose; with 10% dose as bolus and 90% dose as infusion) for
next course maintaining hydration at 200 mL/m2/hour and following original leucovorin
rescue schedule as above. Call study chair if patient still has delayed clearance or Grade III
or IV toxicity. If patient has adequate clearance and ≤ Grade II toxicity with the reduced dose
course then escalate dose by 25% (of the original dose) for each course until administration
of full dose MTX achieved.
• For patients with MTX level > 10 µM more than 42 hours after beginning MTX or with
a creatinine > 1.5x normal or with a calculated creatinine clearance < 60 mL/m2/min
and delayed MTX excretion, notify study coordinator ASAP and consider use of
Carboxypeptidase G2 rescue. Call 301-496-5725 to order Carboxypeptidase-G2.
Management of the patient with clinical toxicity despite appropriate MTX clearance:
• If mucositis ≥ Grade III develops despite an appropriate fall in MTX level begin leucovorin
rescue at hour 36 from the START of HDMTX infusion at a dose of 75 mg/m2 IV x 1, then
15 mg/m2 every 3 hours x 4, then every 6 hours until MTX level < 0.08 µM. Also increase
hydration to a rate of 200 mL/m2/hour with alkalinization as above.
• If mucositis occurs despite increased leucovorin rescue, decrease MTX dose by 25% (of the
original dose) and resume standard dose leucovorin as above.
• If subsequent course is not associated with mucositis resume original leucovorin rescue and
attempt to increase to full dose MTX during next course.
5.4 Reinduction Block 1 (3 weeks)

*Patients with HLA-matched related donors will be moved to the HSCT arm at this point.
5.4.1
The treatment schema is shown in Figure 2.2.1. Patients will begin consolidation block 1 following
initial 3- or 4-drug induction on a frontline CCG, POG or COG trial for ALL or treated on an Induction
regimen given the same as CCG, POG or COG. Once patients have been identified for inclusion on this
study, investigators will be encouraged to begin workups to identify an appropriate HSCT donor.
Patients will be assigned to the bone marrow transplantation regimen if there is an HLA-matched or 1
antigen mismatched (excluding HLA-DR mismatch) related donor. Patients who do not have an
appropriate related donor will be assigned to the chemotherapy regimen.
5.4.2 Reinduction Block 1 (3 weeks)

Begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL; ALT < 20X upper limit of normal; direct
bilirubin and creatinine normal for age. Obtain bone marrow aspirate on day 1 and send for MRD (See
Section 11.1).
5.4.3 IV Vincristine:
1.5 mg/m2/day (maximum dose 2 mg), days 1, 8, 15
5.4.4 IV Daunorubicin:
45 mg/m2/day x 2 days bolus IV, days 1 and 2.
5.4.5 IV Cyclophosphamide:
250 mg/m2/dose over 30 minutes q 12 hr x 4, days 3 and 4;
5.4.6 IM Peg-L-asparaginase:
2500 IUnits/m2, day 4.

Age-adjusted dose days 1 and 15

1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
5.4.8 PO Dexamethasone:
6 mg/m2/day orally, (divided b.i.d.), days 1-7 and 15 - 21

5 µg/kg/day SC day 5 through day 14 or until ANC > 1500, post nadir.
5.4.10 STI571 (Gleevec):

STI571 will be given orally on days 1-21 in a dose escalation for Ph+ patients. 12 Ph+ ALL patients will
be entered per level for a total of 80 Ph+ ALL patients. See dosing schedule in section 7.3. Toxicity
will be monitored as per section 8.11. Withholding of the dose will be as those outlined in section 8.11.
5.5 Intensification Block 1 (8 weeks)

Begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL; ALT < 20 x upper limit of normal; direct
bilirubin and creatinine normal for age. Initiation of therapy at day 15 and day 36 will only begin when
ANC ≥ 750/µL and platelets ≥ 75,000/µL; ALT < 20 x upper limit of normal; direct bilirubin and
creatinine normal for age.
5.5.1 High Dose Methotrexate Infusion (HDMTX
500mg/m2 IV over 30 minutes followed by MTX 4500 mg/m2 over 23.5 hours. Days 1 and 8.
72 hours after the start of the HDMTX infusion and until the MTX level is less than 0.1 µM.

level is less than 0.1 µM.
than 0.18 uM at a minimum.

µM then increase hydration to a rate of 200 mL/m2/hour prior to, during, and for at least 24

hydration, increase leucovorin, monitor BUN, Cr and call study chair, as above. For subsequent courses:
5.5.2 IT Methotrexate:
Age adjusted within 1-2 hours of starting IV Methotrexate , days 1 and 15.

1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
For intrathecal administration, dilute with 5-10 ml preservative-free normal saline or lactated Ringer’s
solution. The volume of CSF removed should equal at least ½ the volume delivered.
5.5.3 IV Etoposide:
100 mg/m2/day in 250 ml/m2 D5W-½ NS over 2 hours, daily x 5 days, days 15 to 19. Begin when ANC
≥ 750/µl and platelets ≥ 75,000/µl; ALT < 20 x upper limit of normal; direct bilirubin and creatinine
normal for age.
300 mg/m2dose I.V. over 30 minutes daily x 5 days, days 15 – 19, immediately following IV etoposide.
Begin when ANC ≥ 750/µl and platelets ≥ 75,000/µl; ALT < 20 x upper limit of normal; direct bilirubin
and creatinine normal for age.
5.5.5 IV MESNA:
150 mg/m2/dose infused with each dose of cyclophosphamide, then 150 mg/m2 in 400 ml/m2
D5W/0.45% NACL over 4 hours following each dose of cyclophosphamide. Days 15 – 19.

5 µg/kg/day SC, beginning on days 20 to 29 or until ANC > 1500 post nadir.
5.5.7 IV Cytarabine:
3 g/m2 in 300 ml/m2 NS over 3 hours q 12h x 4 doses, days 36, 37. Begin when ANC ≥ 750/µl and
platelets ≥ 75,000/µl; ALT < 20 x upper limit of normal; direct bilirubin and creatinine normal for age.
Administer dexamethasone ophthalmic solution 2 drops each q.i.d x 3 days, starting just prior to first
dose of cytarabine.
5.5.8 IM L- Asparaginase (E.coli):

6000 IUnits/m2, day 37, 6 hr after completion of high dose cytarabine on day 37.

(dose as per section 7.3) orally, days 36 – 56.
5.6 Reinduction Block 2 (3 weeks)

*For patients that are to receive HSCT please see section 6.0.
Begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL; ALT < 20X upper limit of normal; direct
bilirubin and creatinine normal for age. Obtain bone marrow aspirate on day 1 and send for MRD
evaluations (See Section 11.1).
5.61 IV Vincristine:
1.5 mg/m2/day (maximum dose 2 mg), days 1, 8, 15
5.6.2 IV Daunorubicin:
45 mg/m2 /day bolus on days 1 and 2 (total daunorubicin dose is 90 mg/ m2).
250 mg/m2 over 30 minutes q 12 hr x 4, days 3 and 4
5.6.4 IM PEG-L-Asparaginase:
2500 IUnit/m2, day 4.

Age-adjusted dose, day 1 and 15

1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
6 mg/m2/day orally, (divided b.i.d.), days 1-7 and 15 – 21.

5 µg/kg/day SC days 5 – 14, or until ANC > 1500, post nadir.

(dosing as per section 7.3) will be given orally days 1-21 for Ph+ patients
5.7 Intensification Block 2 (8 weeks - identical to Intensification 1 in section 5.5)
5.8 Maintenance – Cycles 1-4 (8 week cycles)

bilirubin and creatinine normal for age.
Bone marrow aspiration at the beginning of cycle 1 and send for MRD evaluations (See Section 11.1).
5.8.1 High Dose Methotrexate Infusion (HDMTX

500mg/m2 IV over 30 minutes followed by MTX 4500 mg/m2 over 23.5 hours. Day 1.
72 hours after the start of the HDMTX infusion and until the MTX level is less than 0.1 uM.

level is less than 0.1 uM.
than 0.18 µM at a minimum.

µM then increase hydration to a rate of 200 mL/m2/hour prior to, during, and for at least 24

hydration, increase leucovorin, monitor BUN, Cr and call study chair, as above. For subsequent courses:

(dose adjusted per age) days 1 and 29.

1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
1.5 mg/m2day (maximum dose 2 mg), days 1 and 29.
6 mg/m2/day (divide b.i.d)x 5 days, days 1 – 5 and 29 – 33.
5.8.5 PO 6- Mercaptopurine:
75 mg/m2/day, days 8-28.
Adjust dose of mercaptopurine using half-tablets and different doses as follows, to attain a weekly
cumulative dose as close to 525mg/m2 as possible. See table below for tablet dosing guideline.
DOSES OF MERCAPTOPURINE
Body Surface Area (m²) Daily Dose for 7 days Cumulative Weekly Dose
(1 tablet = 50 mg)
0.35 - 0.39 ½ tab / d x 6; 1 tab / d x 1 (200 mg/wk)
0.40 - 0.44 ½ tab / d x 5; 1 tab / d x 2 (225 mg/wk)
0.45 - 0.49 ½ tab / d x 4; 1 tab / d x 3 (250 mg/wk)
0.50 - 0.54 1 tab / d x 4; ½ tab / d x 3 (275 mg/wk)
0.55 - 0.59 1 tab / d x 5; ½ tab / d x 2 (300 mg/wk)
0.60 - 0.64 1 tab / d x 6; ½ tab / d x 1 (325 mg/wk)
0.65 - 0.69 1 tab / day (350 mg/wk)
0.70 - 0.74 1 tab / d x 6; 1½ tab / d x 1 (375 mg/wk)
0.75 - 0.79 1 tab / d x 5; 1½ tab / d x 2 (400 mg/wk)
0.80 - 0.84 1 tab / d x 4; 1½ tab / d x 3 (425 mg/wk)
0.85 - 0.89 1½ tab / d x 4; 1 tab / d x 3 (450 mg/wk)
0.90 - 0.94 1½ tab / d x 5; 1 tab / d x 2 (475 mg/wk)
0.95 - 0.99 1½ tab / d x 6; 1 tab /d x 1 (500 mg/wk)
1.00 - 1.04 1½ tab / day (525 mg/wk)
1.05 - 1.09 1½ tab / d x 6; 2 tab / d x 1 (550 mg/wk)
1.10 - 1.14 1½ tab / d x 5; 2 tab / d x 2 (575 mg/wk)
1.15 - 1.19 1½ tab / d x 4; 2 tab / d x 3 (600 mg/wk)
1.20 - 1.24 2 tab / d x 4; 1½ tab / d x 3 (625 mg/wk)
1.25 - 1.29 2 tab / d x 5; 1½ tab / d x 2 (650 mg/wk)
1.30 - 1.34 2 tab / d x 6; 1½ tab / d x 1 (675 mg/wk)
1.35 - 1.39 2 tab / day (700 mg/wk)
1.40 - 1.44 2 tab / d x 6; 2½ tab / d x 1 (725 mg/wk)
1.45 - 1.49 2 tab / d x 5; 2½ tab / d x 2 (750 mg/wk)
1.50 – 1.54 2 tab / d x 4; 2½ tab / d x 3 (775 mg/wk)
1.55 – 1.59 2½ tab/ d x 4; 2 tab / d x 3 (800 mg/wk)
1.60 – 1.64 2½ tab/ d x 5; 2 tab / d x 2 (825 mg/wk)
1.65 – 1.69 2½ tab/ d x 6; 2 tab / d x 1 (850 mg/wk)
1.70 – 1.74 2½ tab/ d (875 mg/wk)
1.75 – 1.79 2½ tab/ d x 6; 3 tab / d x 1 (900 mg/wk)
1.80 – 1.84 2½ tab/ d x 5; 3 tab / d x 2 (925 mg/wk)
1.85 – 1.89 2½ tab/ d x 4; 3 tab / d x 3 (950 mg/wk)
1.90 – 1.94 3 tab/ d x 4; 2½ tab / d x 3 (975 mg/wk)
1.95 – 1.99 3 tab/ d x 5; 2½ tab / d x 2 (1000 mg/wk)
5.8.6 PO Methotrexate:
20 mg/m2/week, days 8, 15, and 22.
5.8.7 IV Etoposide:
100mg/m2day in 250 ml/m2 D5W-½NS over 2 hours x 5 days, days 29-33.
300 mg/m2/day over 30 minutes, days 29-33, immediately following etoposide
IV MESNA
150 mg/m2/dose infused with each dose of cyclophosphamide, then 150 mg/m2 in 400 ml/m2
D5W/0.45% NACL over 4 hours following each dose of cyclophosphamide. Days 29 – 33.

5 µg/kg/day SC days 34-43, or until ANC > 1500 post nadir.
5.8.10 STI571 (Gleevec) for Ph+ patients only:

(dose escalation as per table in 7.3 ) orally, days 29 – 49.
5.9 Maintenance – Cycles 5-12 (8 week cycles)

bilirubin and creatinine normal for age.
Bone Marrow aspiration at the end of therapy.

(dose adjusted per age) day 1 each cycle.

1-< 2 8 mg
2-< 3 10 mg
≥3 12 mg
1.5 mg/m2day (maximum dose 2 mg), days 1 and 29.
6 mg/m2/day (divide b.i.d) x 5 days, days 1 - 5, 29 – 33.
5.9.4 PO 6- Mercaptopurine;
75 mg/m2/day, days 1 - 56.
Adjust dose of mercaptopurine using half-tablets and different doses as follows, to attain a weekly
cumulative dose as close to 525mg/m2 as possible. See table below for tablet dosing guideline.
DOSES OF MERCAPTOPURINE
Body Surface Area (m²) Daily Dose for 7 days Cumulative Weekly Dose
(1 tablet = 50 mg)
0.35 - 0.39 ½ tab / d x 6; 1 tab / d x 1 (200 mg/wk)
0.40 - 0.44 ½ tab / d x 5; 1 tab / d x 2 (225 mg/wk)
0.45 - 0.49 ½ tab / d x 4; 1 tab / d x 3 (250 mg/wk)
0.50 - 0.54 1 tab / d x 4; ½ tab / d x 3 (275 mg/wk)
0.55 - 0.59 1 tab / d x 5; ½ tab / d x 2 (300 mg/wk)
0.60 - 0.64 1 tab / d x 6; ½ tab / d x 1 (325 mg/wk)
0.65 - 0.69 1 tab / day (350 mg/wk)
0.70 - 0.74 1 tab / d x 6; 1½ tab / d x 1 (375 mg/wk)
0.75 - 0.79 1 tab / d x 5; 1½ tab / d x 2 (400 mg/wk)
0.80 - 0.84 1 tab / d x 4; 1½ tab / d x 3 (425 mg/wk)
0.85 - 0.89 1½ tab / d x 4; 1 tab / d x 3 (450 mg/wk)
0.90 - 0.94 1½ tab / d x 5; 1 tab / d x 2 (475 mg/wk)
0.95 - 0.99 1½ tab / d x 6; 1 tab /d x 1 (500 mg/wk)
1.00 - 1.04 1½ tab / day (525 mg/wk)
1.05 - 1.09 1½ tab / d x 6; 2 tab / d x 1 (550 mg/wk)
1.10 - 1.14 1½ tab / d x 5; 2 tab / d x 2 (575 mg/wk)
1.15 - 1.19 1½ tab / d x 4; 2 tab / d x 3 (600 mg/wk)
1.20 - 1.24 2 tab / d x 4; 1½ tab / d x 3 (625 mg/wk)
1.25 - 1.29 2 tab / d x 5; 1½ tab / d x 2 (650 mg/wk)
1.30 - 1.34 2 tab / d x 6; 1½ tab / d x 1 (675 mg/wk)
1.35 - 1.39 2 tab / day (700 mg/wk)
1.40 - 1.44 2 tab / d x 6; 2½ tab / d x 1 (725 mg/wk)
1.45 - 1.49 2 tab / d x 5; 2½ tab / d x 2 (750 mg/wk)
1.50 – 1.54 2 tab / d x 4; 2½ tab / d x 3 (775 mg/wk)
1.55 – 1.59 2½ tab/ d x 4; 2 tab / d x 3 (800 mg/wk)
1.60 – 1.64 2½ tab/ d x 5; 2 tab / d x 2 (825 mg/wk)
1.65 – 1.69 2½ tab/ d x 6; 2 tab / d x 1 (850 mg/wk)
1.70 – 1.74 2½ tab/ d (875 mg/wk)
1.75 – 1.79 2½ tab/ d x 6; 3 tab / d x 1 (900 mg/wk)
1.80 – 1.84 2½ tab/ d x 5; 3 tab / d x 2 (925 mg/wk)
1.85 – 1.89 2½ tab/ d x 4; 3 tab / d x 3 (950 mg/wk)
1.90 – 1.94 3 tab/ d x 4; 2½ tab / d x 3 (975 mg/wk)
1.95 – 1.99 3 tab/ d x 5; 2½ tab / d x 2 (1000 mg/wk)
5.9.5 PO Methotrexate:
20 mg/m2/week, days 8, 15, 22, 29, 36, 43, 50
5.9.6 STI571 (Gleevec) for Ph+ patients only:

(dose escalation as per table in 7.3) orally, days 1 – 21 and 29 – 49.
5.9.7 Cranial irradiation for CNS + ve only

18 Gy in 10 fractions (1.8 Gy per day, 5 days per week starting on day 1 of cycle 5).
6.0 HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
All participating centers will be required to have their HSCT program agree that they will follow the
HSCT arm as specified in the protocol before the center can enroll any patients on the VHR trial. As
recommended by the COG transition HSCT committee, the preparative regimen used will include TBI,
cyclophosphamide and etoposide. Supportive care guidelines will be encouraged rather than required
except for GVHD prophylaxis. GVHD prophylaxis will use methotrexate and cyclosporine with a rapid
taper of cyclosporine if no GVHD present.
Patients must have received an HSCT within 10 and 15 weeks from diagnosis or within 4 weeks from
recovery of peripheral counts to an ANC >1000/µL and platelets >50,000/µL after consolidation block
2. If a transplant bed is not available within the specified time frame, please call the study chair, Kirk
Schultz, M.D. (604-875-2316) or HSCT representative, Stella Davies, MBBS (612-626-2786). If the
delay is greater than 4 weeks from recovery of counts before consolidation 2, and the patient is less than
15 weeks from diagnosis the patient should receive the following continuation therapy:
Thioguanine: 75 g/m2 PO q day (2.5 mg/Kg for patients < 3 years of age), with adjustments made to
attempt to keep the absolute neutrophil count (ANC) between 1000 and 1500/µL.
Permission from the study chair (K. Schultz) or HSCT representative (S. Davies) to administer
Thioguanine during the HSCT delay must have been received to continue on study.
6.1 Preparative Regimen

(CNS + ve at diagnosis only, will result in administration of cranial irradiation 6 Gy as part of the
preparative regimen. The cranial irradiation will be administered in 3 fractions, 2Gy per day, given on
the 3 weekdays immediately preceding day 7).
See sections 9.1.1, 9.1.2, and 9.1.3 for guidelines.
6.2 Donors Acceptable for Entry Onto Study

HLA-matched is defined as follows: HLA-A, -B identical by serological typing and HLA-DRB1
identical by molecular typing. Typing for HLA-C, -DP, and -DQ will not be included. Molecular
typing for HLA-A, and –B will be encouraged but not required.
Related donors will be selected by the following priority for bone marrow, peripheral blood, or cord
blood
1. HLA-matched sibling
2. HLA-matched relative
3. 1 antigen mismatched sibling (excluding HLA-DR mismatch).
4. 1 antigen mismatched relative(excluding HLA-DR mismatch).
Donors NOT acceptable for entry onto study will include the following:
5 Unrelated adult volunteer donor peripheral blood, bone marrow or cord blood.
6 Related donor with 1 Ag mismatch at the HLA-DR locus
7 2 or more HLA antigen mismatched related donor.
8 Any hematopoietic cell source that is either T-cell depleted or positively selected for stem cells (i.e.
CD34+)
9 Autologous hematopoietic stem cell source.
6.3 Non-Random Assignment to HSCT Therapy
6.3.1 Notification of HSCT Therapy Assignment

This will be reported on the appropriate end of course report, along with the matching information.
Reporting for transplant patients will continue on the HSCT End of Reporting Period Screens, as well as
all other required forms, as indicted in the AALL0031 Data Entry and Submission Schedule
7.0 DOSE ESCALATION OF STI571
7.1 Stratum For Treatment

Stratum 1: All Ph+
Stratum 2: Hypodiploid, Ph negative or indeterminate
Stratum 3: Induction failure, Ph negative or indeterminate, not hypodiploid
Stratum 2 and 3 will receive no STI571. The dose escalation schema in section 7.3 will apply only to
stratum 1.
7.2 STI571
This design limits STI571 to 21 days with each drug combination. There would be 5 drug combinations.
They are listed below and given a Treatment number
Drug combination 1. Ifosfamide and etoposide (Consolidation block 1)

Drug combination 2. 4-drug reinduction (Reinduction block 1 and 2)
Drug combination 3. High dose cytarabine (Intensification block 1 and 2)
Drug combination 4. Cyclophosphamide and etoposide (Maintenance 1 – 4 cycles)
Drug combination 5. Maintenance therapy cycles 5-8 (3 weeks each with Vcr/Dex and 6-MP/Mtx)
The treatment principles would be as follows:

1. The first 3 Drug combinations would be escalated independently of the maintenance courses 1
and 2.
2. Each of the more intensive first 3 treatment combinations will be evaluated alone before
sequential combinations of Drug combinations 1 - 3 are evaluated.
3. An emphasis on giving STI571 with maintenance therapy will be pursued with all patients to
receive 21-day cycles.
4. Cohorts 1 –3 will all be enrolled before final evaluation of toxicity.
a. Dose limiting toxicity (DLT) will be monitored continuously and STI571 will be
decreased to 30% (230 mg/m2/dose) if grade 3 or 4 non-hematopoietic toxicity is
observed in 2 of the first evaluable group of 6 patients. If at any time for the remaining
patients in the cohort, the percentage of DLT for the full group of evaluable patients
reaches 33%, this would result also result in dose modification. Toxicity will also be
compared to the regimen for non-Ph+ patients which will indicate whether a decrease in
the chemotherapy is required rather than STI571.
b. In maintenance 2, modification of STI571 will be performed before any modification of
Mtx or mercaptopurine as per routine protocol in previous protocol. More detailed
information as to alterations in these Methotrexate and mercaptopurine drugs will be
performed and compared to the Ph- ALL patient arm.
c. Escalation to cohort 4 will occur if acceptable toxicity had been observed in the first 6
patients in cohorts 1 and 2 (Drug combinations 2 and 3).
d. Escalation to cohort 5 will depend on acceptable toxicity of the first 6 patients in cohorts
1 and 3 (Drug combinations 1 and 3).
e. Escalation to cohort 6 will depend on acceptable toxicity of the first 6 patients in cohorts
2 and 3 (Drug combinations 1 and 2).
f. Escalation to cohort 7 will depend on whether acceptable toxicity has been observed in
cohorts 4, 5, and 6 (Drug combinations 1 - 3).
g. Controls for non-STI571 combinations will come from cohorts 1 – 3 and non-Ph+ ALL
patients.
5. Analysis of toxicity will be performed after the first 6 evaluable patients in each cohort and
continuously for the following 6 patients of the cohort. Analysis of toxicity for maintenance
cycles (especially the later cycles) will probably require combining data from different cohorts
because of the expected attrition due to relapse in these poor prognosis patients.
STI571 will be given orally on the days as outlined in Sections 7.3 & 7.4 for Ph+ patients. The initial
dose of STI571 for each cycle of therapy will begin 4-12 hours before the initial dose of each cycle of
chemotherapy. Twelve Ph+ ALL patients will be entered per cohort level for a minimum of 84 patients.
It is anticipated that approximately 20% of the patients entered will receive HSCT, resulting in a longer
accrual for patients on the dose escalation after HSCT. Toxicity will be monitored as per section 8.11.
Withholding of the dose will be as those outlined in section 8.11. The cohorts of 12 patients are based
on the calculation that we need a minimum of 6 evaluable patients to enter maintenance 1 at 15 months
of therapy, and also should provide a minimum of 12 patients for the chemotherapy plus HSCT
escalation. Based on previous CCG data regarding Ph+ EFS we calculate that approximately 95% of
children who receive chemotherapy throughout will be event free at 10 weeks (time for assignment to
HSCT arm), and 50% will be event-free at 15 months (time to start maintenance 2).
Dose reduction for both maintenance 1 and 2 will be based on the first 6 patients that complete cycle 1
of maintenance 1 or 2 respectively. Decisions to reduce STI571 dose duration (e.g., from 340
mg/m2/dose to 230 mg/m2/dose) would be done at interim monitoring if DLT were observed on specific
treatment blocks. Reduction of dose would only apply to that specific block of treatment where
unacceptable toxicity was observed.
7.3 STI571 dose escalation schedule for chemotherapy and pre HSCT arm
Dose Levels Dose Dose escalation

(mg/m2 rounded Schedule
to the nearest 50 mg)
Cohort 1 (N = 12)
Intensification block 1 and 2 340 Days 36 – 56
Maintenance 1-4 cycles 340 Days 29– 49
Maintenance 5-8 cycles 340 Days 1 – 21 and 29 – 49
Cohort 2
Reinduction Block 1 and 2 340 Days 1– 21
Cohort 3
Consolidation block 1 340 Days 1 – 21
Cohort 4
Reinduction block 1 and 2 340 Days 1 – 21
Cohort 5
Cohort 6
Reinduction block 1 and 2 340 Days 1– 21
Cohort 7
Reinduction block 1 and 2 340 Days 1– 21
There are 12 patients per chemotherapy dose escalation with a total of 84 patients enrolled.
Eighteen of the total 84 Ph+ patients (20%) are expected to receive the HSCT arm.
7.4 STI571 dose escalation schedule for HSCT arm

(to be assigned upon entry onto the HSCT arm irregardless of STI571 assignment on the chemotherapy
arms).
Patients will be initiated at 16-24 weeks post HSCT at dose level 1 and will be increased to dose level 2
if no grade 3 – 5 toxicity is observed after 4 weeks while receiving STI571. STI571 will not be started
until both the ANC is ≥ 750 and the platelet count is ≥75,000. If the ANC is <750 or the platelet count
is < 75,000 re-evaluaiton of peripheral count should occur at least every 2 weeks and the drug started
when the patient meets the peripheral count criteria. The patients will be allowed to start STI571 any
time between week 16 - 24 post HSCT when the ANC is ≥ 750 and the platelet count is ≥ 75,000.
STI571 will then be given for a total of 24 weeks of therapy.
Dose Levels Dose Dose escalation

(mg/m2 rounded Schedule
to the nearest 50 mg) post HSCT days
Dose Level 1 includes the following:
230 Once daily starting between week 16-
24 post HSCT
Patients will be escalated to dose Level 2 if no grade 3 or 4 toxicity x 28 days:
340 Once daily starting between weeks 20-
28 post HSCT
STI571 therapy will continue from the time initiation for a total of 24 weeks
7.5 Dosage of STI571
STI571 is available in 50 mg or 100 mg tablets. The following is the actual dose to be given for
patients designated to receive either 340 mg/m2 or 230 mg/m2.
DOSES OF STI571 (340 mg/m2/dose)
Body Surface Area (m2) Daily dosage Range of actual
100 mg tab 50 mg tab dose given
<0.37 100 mg/day 1 (xxx – 278 mg/m2)
0.37 - 0.51 150 mg/day 1 1 (405 – 294 mg/m2)
0.52 - 0.66 200 mg/day 2 (385 – 303 mg/m2)
0.67 - 0.80 250 mg/day 2 1 (373 – 313 mg/m2)
0.81 - 1.02 300 mg/day 3 (370 – 300 mg/m2)
1.03 - 1.32 400 mg/day 4 (388 – 303 mg/m2)
1.33 - 1.61 500 mg/day 5 (376 – 311 mg/m2)
1.62 - 1.91 600 mg/day 6 (370 – 314 mg/m2)
1.92 - 2.20 700 mg/day 7 (365 – 318 mg/m2)
2.21 – 2.50 800 mg/day 8 (362 – 320 mg/m2)
DOSES OF STI571 (230 mg/m2/dose)
Body Surface Area (m2) Daily dosage Range of actual
100 mg tab 50 mg tab dose given
0.36 - 0.54 100 mg/day 1 (278 – 185 mg/m2)
0.55 - 0.76 150 mg/day 1 1 (273 – 197 mg/m2)
0.77 - 0.97 200 mg/day 2 (260 – 206 mg/m2)
0.98 - 1.19 250 mg/day 2 1 (255 – 210 mg/m2)
1.20 - 1.52 300 mg/day 3 (250 – 197 mg/m2)
1.53 - 1.95 400 mg/day 4 (261 – 205 mg/m2)
1.96 - 2.39 500 mg/day 5 (255 – 209 mg/m2)
2.40 - 2.50 600 mg/day 6 (250 – 240 mg/m2)
8.0 THERAPY MODIFICATIONS FOR TOXICITY (ALL PHASES)
Contact the Study Chair prior to removing any patient from protocol therapy for toxicity. Drugs for all
regimens are listed below in alphabetical order.
8.1 Asparaginase (E. coli; Erwinia; PEG)
8.1.1 Coagulopathy
When significant bleeding or thrombosis occurs, withhold asparaginase until resolved. Do not make up
missed doses. Coagulopathy without bleeding or thrombosis is not an indication to withhold
asparaginase.
8.1.1.1 Major Thrombosis
a) Intracranial (sagittal) thrombosis

Asparaginase should be discontinued. ATIII and fibrinogen blood concentrations should be
ascertained and the Study chair notified. The patients should not receive intrathecal chemotherapy
or cranial irradiation until after complete resolution of the thrombus. Reinitiation of Asparaginase
should be discussed with the PI and given while on prophylactic heparin.
b) Peripheral thrombosis
Patients should be managed as in the above section. Removal of the line if the thrombosis is
associated with the line placement should be strongly considered.
8.1.2 Systemic Allergic Reaction

If a systemic allergic reaction (urticaria, wheezing, laryngospasm, hypotension, etc) to asparaginase
develops, the specific preparation of asparaginase in use should be discontinued.
a) Systemic allergic reaction to Pegasparaginase:

Patients should receive 6 doses Erwinia asparaginase (10,000 IUnits/m2) every other day
without a Saturday or Sunday break substituted for one dose of PEG (2500 IUnits/m2). If
patient develops systemic allergy to Erwinia, no further L-asparaginase should be given.
8.1.3 Symptomatic pancreatitis (Grade 2-4)

Discontinue all forms of asparaginase in the presence of symptomatic pancreatitis documented by an
elevated serum amylase, lipase or ultrasonographic abnormalities. If there is a prior history of
asparaginase-induced pancreatitis give further drug very cautiously, or not at all, during later phases of
treatment.
8.1.4 Hyperglycemia
Do not modify dose. Insulin may be administered for hyperglycemia.
8.1.5 Ketoacidosis
Withhold asparaginase until blood glucose can be regulated with insulin.
8.1.6 Liver Dysfunction

If total bilirubin is > 2 mg/dL, obtain fractionated bilirubin. Withhold dose if direct (conjugated) bilirubin is
> 1 mg/dL and/or AST/ALT is > 1,000 U/L and/or PT/INR is prolonged (unrelated to Vitamin K
deficiency) on two determinations at least one week apart. Restart at full dose when AST/ALT is < 400
U/L and direct (conjugated) bilirubin is < 1 mg/DL and PT/INR is normal.
Exclude infectious hepatitis (A, B, C, HHV-6, HHV-7) and check PT/INR for AST/ALT > 400 U/L
persisting for > 1 month.
Notify study chair of any major interruptions of therapy or persistently abnormal liver function tests.
8.2 Cyclophosphamide
8.2.1 Prior history of gross hematuria or microscopic hematuria

Please contact the study chair. A recommended approach would be to hydrate at 125 ml/m2/hour for 24
hours after the dose and give MESNA 360 mg/m2 IV bolus over 15 min immediately before the dose of
cyclophosphamide and at hours 4, 7, 11 after the dose.
8.2.2 Acute fluid retention (SIADH):

Treat with furosemide and saline; do not modify cyclophosphamide administration.
8.3 Cytarabine (Ara-C), Intravenous or Subcutaneous
8.3.1 Ara-C Syndrome

a) Fever
If fever is likely to be from Ara-C and ANC is ≥ 500/µL, do not withhold Ara-C. Obtain
blood culture if central line is present.
b) For Grade 3-4 rash or conjunctivitis, withhold until resolved and make up missed doses. For
conjunctivitis, consider concurrent treatment with oral hydrocortisone, or with
dexamethasone ophthalmic drops.

See Section 8.1.6.
8.4 Daunorubicin
8.4.1 Congestive heart failure or SF < 28%

Do not administer dose.
Daunorubicin is contraindicated in congestive heart failure and cardiac dysfunction (SF < 28%).
Resuming Daunorubicin therapy depends on the cause of the cardiac dysfunction and the results of
further cardiac evaluation. Inform Study Chair if patient cannot have further anthracycline therapy.

If total bilirubin is > 2 mg/dL, obtain fractionated bilirubin:
for direct (conjugated) bilirubin < 1 mg/dL, give full dose
for direct (conjugated) bilirubin ≥ 1.0 and ≤ 2.0 mg/dL, give ½ dose
for direct (conjugated) bilirubin > 2 mg/dL, omit dose
If direct (conjugated) bilirubin is elevated persistently (> 1 month), check PT/INR and AST/ALT.
Exclude infectious hepatitis (A, B, C, HHV-6, HHV-7) and check PT/INR for AST ALT > 400 U/L
8.5 Dexamethasone
8.5.1 Hypertension
Steroid dose should not be reduced. Sodium restriction and antihypertensives should be employed in an
effort to control hypertension. If this fails, contact Study Chair.
8.5.2 Hyperglycemia
Steroid dose should not be reduced if the patient develops clinical signs of diabetes. Insulin therapy may
be used to control hyperglycemia.
8.5.3 Pancreatitis
Do not modify dose (see Section 8.1.3 regarding L-asparaginase).
8.5.4 Psychosis
Contact Study Chair.
8.5.5 Myopathy
Measure CPK with isoenzymes, aldolase and LDH. Consider EMG studies and contact Study Chair.
8.5.6 Avascular Necrosis

Contact Study Chair if avascular necrosis develops before Maintenance has begun. Omit further steroids if
AVN develops during Maintenance.
8.5.7 Varicella Zoster

Steroids should be withheld during active infection except during Induction. Steroids should not be
withheld during incubation period following exposure (see Section 13.3 for Supportive Care Guidelines).
8.5.8 Insomnia
Sleeping sedative may be used for patients with sleep disturbances.
8.6 Mercaptopurine
8.6.1 Myelosuppression
Modify as detailed below:

a) ANC ≥ 750/µL and < 1000/µL and/or platelets ≥ 75,000/µL and < 100,000/µL
Do not modify dose but recheck CBC in one week. If during subsequent 4 weeks CBCs,
ANC remains ≥ 750/µL and platelets remain ≥ 75,000/µL, continue at 100% doses and
monitor CBC every 2-4 weeks.
b) ANC ≥ 500/µL and < 750/µL and and/or platelets ≥ 50,000/µL and < 75,000/µL:
Reduce dose to 50% of original dose until ANC recovers to ≥ 750/µL and platelets recover
to ≥ 75,000/µL. Increase dose approximately every two weeks, first to 75% of the original
dose and then to full dose, provided ANC remains ≥ 750/µL and platelets remain ≥
75,000/µL.
c) ANC < 500/µL and/or plts < 50,000/µL:
Discontinue dose until ANC is ANC ≥ 750/µL and platelets ≥ 75,000/µL. Restart
mercaptopurine at 50% of the original dose on the same day the counts recover. Increase to
75% and then 100% of the original dose at 2-week intervals provided ANC remains ≥
750/µL and platelets remain ≥ 75,000/µL.
d) Prolonged Cytopenias
Prolonged cytopenia is indicated defined as ANC < 750/µL and platelets < 75,000/µL after
withholding therapy for > 2 weeks. Perform a bone marrow examination after two weeks of
withholding chemotherapy, if no recovery is apparent. If monocyte count is increasing or
viral myelosuppression is clinically suspected, the bone marrow examination may be
postponed for 1-2 weeks and omitted if ANC and platelets fully recover by the 4th weeks
after therapy is withheld.

See Section 8.1.6.
8.7 Methotrexate, Intrathecal
8.7.1 Grade 2 Neurotoxicity

Report any significant neurotoxic reactions not due to lumbar puncture syndrome or “spinal leak” (low
opening pressure, slow CSF flow, orthostatic symptoms) directly to Study Chair.
8.7.2 Seizure, paresis or organic brain syndrome

Before next intrathecal dose, discuss clinical details and indications for CSF studies with Study Chair. If
symptoms fully resolve, subsequent intrathecal methotrexate should be given with oral citrovorum factor
(leucovorin, 10 mg) 48 hours after each intrathecal dose. If symptoms recur, omit further methotrexate
and substitute Ara-C 30, 50, 70 mg for ages 1, 2, ≥ 3 years, respectively. If initial symptoms do not fully
resolve, call Study Chair.
8.7.3 Systemic toxicity

Do not modify dose for systemic toxicity (myelosuppression, mucositis, etc.). Use citrovorum factor
(Leucovorin) as a single 10 mg oral dose 24-36 hours following intrathecal methotrexate in order to reduce
the risk of worsening already existent myelosuppression (ANC < 500/µL) or mucositis.
8.7.4 Uric acid > 7 mg/dL, phosphorus > 7 mg/dL, or creatinine > 1.0 mg/dL
Omit Methotrexate and substitute Ara-C 30, 50, 70 mg for ages 1, 2, ≥ 3 years, respectively.
8.7.5 Hydrocephalus or known abnormality of CSF flow

Call Study Chair.
8.7.6 Viral, bacterial, or fungal meningitis

Omit until resolved.
8.8 Methotrexate, Intravenous
8.8.1 ANC < 500/µL and platelet count < 50,000/µL

Methotrexate should be delayed for ANC less than 500/µL and platelet count less than 50,000/µL. Once
ANC recovers to equal or above 500/µL, and platelet count to equal or above 50,000/µL, Methotrexate
should be administered on first due date following held dose.
8.8.2 Liver Dysfunction (Grade 3-4)

See Section 8.1.6.
8.8.3 Kidney Dysfunction (Grade 2-4)

Omit IV Methotrexate until Grade 0 toxicity (resolved). Resume at 100% dose.
8.8.4 Mucositis
For Grade 3-4 stomatitis, withhold intravenous methotrexate until resolved please contact the study chair.
8.9 Methotrexate, Oral
8.9.1 Neutropenia and/or thrombocytopenia

a) ANC ≥ 750/µL and < 1000/µL and/or platelets ≥ 75,000/µL and < 100,000/µL
Do not modify dose but recheck CBC in one week. If during subsequent 4 weeks CBCs,
ANC remains ≥ 750/µL and platelets remain ≥ 75,000/µL, continue at 100% doses and
monitor CBC every 2-4 weeks.
b) ANC ≥ 500/µL and < 750/µL and and/or platelets ≥ 50,000/µL and < 75,000/µL
Reduce dose to 50% of original dose until ANC recovers to ≥ 750/µL and platelets recover
to ≥ 75,000/µL. Increase dose approximately every two weeks, first to 75% of the original
dose and then to full dose, provided ANC remains ≥ 750/µL and platelets remain ≥
75,000/µL.
c) ANC < 500/µL and/or plts < 50,000/µL

Discontinue dose until ANC is ≥ 1000/µL and platelets are ≥ 100,000/µL. Restart
methotrexate at 50% of the original dose according to established weekly schedule.
Increase dose approximately every two weeks, first to 75% of the original dose and then to
full dose, provided ANC remains ≥ 750/µL and platelets remain ≥ 75,000/µL.
d) Prolonged Cytopenias
Prolonged cytopenia is indicated defined as ANC < 750/µL and platelets < 75,000/µL after
withholding therapy for > 2 weeks. Perform a bone marrow examination after two weeks of
withholding chemotherapy, if no recovery is apparent. If monocyte count is increasing or
viral myelosuppression is clinically suspected, the bone marrow examination may be
postponed for 1-2 weeks and omitted if ANC and platelets fully recover by the 4th weeks
after therapy is withheld.
8.9.2 Severe Diarrhea or Persistent Vomiting

Discontinue oral methotrexate. Restart at 50% of the original dose when symptoms remain absent for one
week and escalate as appropriate. If symptoms recur, adjust the maximum tolerated dose to prevent
recurrent symptoms.
8.9.3 Mucositis Grade 3-4
Reduce methotrexate dose to 50% for Grade 3 toxicity; withhold for Grade 4 toxicity until resolution, then
resume at 50% of original dose with gradual dose escalation. If mucositis persists or recurs, consider
culturing for herpes simplex.
8.9.4 Liver Dysfunction:

See Section 8.1.6.
8.10 Vincristine
8.10.1 Seizures
Hold 1 dose, then reinstitute at full dose. If seizures recur, obtain neurology consultation and contact Study
Chair.
8.10.2 Severe foot drop, paresis, severe constipation, or ileus

Hold dose(s); institute aggressive regimen to treat constipation, if present. When symptoms abate, resume
at 1.0 mg/m²; escalate to full dose as tolerated.
8.10.3 Jaw pain and leg pain

Treat with analgesics; do not modify vincristine dose.

If total bilirubin is > 2 mg/dL, obtain fractionated bilirubin:
for direct (conjugated) bilirubin ≥ 0.6 and ≤ 1.0 mg/dL, give ½ dose
for direct (conjugated) bilirubin > 1 mg/dL, omit dose
If direct (conjugated) bilirubin is elevated persistently (> 1 month), check PT/INR and AST/ALT.
Exclude infectious hepatitis (A, B, C, HHV-6, HHV-7) and check PT/INR for AST/ALT > 400 U/L
8.11 STI571 (Gleevec)
8.11.1 General guidelines for alterations and reductions in STI571 dosage

Toxicity for STI571 in combination with chemotherapy will be assessed specifically in combination
with each course of therapy. Although dose reductions may have been implemented in combination
with a specific course (i.e., consolidation block 1), the patients would still receive the assigned initial
dose for the next planned course (i.e., reinduction block 1). The patients would receive the reduced dose
for all subsequent identical courses (i.e., if dose reduction in consolidation block 1, would also receive
reduced dose in consolidation block 2). The study chair should be called for all dose reductions of
STI571.
8.11.2 Grade II Non-Hematological Toxicity

If a patient experiences Grade II toxicity that does not resolve despite symptomatic treatment, study drug
should be withheld until the toxicity resolves to ≤ Grade I. If the toxicity resolves to ≤ Grade I within 7
days, study drug may be resumed at the same dose. If the toxicity recurs, study drug must be withheld
until the toxicity resolves to ≤ Grade I. Upon recovery, study drug may be resumed at one dosage level
lower than the initial dosage prescribed, or at a 30% dose reduction (calculated on the basis of the dose
actually administered) if the toxicity occurred at the first dosage level. If Grade II toxicity recurs,
further dose reductions can be performed, using the above procedures. The study chair should be
notified of all dose reductions of STI571.
8.11.3 Grade III/IV Non-Hematological Toxicity

If a patient experiences Grade III/IV non-hematological toxicity the study drug must be withheld until
the toxicity resolves. Upon recovery, study drug will be given at a 30% dose reduction (reduction from
340 mg/m2 to 230 mg/m2). If the Grade III/IV toxicity recurs, further 30% dose reductions will be
performed (reduce from 230 mg/m2 to 120 mg/m2), using the above procedures. If after a second
reduction the toxicity recurs, STI571 should be discontinued. The study chair should be called for all
dosage reductions of STI571.
8.11.4 Hepatic Toxicity

Patients assigned to the HSCT arm who have ≥ Grade III hepatic toxicity before HSCT should have a
liver biopsy and VOD precautions after HSCT considered. The study chair should be called for all dose
reductions of STI571.
8.11.4.1 Dosage modification for Hepatic Toxicity while receiving STI571 during Consolidation Block
1; Reinduction blocks 1 and 2; and Intensification block 1 and 2
Patients will have ALT, total and direct Bilirubin evaluated days 7, 14, and 21 of STI571 administration
(identical evaluations will occur at the same time points in patients not receiving STI571). If grade III
or IV toxicity occurs as evidenced by elevation of ALT or Bilirubin at day 7, STI571 will be held for 7
days and the ALT and Bilirubin evaluated at day 14. If these measures have return to below grade III or
IV, the drug will be reinstituted at the identical dosage for days 15 – 21 of that 21 block of STI571 and
the liver function evaluations performed at day 21. If there is a recurrence of grade III or IV elevation of
ALT/Bilirubin, subsequent dosing of STI571 in Reinduction block 2 or Intensification 2 will be given a
dosage of STI571 reduced by 30% (decrease from 340 mg/m2 to 230 mg/m2/dose). An identical
reevaluation at day 7, 14 and 21 will be performed in the second block with the drug held if toxicity
recurs. Toxicity in Consolidation 1, Reinduction blocks 1 and 2; and Intensification block 1 and 2 will
NOT affect the dosing of STI571 given in maintenance 1 – 12.
8.11.4.2 Dosage modification for Hepatic Toxicity while receiving STI571 during Maintenance cycle 1 -
4; and 5 – 12
ALT and Total/direct Bilirubin will be evaluated weekly weeks 1, 3, and 5 – 8 of cycle 1 and every 2
weeks in cycles 2 – 4. Weekly evaluations will occur in cycle 5 and then every 2 weeks in all
subsequent therapy. If grade III/IV toxicity as measured by ALT or Total/direct Bilirubin is observed
the drug will be held for the rest of that 21 day cycle or until the level is not grade III or IV. STI571
will be reinitiated at the identical dose in the next 21 day cycle and observed with weekly evaluations of
ALT and Bilirubin. If the grade III or IV recurs, the drug will be held for the rest of that 21 day course.
Subsequent 21 day cycles will receive a 30% reduction (decrease from 340 mg/m2 to 230 mg/m2/dose)
with weekly evaluation of ALT and Bilirubin. If no grade III or IV hepatic toxicity is observed the
patient will be evaluated every 2 weeks as is routinely done for all other patients. If grade III/IV
hepatic toxicity recurs with 30% reduced dosing STI571 will be held for the rest of that 21 day course
and restarted at the next 21day course at a further 30% reduction (decrease from 230 mg/m2/dose to 120
mg/m2/dose). The study chair should be called for all dosage reductions of STI571.
8.11.5 Grade III/IV hematological toxicity (neutropenia)
If grade IV neutropenia (ANC <500) greater than 2 weeks after planned initiation of the next course of
therapy, a bone marrow aspiration and biopsy must be performed.
If marrow cellularity is <10%, study drug must be held until ANC > 1000/ul at which time treatment
may be resumed at full dose. If Grade IV neutropenia persists, a bone marrow aspirate and biopsy will
be performed weekly to assess the cellularity and percentage of blasts. If Grade IV neutropenia recurs
after resuming trial treatment, study drug will be held until ANC > 1000/ul. Study drug will then be
resumed at one dosage level lower than the initial dosage prescribed, or at a 30% dose reduction
(calculated on the basis of the dose actually administered) if the toxicity occurred at the first dosage
level. If the toxicity recurs, further dose reductions can be performed, using the above procedures.
If marrow cellularity is >10% and/or contains >30% blasts and/or is secondary to bone marrow fibrosis,
treatment will be continued (or restarted if it has been withheld because of marrow hypocellularity
and/or granulocytopenia). If Grade IV neutropenia persists for an additional week, a bone marrow
aspirate and biopsy will be repeated and the above criteria applied. If Grade IV neutropenia persists for
two weeks, study drug will be withheld (regardless of the bone marrow appearance) until ANC >
1000/ul at which time treatment will be resumed at full dose. (Note that persistent leukemia after 2
courses, 8 weeks total, or an increasing blast percentage in the bone marrow at day 29, are off therapy
criteria – see section 7.1) If Grade IV neutropenia recurs, STI571 will again be withheld until ANC >
1000/ul. STI571 will be resumed at one dosage level lower than the initial dosage prescribed, or at a
30% dose reduction (calculated on the basis of the dose actually administered) if the toxicity occurred at
the first dosage level. If the toxicity recurs, further dose reductions can be performed, using the above
procedures. Dose reductions will not be performed for thrombocytopenia. The study chair should be
notified of all dose reductions in STI571.
8.11.6 Maintenance of platelet counts

All patients receiving STI571 will have a minimum platelet count of ≥20,000/µL maintained by
transfusion.
8.12 VP-16 (etoposide, VePesid)

Mild allergic reaction
Pretreat with Benadryl.
8.13 Ifosfamide
Hematuria
Grade 2 – 3: Administer Mesna as under section 5.2 with ifosfamide and as: Mesna 360 mg/m2 in 375
mL/m2 D5W 0.45% NaCl at 125 mL/m2 over 3 hours at hours 1, 4, 8, 12, 15, 18, and 21. Grade 4 call
study chair.
8.14 Toxicity of TBI

Nausea and vomiting
These complications are seen in almost all patients. This varies in degree with most patients experiencing
some intermittent nausea and a minority having mild emesis; this usually resolves in 24 hours. Patients will
be premedicated as necessary 30 minutes before starting radiation and thereafter q4-6 hours prn, with care
to avoid oversedation and risk of aspiration.
Uric acid nephropathy
May be seen depending upon tumor burden. Measures to be taken include administration of allopurinol,
hydration, alkalinization of urine to pH 7-7.5, and furosemide as needed to maintain adequate urine output.
Alopecia.
Parotitis and pancreatitis

Transient parotitis with pain and swelling is unusual but may be seen within 24-48 hours after the first dose
of TBI and resolves within a day or two. Salivary secretions may be decreased over a period of several
weeks to months. Pancreatitis is occasionally seen (10% of patients) and is usually mild and transient.
Diarrhea
Diarrhea is of variable severity and may occur starting in the first week, and will be managed
symptomatically. Skin erythema progressing to blistering and desquamation may occur within 1-2 weeks
following fractionated TBI and resolve within a week. Some patients may have a temporary darkening of
the skin that gradually appears following TBI and remains for several months.
Mucositis
This complication is usually moderate to severe for 1-2 weeks following TBI due to the combination of
chemotherapy, TBI, neutropenia and subsequent methotrexate administration. Hyperalimentation is used to
supplement intake and good mouth care with swabs and mouth washes is used for the patient’s comfort.
Pain medications are used as necessary.
Late effects of TBI

These include cataracts, sterility, growth retardation, and risk of a second malignancy. At present, accurate
estimates of these risk have not been established.
9.0 GUIDELINES FOR HEMATOPOIETIC STEM CELL TRANSPLANT
9.1 Transplant Guidelines
9.1.1 Local Irradiation for CNS positive at diagnosis

Patients with CNS disease at study entry should receive cranial radiation therapy 6 Gy in 3 fractions on
the 3 weekdays just prior to the TBI.
9.1.2 Preparative regimen

Day –7 TBI 200 cGy BID
Day –4 Etoposide (1500 mg/m2)
Day –3 Cyclophosphamide (1800 mg/m2)
Day –2 Cyclophosphamide (1800 mg/m2)
Day –1 Rest
Day 0 - Infusion of allogeneic hematopoietic stem cells
9.1.3 Total Body Irradiation

Fractionated TBI 200 cGy will be administered BID x 3 days (Days –7, –6, -5) (see Radiation Therapy
Guidelines, Section 16.4)
9.2 GVHD Prophylaxis
9.2.1 Cyclosporin A (CSA)

Begin on Day –1 at 1.5 mg./kg IV q12h until recovery from ablation-induced gastrointestinal toxicity
and resumption of oral intake. At that point, change CSA from IV to PO administration. A suggested
oral starting dose is 6.25 mg/kg b.i.d.
CSA should continue at full dose until Day +60. If the patient has GVHD of Grade I or less, then begin
to taper 5% per week until off.
Maintain whole blood CSA trough between 150 and 400 by TDX (parent compound and metabolites)
Halve dose if the serum creatinine doubles from pre-BMT baseline or surpasses upper limit of normal
for patient’s age. Hold for serum creatinine ≥2.0 mg/dl
9.2.2 Methotrexate
- 15 mg/m2 on Day +1
If the 24 hour post methotrexate level is greater than 0.05 micromolar (5 x 10-8 molar), then give a
rescue leucovorin dose of 9 mg IV and follow levels daily and repeat leucovorin daily until the
methotrexate level is less than 0.05 micromolar. Adjust subsequent doses of methotrexate.
If the serum creatinine is greater than 2.0 mg/dl or greater than 2 x baseline, then omit methotrexate.
In the presence of ascites or pleural effusion, omit methotrexate.
9.2.3 Administration of G-CSF during HSCT.

G-CSF is not generally recommended. If a center wishes to give G-CSF, 5 mcg/Kg daily starting on day
+7 post HSCT is recommended.
9.2.4 Active Acute GVHD

Patients with GVHD of Grades 2-4 on Day 60 or who develop GVHD of Grades 2-4 during the CSA
taper should continue on ‘full dose’ CSA and receive additional immunosuppressive therapy. Suggested
approaches include prednisone 2 mg/kg/day x 14 days and/or anti-thymocyte globulin 10 mg IgG/kg qod
x 6 doses. An alternate prednisone dosing schedule is prednisone/solumedrol 6 mg/Kg divided q8h x 2
days, then 3 mg/Kg divided q8h x 2 day, then 1.5 mg/Kg x 2 day followed by a slow taper.
9.3 Supportive care
9.3.1 Isolation by Institutional standard

BMT patients are to be admitted to an appropriate room as per institutional BMT procedures. Routine
central venous catheter dressing changes as per individualized institutional protocols.
9.3.2 Nutrition and Diet

A dietitian should be part of the BMT team and should help institute a low bacteria diet.
9.3.3 Herpes simplex and CMV prophylaxis
The following is a recommended prophylaxis protocol. Institutional protocol should take precedence.
Patients should start on acyclovir between Day –6 to –1 (as per institutional practice) and continue until
Day +30 or discharge (whichever occurs earlier) according to the following table:
Patient Donor (marrow)

CMV HSV CMV
+ + + or - IV acyclovir 500 mg/m2 q8h
+ - + or - IV acyclovir 500 mg/m2 q8h
- - + IV acyclovir 500 mg/m2 q8h
- + + IV acyclovir 500 mg/m2 q8h
- + - IV acyclovir 250 mg/m2 q8h plus
CMV seronegative blood products
- - - IV acyclovir 250 mg/m2 q8h plus
CMV seronegative blood products
CMV negative recipients who receive marrow from CMV negative donors should be transfused with
CMV safe blood products (either antibody screen or leukofiltered).
Centers should employ standard methods for the reduction of invasive disease. This would include either
routine testing for reactivation and pre-emptive use of ganciclovir or the prophylactic administration of
ganciclovir.
9.3.4 Blood products

All blood products must be irradiated. The recommended dose is 25 Gy.
Concentrated irradiated red cell transfusions should be given to maintain a hemoglobin concentrate of
greater than or equal to 8 g/dl.
Irradiated platelet transfusions should be given to maintain a platelet count greater than or equal to
20,000/µl. Pheresed units are preferred.
9.3.5 Pneumocystis carinii prophylaxis

Trimethoprim-sulfamethoxazole (5 mg/kg/d divided BID) should be given until Day –1 and re-initiated
three times a week (M-W-F) post BMT when the ANC has been greater than or equal to 500/ml x 2
consecutive days. Patients who cannot tolerate trimethoprim-sulfamethoxazole may have pentamidine
nebulization or other local institutional protocols used as a substitute post BMT.
9.3.6 Skin Care, Mucositis, Menstruating Females

The patient should have a daily bath/shower.
Patients should receive treatment for mucositis per their institutional BMT protocol.
Menstruating females may receive norethindrone 10 mg qAM during the transplant until one month post
discharge.
9.3.7 Fever, Neutropenia, and Antimicrobial Therapy
Any temperature greater than 38.3oC, on any occasion, should be an indication to start antimicrobial
therapy. Specific antimicrobial therapy should be dictated by institutional experience and institutional
preference. Combination of a semi-synthetic penicillin and an aminoglycoside are recommended.
Vancomycin is also recommended as a component of initial therapy for patients with multilumen
Hickman or Broviac catheters due to the high incidence of staphylococcal infection in this population.
If ‘high’ fevers persist for more than 3 days, despite broad spectrum antimicrobial therapy, empirical
antifungal therapy with Amphotericin B is recommended.
9.3.8 Fluconazole prophylaxis

If a center wished to give Fluconazole, start Day –6
6 mg/kg/day (200 mg/day maximum)
Fluconazole may impede CSA metabolism. It is recommended that Fluconazole NOT be given in
conjunction with STI571 (STI571 is started week 16-24 post HSCT)
9.3.9 Intravenous immunoglobulin (IVIG)

IVIG should be given as per institutional policy.
10.0 REQUIRED OBSERVATIONS
The studies listed below constitute a minimum evaluation for the purposes of COG reporting and
toxicity monitoring. Other diagnostic studies or more frequent determinations may be indicated for
optimal standard care. Instructions for submission of specimens also are included in this section.
10.1 Observations from time of initial diagnosis for all patients enrolled on study
10.1.1 Physical Examination
10.1.2 Radiographic Examinations
10.1.3 CBC results
10.1.4 Bone Marrow Evaluations
10.1.5 Slides for Morphology
10.1.6 Institutional Immunophenotyping
Johns Hopkins University Immunophenotyping Reference Laboratory confirmation – previous POG

institutions (POG 9900)
10.1.7 Prior registration on Cytogenetics Protocol (POG 9907) for previous POG institutions
10.1.8 Molecular (automated RT-PCR) assessment for BCR-ABL
Former CCG institutions – All patients registered on CCG 1961 High risk protocol. Other standard
risk patients will be identified by institutional molecular diagnostics laboratories. Former POG
institutions – All patients registered on POG 9900 Classification Protocol.
10.1.9 Central review of cytogenetics and FISH
10.1.10 CSF evaluation

a) initial WBC and platelet counts
b) initial hemoglobin (prior to transfusion)
c) percent blasts
10.2 Evaluations at time of entry onto COG AALL0031
10.2.1 Physical examination
10.2.2 CBC results

a) WBC
b) percent blasts
c) hemoglobin
d) platelet count
10.2.3 Bone marrow evaluation (sample from end of induction can be used)
a) morphology
b) MRD assessment (reference laboratory - see section 11.0.)
10.2.4 CSF evaluation

a) CSF WBC/µL
b) CSF RBC/µL
c) Cytospin for determination of % blast cells (see section 4.3.3)
10.2.5 Serum creatinine, ALT, total bilirubin (obtain fractionated bilirubin for cases of
hyperbilirubinemia)
10.2.6 Serum for evaluation of alpha-1-glycoprotein (send to Dr. Avramis laboratory) (See 10.8.3).
10.3 Evaluations during Treatment on COG AALL0031
10.3.1 Indications for BM aspirations except as indicated for MRD evaluations during treatment are:
1) circulating blast cells
2) unexplained hepatomegaly, splenomegaly, or lymphadenopathy
3) unexplained bone pain
4) suspected or documented extramedullary leukemia or
5) prolonged myelosuppression (ANC < 1000/µL and platelet count < 100,000/µL) for a period
of two weeks after withholding chemotherapy; if no recovery is apparent.
If monocyte count is increasing or viral myelosuppression is clinically suspected, the bone marrow
examination may be postponed for 1-2 weeks and omitted if ANC and platelets fully recover by the 4th
weeks after therapy is withheld. Patients with an M2 marrow should have a repeat aspiration in two to
four weeks.
10.3.2 Consolidation block 1
10.3.2.1 Blood/Bone Marrow Evaluation

a) CBC, including differential and platelet count: Weekly
b) bone marrow aspirate: Day1
c) Serum creatinine, ALT, total bilirubin (obtain fractionated bilirubin for cases of
hyperbilirubinemia) weekly
10.3.2.2 CSF Evaluations

a) All Regimens: prior to administration of intrathecal methotrexate on Day 1
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin
10.3.3 Consolidation block 2

a) CBC, including differential and platelet count weekly
b) Serum creatinine, ALT, total bilirubin (obtain fractionated bilirubin for cases of
c) Bone marrow aspirate: Day 1. Submit for MRD evaluation (See Section 11.1)
10.3.3.2 CSF Evaluation

a) Prior to administration of intrathecal methotrexate on Day 1
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin.
10.3.4 Reinduction block 1 and 2

* Please see section 9.0 for patients that are to receive the HSCT arm.

c) Bone marrow aspirate: Day 1 of blocks 1 and 2. Submit for MRD evaluation (See Section
11.1)

a) Prior to administration of intrathecal methotrexate on Days 1 and 15
b) CSF WBC/µL
c) CSF RBC/µL
d) Cytospin – Day 1 only
10.3.4.3
Echocardiogram prior to Day 1 daunorubicin.
10.3.5 Intensification blocks 1 and 2
10.3.5.1 Blood

a) Prior to administration of intrathecal methotrexate on Day 1
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin.
10.3.6 Reinduction block 2 – Same as Reinduction block 1
10.3.7 Maintenance cycle 1 – 4
10.3.7.1 Blood/CSF Evaluations

a) CBC, including differential and platelet count: Day 1, 29, and 56 of each 56-day cycle.
b) ALT, Total bilirubin, Serum creatinine, and BUN (obtain fractionated bilirubin for cases of
hyperbilirubinemia) days 1, 15, 29, and 43 of each cycle. Weekly evaluations for ALT and
Bilirubin will occur days 29 - 56 of cycle 1.
c) CSF exam: day 1 of each 56-day cycle
d) CSF WBC/µL
e) CSF RBC/µL
f) Cytospin
d) Bone marrow evaluation for MRD studies is required day 1 of cycle 1 of maintenance.
e) Serum for alpha-1-Glycoprotein to go to Dr. V. Avramis laboratory Day 1 of cycle 1 of
maintenance (See section 10.8.3).
10.3.8 Maintenance cycle 5 – 12
10.3.8.1 Blood/CSF Evaluations

a) CBC, including differential and platelet count: Day 1, 29 of each 56-day cycle
b) ALT, Total bilirubin, Serum creatinine, and BUN (obtain fractionated bilirubin for cases of
hyperbilirubinemia): Days 1, 15, 29, and 43 of each 56-day cycle. Weekly evaluations for
ALT and Bilirubin will occur on days 1, 8, 15, and 22 of cycle 5.
c) CSF exam: day 1 of each 56-day cycle
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin for determination of % blast cells
10.4 End of Therapy

Bone marrow and CSF samples are required at the completion of therapy.
10.5 Follow-up Phase (Off Protocol Therapy-Chemotherapy)
Patients will be considered off protocol therapy (but not off study) and in follow-up when they have
completed protocol-specified therapy.
Patients continue in follow-up until death, lost to follow-up, or entry onto another CCG, POG or COG
therapeutic study.
Patients considered off protocol therapy because of relapse, who are not enrolled on another COG
therapeutic study, should be followed by Off Protocol Therapy Follow-up Report.
10.5.1 Interval History, Physical Exam, and Complete Blood Count

a) every 4-8 weeks during the first year following cessation of therapy
b) every three months during the second year off-treatment
c) every six months during the third year
d) yearly thereafter.
10.5.2 Bone Marrow Examinations and Lumbar Punctures

NOT required except when indicated by abnormal results from the interval history, physical exam or
complete blood count.
10.5.2.1 A bone marrow aspiration is required if any one of the following occurs
1) peripheral blasts
2) hepatomegaly, splenomegaly, or lymphadenopathy
3) unexplained bone pain
4) suspicion or proof of extramedullary disease
5) ANC < 1,000/µL or platelets < 100,000/µL without obvious explanation
10.5.2.2
Patients with M2 marrows should have a repeat aspiration in approximately two weeks.
10.5.2.3
A lumbar puncture is required for:
1) evidence of a CNS relapse: neurological symptoms or signs are present, including persistent
headache and/or vomiting, bulbar nerve palsy, pathologic weight gain, or other signs of
increased intracranial pressure.
2) evidence of other relapses (bone marrow or non-CNS extramedullary site).
10.6 Observation before start of HSCT
10.6.1 Blood/Bone Marrow Evaluation

a) CBC, including differential and platelet count at least twice weekly
hyperbilirubinemia) at least weekly.
c) Bone marrow aspirate: within one week of starting the preparative regimen.
d). BM aspirate and peripheral blood to be sent for MRD evaluations within 2 weeks of
initiating the preparative regimen for HSCT.
10.6.2 CSF Evaluation
Day 1 and 15
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin – Day 1 only.
10.6.3 Echocardiogram prior to HSCT.
10.6.4 EKG prior to HSCT
10.6.5 Pulmonary function tests
10.6.6 Glomerular filtration rate (GFR) by nuclear medicine scan before HSCT.
10.6.7 Serology for CMV, HSV, EBV, Hepatitis B, C.
10.7 Follow-Up Phase (Off Protocol Therapy - HSCT)
10.7.1 Blood
a) CBC, including differential and platelet count at least twice weekly
hyperbilirubinemia) at least weekly
10.7.2 CSF Evaluation

Days 1 and 15
1) CSF WBC/µL
2) CSF RBC/µL
3) Cytospin – Day 1 only.
10.7.3
Echocardiogram at 3 and 12 months after HSCT.
10.7.4 EKG at 3 and 12 months after HSCT.
10.7.5 Pulmonary function tests 3 and 12 months after HSCT
10.7.6 Serology for CMV, HSV, EBV, Hepatitis B, C at 12 months after HSCT.
10.7.7 MRD evaluations blood and BM

BM aspirate and peripheral blood to be sent for MRD evaluations: 24 weeks and 48-52 weeks after
HSCT if not receiving STI571. For patients receiving STI571 the MRD evaluations should be obtained,
before the initiation of STI571 and 24 weeks later.
10.7.8 GVHD Scoring at 1,3,12,24 months after HSCT.

10.7.9 Alpha-1-Glycoprotein serum concentration at 48-52 weeks after HSCT (See section 10.8.3).
10.8 At Relapse (On or Off Therapy) – Contact the study chair as soon as is possible.
10.8.1 Bone marrow aspirate. Submit for evaluation for MRD.
10.8.1.1 Immunophenotyping
Repeat immunophenotyping at local institution.
10.8.1.2 Cytogenetics
Repeat blast cell cytogenetics at local institution.
10.8.1.3 Tissue Banking

If consent for tissue banking was obtained, a 3 ml aspirate to be sent to COG ALL Biology Reference
Laboratory for cryopreservation (obtained on frontline study for Ph+ and hypodiploid. Induction failures
will have a BM submitted for tissue banking.)
10.8.1.4 COG ALL Biology Reference Laboratory

If consent for tissue banking was obtained, a 6 ml diagnostic bone marrow aspirate* in 500 units of
preservative–free sodium heparin** should be sent to the ALL Biology Reference Laboratory for
specimen banking and for Reference Laboratory Biology Studies.
* Bone marrow aspirate is preferred. If an aspirate is not available, a bone marrow biopsy
in media may be submitted. If biopsy cannot be obtained, a sample of peripheral blood
with blasts may be submitted.
** Preservative-free preparation is recommended, but not mandatory if not available
All samples should be kept sterile, either at room temperature or 4°C. Samples should not be heated or
frozen. Materials should be packed and shipped out immediately to the reference laboratory. Marrow
may be shipped within the heparinized syringes or alternatively, placed in sterile plastic tissue culture
tubes. If a specimen for the Reference Laboratory is expected to be in shipment more than 24 hours, it
should be diluted with approximately 5 mls of tissue culture medium.
Samples should be sent for guaranteed overnight delivery or for Monday delivery if shipped on Friday.
The available carriers include: a) Express Mail; b) Federal Express; c) Emery Express; d) other carriers.
Speed is of the essence. All specimens should be sent prepaid and should be delivered directly to the
Reference Laboratory. Samples must not be left at airline counters or at airports.
Molecular studies:
Cheryl Willman, M.D.
David Viswanatha, M.D.
CMCD Labs - Att'n POG SAMPLE SUBMISSION
Univ. of New Mexico Cancer Research Facility
2325 Camino de Salud N.E., Room 109
Albuquerque, NM 87131-5636
Tel: (505) 272-6037
FAX: (505) 272-4039
Saturday Delivery:
c/o FedEx Station 1501 Renaissance Blvd.
Albuquerque NM 87107
CHECK ON AIRBILL: HOLD AT STATION SATURDAY

Notify laboratory of each Saturday delivery at (505) 272-6037
10.8.2 CSF examination

a) CSF WBC/µL
b) CSF RBC/µL
c) Cytospin for determination of % blast cells (see Section 14.2)
10.8.3 Serum for evaluation of Alpha-1-Glycoprotein

Send 5ml blood in red top tube allow to clot in ice-cold conditions centrifrige in a refrigerated clinical
centrifrige x 5 to 8 minutes at 800g, separate, label and freeze.
Vassilios I. Avramis PhD

Childrens Hospital Los Angeles
Division Hem-Onc, MS#57
4650 Sunset Blvd
Los Angeles CA 90027
Phone: (323) 669-2288
FAX: (323) 661-5058
E-Mail: vavramis@chla.usc.edu
10.9 Rapid Reporting of Toxicity

All toxicity ≥ grade 3 are to be reported on the Rapid Toxicity Report. These reports must be
submitted within 24 hours of the occurrence of the toxicity to the COG office. The study chair,
statistician and office will be immediately notified upon receipt of this notification. The COG
Rapid Toxicity Report does not preclude the submission of the AdEERS report submitted to
CTEP (see section 19.0).
The following adverse events do NOT require submission of the Rapid Toxicity Report .
Hematologic codes 132-154
Grade 3 infection codes 492-506
Grade 3 mucositis code 418
Grade 3 diarrhea codes 374-377
Grade 3 gastritis code 401
Grade 4 febrile neutropenia code 494
10.9.1
In cases of patient death, in addition to Rapid Reporting via RDE, the study chair must be notified
(pager # (604) 875-2161).
11.0 MINIMAL RESIDUAL DISEASE EVALUATIONS
Flow Cytometry:
Michael J. Borowitz, MD, PhD
Flow Cytometry Laboratory
Johns Hopkins Medical Institutions
Weinberg 2300
401 N. Broadway
Baltimore, MD 21231
Phone: (410) 614-2912
Fax: (410) 614-2912
Molecular studies:
Cheryl Willman, M.D.
David Viswanatha, M.D.
2325 Camino de Salud N.E., Room 109
Albuquerque, NM 87131-5636
Tel: (505) 272-6037
FAX: (505) 272-4039
Saturday Delivery:
c/o FedEx Station 1501 Renaissance Blvd.
Albuquerque NM 87107
CHECK ON AIRBILL: HOLD AT STATION SATURDAY

Notify laboratory of each Saturday delivery at (505) 272-6037
11.1 Quantitative evaluations for MRD

Bone marrow samples will be obtained and evaluated for the presence of MRD at the following time
points:
1) at study entry – Immunophenotyping and molecular
2) before consolidation block 2 – Immunophenotyping and molecular
3) before reinduction block 1 or HSCT – Immunophenotyping and molecular
4) before reinduction block 2 or 24 weeks post HSCT (or before start of STI571) – molecular only
5) before maintenance cycle 1 or 48 weeks post-transplant (or at the end of STI571) – molecular only
6) Relapse – see relapse section. Call Study chair ASAP upon relapse.
MRD will be measured by RT-PCR for BCR-ABL, PCR/capillary electrophoresis for immunoglobulin
heavy chain (IgH) gene rearrangements or T-cell receptor (TCR) gene rearrangements, and
multiparameter flow cytometry. A sample from initial diagnosis will be used to identify the choice of
flow cytometry (B- or T-lineage) reagents or PCR probes to be used for each patient. Diagnostic
samples will already have been analyzed by these methods for all POG patients as part of their
groupwide frontline induction protocol. These assays will also be performed retrospectively on banked
diagnostic samples from CCG patients identified as eligible for this study. Fresh samples will be
obtained from all patients on day 1of the VHR study, prior to administration of drugs, for analysis of
MRD by all three methods. At subsequent time points, only MRD will be analyzed by RT-PCR for
BCR-ABL (Ph+ patients) and by PCR for IgH and TCR gene rearrangements (all patients).
11.2 Immunophenotypic Analysis

For multiparameter flow cytometry, bone marrow aliquots will be stained with combinations of
antibodies conjugated to 4 fluorochromes with different emission spectra: fluorescein isothiocyanate
(FITC); phycoerythrin (PE); peridin chlorophyll alpha protein (perCP); and allophycocyanin (APC).
Two different four-color combinations of antibodies, CD19-APC/CD45-perCP/CD20-PE/CD10-FITC
and CD19-APC/CD45-perCP/CD9-PE/CD34-FITC will be used to distinguish normal and B-lineage
leukemic cells in the bone marrow, essentially as previously described by Weir et al.64 Since normal B-
precursors exhibit a reproducible antigen expression pattern, a fixed set of geometrical regions can be
used to define normal, and leukemic cells then can be identified by difference.
11.3 Molecular Evaluations

Molecular analysis of MRD will be done by real time quantitative "TaqMan" PCR75-77 for highly
sensitive detection of the BCR-ABL fusion transcript and PCR/capillary electrophoresis analysis78-80
for detection IgH or TCR gene rearrangements. TaqMan PCR analysis typically resolves MRD in the
range of 10-5 to 10-6 (cell dilution factor) and antigen receptor methodology is in the range of 10-3.
Antigen receptor PCR will be performed in all cases and will provide an additional parameter of MRD
measurement for those patients who are Ph+.
11.4 MicroArray Evaluations

Microarray on initial diagnosis samples will be performed in Dr. Willman’s laboratory and correlated
with outcome and MRD by both PCR and immunophenotyping.
12.0 DRUG INFORMATION
12.1 ASPARAGINASE
12.1.1 L-ASPARAGINASE E. coli

(Elspar, Kidrolase, Crasnitin, Leunase) NSC #109229
Source and Pharmacology: E. coli asparaginase deaminates asparagine, thus, is lethal for cells which
cannot synthesize asparagine. It is lethal during all phases of the cell cycle. Plasma T - 1/2 varies from
8 to 30 hours after IV administration and 39 to 49 hours after IM administration. Very little is excreted
in the urine and bile. Although L-asparaginase does not diffuse into the CSF, low CSF asparagine levels
occur. Asparagine levels remain low after L-asp is no longer detectable. There is a shallow dose
response curve.
Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to <5 children out of every 100
children out of every 100 out of every 100
Immediate: Local allergic reactions Rash Hypersensitivity with anaphylaxis nausea, vomiting,
Within 1-2 days of receiving drug somnolence, lethargy, headache, seizures (L),
hyperuricemia, azotemia
Prompt: Hyperammonemia (L), Hyperglycemia, abnormal Pancreatitis (L), convulsions (L), hemorrhage (L), anorexia,
Within 2-3 weeks, prior to the next course decreased synthesis of liver function tests CNS ischemic attacks, edema, renal complications,
albumin, fibrinogen and thrombosis, myelosuppression, irritability, depression,
other clotting factors (L) confusion, EEG changes, hallucinations
Delayed:
Any time later during therapy, excluding
the above conditions
Late:
Any time after the completion of treatment
(L) Toxicity may also occur later.
Formulation and Stability:

Asparaginase powder for injection should be stored at 2-8°C but is stable 48hr – 1 year at room
temperature. When asparaginase is reconstituted with 2-5ml of preservative-free sodium chloride it is
stable for 7 days at room temperature with no loss of potency, if further diluted for I.V. solutions, it is
stable for 8 hours at room temperature and 48hr when stored at 2-8°C. Cloudy solutions should not be
used. Occasionally a very small number of gelatinous, fiber-like particles may develop in asparaginase
solutions on standing. The particles may be removed without loss of potency by filtration through a 5-
micron filter during administration of the drug. Some loss of potency has occurred with the use of a 0.2-
micron filter.
Guidelines for Administration:

IM is the preferred route due to the lower incidence of anaphylactic reactions. For IM use, asparaginase
is reconstituted by adding 0.5 - 2 ml of 0.9% sodium chloride injection to the vial containing 10,000 IU
of asparaginase and rotate the vial to dissolve (shaking will cause excessive foaming). No more than 2
ml should be given at one IM injection site. IV infusions should be given slowly over 30 minutes.
Special precautions: Because of the possibility of anaphylaxis, the patient should be kept under
observation for 1/2 to 4 hours with resuscitative equipment available and IV epinephrine 1:10,000 and
IV diphenhydramine. Monitor/assess for hyperglycemia, coagulopathies, cerebrovascular episodes and
pancreatitis.
Supplier:
E. coli L-asparaginase is commercially available. See package insert for further information.
12.1.2 PEG-L-ASPARAGINASE
(Pegaspargase, Oncaspar®, Polyethylene Glycol Conjugated L-asparaginase-H) NSC #644954
Source and Pharmacology: The drug is an L-asparaginase combination (L-asparaginase amidohydrolase,

EC 3.5.1.1), covalently attached to strands of monomethoxypolyethylene glycol of 5,000 daltons (PEG) by
means of a coupling moiety. The source of the L-asparaginase is Escherichia coli. This conjugate is
named PEG-L-asparaginase EC. The plasma half-life is 5.7 days. The half-life of PEG-L-asparaginase is
significantly longer than that of the native enzyme. Previous allergic reactions to L-asparaginase are
associated with a shorter half-life (3.2 days), and in patients with a history of L-asparaginase allergic
reaction, doses are sometimes administered weekly instead of every two weeks.
Toxicity:
Happens to 21-100 children out Happens to 5-20 children out of Happens to <5 children out of every 100
of every 100 every 100
Immediate: Local allergic reactions Rash Hypersensitivity with anaphylaxis nausea,
Within 1-2 days of receiving drug vomiting, somnolence, lethargy, headache,
seizures (L), hyperuricemia, azotemia
Prompt: Hyperammonemia (L), Hyperglycemia, abnormal liver Pancreatitis (L), convulsions (L), hemorrhage
Within 2-3 weeks, prior to the next course decreased synthesis of albumin, function tests (L), anorexia, CNS ischemic attacks, edema,
fibrinogen and other clotting renal complications, thrombosis,
factors (L) myelosuppression, irritability, depression,
confusion, EEG changes, hallucinations
Delayed:
Late:
Formulation and Stability: Pegaspargase is available in 3750 units per 5ml vial (750 IU/ml). Keep
under refrigeration at 2-8° C (36-40°F). DO NOT FREEZE. If stored at room temperature, stable no
greater than 48 hours. Do not use cloudy solutions or if particulate matter is seen. Do not shake the vials –
the asparaginase portion of the compound may be separated from the PEG portion.
Guidelines for Administration: IM only. Maximum volume per IM injection site is 2ml. Special
Precautions: Because of the anaphylaxis, the patient should be kept under observation for 30 min - 4 hour
with resuscitative equipment available. Have IV epinephrine 1:10,000 and IV Benadryl immediately
available. Delayed hypersensitivity can be seen 1-2 days after the drug administration. Monitor the patient
for hyperglycemia, coagulopathies, cerebrovascular episodes, and pancreatitis symptoms.
Supplier: Commercially available with restrictions. Due to particulate matter in the product the
distribution of drug has been restricted. The product must be ordered through Genitive Health Services (1-
888-276-2217). Product will only be sent for the following week and it must be ordered for each particular
patient. The patient must be hypersensitive to native E.coli Asparaginase or being treated according to a
protocol that requires the use of Pegaspargase or may be a relapsed patient. Contact Genitive Health
Services for forms and ordering information. See package insert for further information.
12.1.3 ERWINIA ASPARAGINASE
(Porton asparaginase) NSC #106977
Source and Pharmacology: Erwinia asparaginase is an enzyme from the plant pathogen Erwinia
carotovora (Erwinia chrysanthemi). Asparaginase deaminates asparagine, thus, is lethal for cells which
cannot synthesize asparagine. It is lethal during all phases of the cell cycle. Plasma T - 1/2 varies from
8 to 30 hours after IV administration and 39 to 49 hours after IM administration. Very little is excreted
in the urine and bile. Although asparaginase does not diffuse into the CSF, low CSF asparagine levels
occur. Asparagine levels remain low after asparaginase is no longer detectable. There is a shallow dose
response curve.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out of Happens to <5 children out of every 100
out of every 100 every 100
Immediate: Local allergic reactions Rash Hypersensitivity with anaphylaxis nausea,
Within 1-2 days of receiving drug vomiting, somnolence, lethargy, headache,
seizures (L), hyperuricemia, azotemia
Prompt: Hyperammonemia (L), Hyperglycemia, abnormal liver Pancreatitis (L), convulsions (L), hemorrhage
Within 2-3 weeks, prior to the next decreased synthesis of function tests (L), anorexia, CNS ischemic attacks, edema,
course albumin, fibrinogen and renal complications, thrombosis,
other clotting factors (L) myelosuppression, irritability, depression,
confusion, EEG changes, hallucinations
Delayed:
Any time later during therapy,
excluding the above conditions
Late:
Any time after the completion of
treatment
Formulation and Stability: For injection: 10,000 U vial. Supplied as a lyophilized powder with
glucose BP (dextrose monohydrate), 5mg and sodium chloride, 0.5 mg in 3 ml flint glass vials. When
the 10,000 U vial is constituted with 2 ml of preservative-free 0.9% Sodium Chloride Injection, USP,
each ml of solution contains 5,000 U of Erwinia asparaginase, pH 6 to 7.5. This solution is stable for up
to 20 days both at room temperature and refrigerated. May dilute with 1ml for a 10,000 U per ml
concentration, stability is 48hr under refrigeration. However, the manufacturer recommends that the
product be used immediately after reconstitution. Refrigerate the intact vials (2-8°C). The intact
vials are stable for at least 3 years both refrigerated (2-8°C) and at room temperature (22-25°C). Turbid
solutions should be discarded. NOTE: To minimize protein denaturation arising from contact with the
stopper, it is recommended that the vial be gently rotated to facilitate dissolution and to minimize
contact with the stopper. The constituted solution should be withdrawn from the vial within 15 minutes.
It may then be directly injected or further diluted in 5% Dextrose Injection, USP, or 0.9% Sodium
Chloride Injection, USP.
Guidelines for Administration: IM is the preferred route. The maximum volume per IM injection site
is 2ml. IV infusions should be given slowly over a period of at least 30min. The reconstituted product
(as described above) may be further diluted in 0.9% sodium chloride or 5% dextrose and this solution
should be infused within 8 hours of preparation. Special Precautions: Because of the possibility of
anaphylaxis, the patient should be kept under observation for 1/2 to 4 hours with resuscitative equipment
available. Anaphylaxis is much less common following IM administration rather than IV, but have IV
epinephrine 1:10,000 and IV diphenhydramine immediately available. Monitor/assess for
hyperglycemia, coagulopathies, cerebrovascular episodes and pancreatitis.
Supplier: Available from Speywood Pharmaceuticals Ltd., through its U.S. distributor, McKesson
BioService Corporation - Tel: (301) 762-0069; FAX (301) 738-2478. This product is NOT provided
free of charge.
12.2 CYCLOPHOSPHAMIDE (CTX, Cytoxan)
NSC #026271/IND #7089
Source and Pharmacology: An alkylating agent, related to nitrogen mustard, which is biochemically
inert until it is metabolized to its active components by the liver phosphamidases. It is non-phase-
specific. The drug and its metabolites are excreted exclusively by the kidney after parenteral
administration. The plasma half-life ranges from 4 to 6.5 hours. When taken orally, 25% may be passed
in the stool unchanged.
Toxicity:
Happens to 21-100 children out of Happens to 5-20 children Happens to <5 children out of
every 100 out of every 100 every 100
Immediate: Anorexia (L), nausea (L), Metallic taste (L), Transient blurred vision1 cardiac
Within 1-2 days of receiving drug vomiting(L) Inappropriate ADH1 toxicity with arrhythmias1
2
myocardial necrosis (L)
Prompt: Myelosuppression (L), alopecia Hemorrhagic cystitis (L)
Within 2-3 weeks, prior to the next (L)
course
Delayed: Immunosuppression, gonadal Pulmonary fibrosis3(L)
Any time later during therapy, excluding dysfunction /sterility (L)
Late: Secondary malignancy, bladder
Any time after completion of treatment fibrosis
Unknown Frequency and Timing: **Fetal and teratogenic toxicities and toxicities in breast-fed children
(L) Toxicity may also occur later
1
Less common with lower doses.
2
Only with very high doses.
3
Risk increased with chest radiation.
**Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other antineoplastic agents) have been
noted in humans. Toxicities include: chromosome abnormalities, multiple anomalies, pancytopenia, and low birth weight.
**Cyclophosphamide is excreted into breast milk. Neutropenia has been reported in breast-fed infants. Cyclophosphamide is
considered to be contraindicated during breast feeding because of the reported cases of neutropenia and because of the potential
adverse effects relating to immune suppression, growth, and carcinogenesis.
Formulation and Stability: Oral drug is supplied as 25mg and 50mg tablets. Injectable form is
available as white crystals with sodium chloride added, in vials containing 100mg, 200mg, 500mg, 1gm
and 2gm. All preparations are stable at room temperature (not to exceed 30°C). Reconstitute with sterile
water to a concentration of 20 mg/ml. Also available in 1g and 2g vials; reconstitute with 50ml and
100ml sterile water, respectively. Discard solution after 24 hours at room temperature; stable up to 6
days if refrigerated (2°-8°C). Since there is no preservative, precautions should be taken to insure
sterility, or solution should be discarded within 8 hours.
Guidelines for Administration: Doses <600mg/m2 (low dose) may be given PO in the a.m. on an
empty stomach followed by good oral hydration; doses >600mg/m2 should be given as a 1-hour IV
infusion. Patients should be asked to void at least every 2 hours during the 12-hour period immediately
following a dose of cyclophosphamide. Administration of high doses of cyclophosphamide should be
preceded by IV fluids and MESNA, and followed by IV fluids and MESNA.
Supplier: Commercially available. See package insert for further information.

12.3 CYTARABINE (cytosine arabinoside, AraC, Cytosar)
NSC #063878
Source and Pharmacology: Deoxycytidine analogue which is metabolized to ARA-CTP, a substance

which inhibits DNA polymerase. It is S phase specific, and thus affects DNA synthesis. It has an initial
plasma half-life of about 15 minutes, with a secondary phase of about 2 hours. Rapidly catabolized by
hepatic cytidine deaminases to AraU. Intrathecally administered doses are catabolized and eliminated
more slowly with a half-life of 1-11 hours.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out Happens to <5 children out of every 100
out of every 100 of every 100
Immediate: Nausea, vomiting, anorexia Flu-like symptoms with fever Rash (L), encephalopathy1 (L), cerebellar
Within 1-2 days of receiving drug (L), conjunctivitis1 (L) dysfunction1 (L)
Prompt: Myelosuppression, Diarrhea Hepatotoxicity (L)1, veno-occlusive
Within 2-3 weeks, prior to the next stomatitis, alopecia disease1 (L), pulmonary capillary leak1
course
Delayed: Pneumonitis
Late: Gonadal dysfunction
Any time after completion of
treatment
Unknown Frequency and Timing: **Fetal and teratogenic toxicities
1
Rare with low doses.
**Fetal toxicities and teratogenic effects of cytarabine (alone or in combination with other antineoplastic agents) have been noted in
humans. Toxicities include: congenital defects, chromosome abnormalities, pancytopenia, and low birth weight.
Formulation and Stability: A freeze-dried powder available in 100mg, 500mg, 1g and 2g vials. The
unreconstituted form of the drug is stable at room temperature for at least 2 years. Reconstitute with
sterile water or Bacteriostatic Water to a recommended concentration of 20mg/ml up to 100mg/ml,
except for IT administration. (See Guidelines below.) Reconstituted solution stable for 28 days at room
temperature or refrigerated (concentration dependent). Further diluted solutions of 0.5 mg to 25 mg/mL
are stable at least 7 days at room temperature. A solution of 40 to 80 mg/mL diluted with bacteriostatic
water in polypropylene syringes is stable 15 days at room temperature. A solution of 1 mg/mL in
selected portable pump reservoirs is stable for 15 days at 37°C. Discard solution if haze develops.
Compatible with potassium chloride and sodium bicarbonate. (Trissel, 9th edition)
INTRATHECAL ADMINISTRATION: IT cytarabine should be reconstituted with physiologic

buffered diluents (lactated Ringer's, 0.9% sodium chloride, Elliott’s B solution) or patient's own CSF.
Do not use Bacteriostatic Water to reconstitute for IT use, use only preservative free solutions.
Guidelines for Administration: IM, IT, SQ, IVP, intermittent IV infusion or continuous IV infusion.
When given in high doses, antiemetics and dexamethasone or artificial tear eye drops are indicated. Flu-
like syndrome may occur 6-12 hours after drug administration and may recur with successive therapy.
Corticosteroid, antihistamine and/or acetaminophen administration may be helpful. Monitor for signs of
neurotoxicity (peripheral neuropathy, cerebellar dysfunction) with high dose regimens and stop therapy
immediately if toxicity is observed. Emesis usually occurs 4-6hr after intrathecal administration, use
premedications to prevent.

12.4 DAUNORUBICIN (Daunorubicin, DNR, Cerubidine)
NSC #82151
Source and Pharmacology: An anthracycline compound derived from Streptomyces coeruleorubidus,

which intercalates with DNA, interfering with DNA synthesis. Maximal cytotoxic activity occurs in late
S or G2 phase. (At high doses, it is non phase specific.) Primary route of excretion is biliary, with some
urinary excretion. Its initial plasma half-life is very rapid, with a terminal t½ of 18.5 hours. It is
catabolized to daunorubicinol, an active metabolite which disappears with a half-life of 26.7 hours. It is
widely distributed in the body, with highest levels found in the spleen, kidney, liver and lung. 20% is
excreted in the urine and 40% in the bile.
Toxicity:
Happens to 21-100 children out of Happens to 5-20 children out Happens to <5 children out
every 100 of every 100 of every 100
Immediate: Cardiac arrhythmias1, nausea, Anaphylaxis, allergic
Within 1-2 days of receiving drug vomiting, worsens side effects due to reactions, rash
radiation, local ulceration if
extravasated, pink or red color to urine
Prompt: Myelosuppression (L), Stomatitis (L), hepatotoxicity Rash
Within 2-3 weeks, prior to next course alopecia (L) (L), mucositis (L)
Delayed: Myelosuppression (mainly leukopenia Cardiomyopathy (cumulative
Anytime later during therapy, excluding and thrombocytopenia), and dose dependent) 2 (L)
the above conditions immunosuppression, alopecia
Late: Secondary malignancy
Anytime after completion of treatment
1
Rarely clinically significant.
2
Risk increases with chest radiation
Formulation and Stability: Available in a 20mg vial of reddish, lyophilized powder. Stored at room
temperature, away from light, it is stable up to two years. Reconstitute with 4ml normal saline or sterile
water. Solution is stable for 48 hours when refrigerated (2°-8°C). Keep away from light.
Guidelines for Administration and Follow-up: IV infusion over 5 minutes or more into a recent,
patent IV site. Special Precautions: Avoid extravasation. Flush vein before and after treatment.
[Shortening fractions (or ejection fractions) at which anthracycline is to be discontinued needs to be

specified for each anthracycline-containing protocol as determined by the appropriate tumor committee
and study coordinator.]

12.5 DEXAMETHASONE (Decadron)
NSC #034521.
Source and Pharmacology: Dexamethasone is a synthetic fluorinated glucocorticoid devoid of

mineralocorticoid effects. At the cellular level, glucocorticoids appear to act by controlling the rate of
protein synthesis. The half-life of dexamethasone is approximately 3 hours, however the metabolic
effects at the tissue level persist for up to 30-50 hours. It is primarily metabolized in the liver and
excreted by the kidneys. It is 6 to 10 times more potent than prednisone mg per mg.
Toxicity:
Happens to 21-100 children out Happens to 5-20 children Happens to <5 children out of
of every 100 out of every 100 every 100
Immediate: Poor wound healing, Pancreatitis (L), electrolyte
Within 1-2 days of receiving stomach upset imbalance (L), GI bleeding (L),
drug increased intraocular pressure
(L), hypertension
Prompt: Hyperphagia, hyperglycemia
Within 2-3 weeks, prior to the immunosuppression, personality
next course changes, Cushing’s syndrome
(L), pituitary-adrenal axis
suppression, acne (L)
Delayed: gastritis, muscle weakness Aseptic necrosis of the femoral
Any time later during therapy, head (L), growth retardation
excluding the above (L), striae (L), osteopenia (L),
conditions Peptic ulcer
Late: Cataracts
Any time after completion of
treatment
Formulation and Stability: Available in 0.25, 0.5, 0.75, 1.5, 4 , and 6 mg tablets. It also comes as a
0.5mg/5ml elixir, and as 4mg/ml, 10mg/ml, and 20mg/ml solution for injection. Follow manufacturer's
instructions for mixing.
Guidelines for Administration: PO Note: best given with meals. IV May be administered diluted in
IV fluids over 10-20 minutes.

12.6 6-MERCAPTOPURINE (6-MP, Purinethol)
NSC #000755
Source and Pharmacology: An analogue of the nucleic acid constituent adenine and the physiological
purine base hypoxanthine. It must be metabolized to 6MPdR before it can be active. It is S phase specific
and interferes with purine synthesis. It has a short plasma half-life of 21 minutes in children and 47
minutes in adults, with rapid renal excretion: 20% is bound to protein. There is a 25% diffusion into the
CSF. It is metabolized by xanthine oxidase in the liver to 6-TU. Oral absorption is erratic.
Toxicity:
Immediate: Anorexia, nausea, Hematuria1, anaphylactic reaction,
Within 1-2 days of receiving vomiting, diarrhea crystalluria1, urticaria
drug
Prompt: Myelosuppression Mucositis
Within 2-3 weeks, prior to the
next course
Delayed: Hepatic fibrosis, hyperbilirubinemia
Late:
Any time after the completion
of treatment
1
Only with high doses
Formulation and Stability: ORAL: Available as a 50mg tablet that may be stored at room temperature,
protected from light. INJECTION: Available in 500mg vials of lyophilized powder, also to be stored at
room temperature. Reconstitute the 500mg vial by diluting with 49.8ml of sterile water for injection, USP.
The solution contains 10mg/ml 6-MP which is chemically stable for 21 days after dilution at refrigerated
or room temperatures. It should be further diluted with D5W or normal saline to a concentration of 1-2
mg/ml and is chemically stable for 3 days. Because of a lack of antibacterial preservative, reconstituted
vials should be discarded within 8 hours of initial entry. Some lots of 6-MP have been reported to turn
dextrose containing solutions a tan to brown color. This is thought to be due to the high pH of the 6-MP,
and does not result in reduced 6-MP concentration.
Guidelines for Administration: PO 1/2 hour before or 2 hours after meals. IV administration should be
by slow IV push over several minutes or by continuous infusion. Oral 6-MP to be given at bedtime on an
empty stomach, on standard leukemia protocols. If allopurinol is also given, the oral dose of 6-MP should
be reduced by 75%. No change in dosage is indicated if 6-MP is given concurrently by IV. Caution:
Avoid extravasation.
Supplier: 50mg tablets are commercially available. See package insert for further information. IV
preparation is available from the NCI. See Clinical Brochure prepared by Burroughs Welcome for
additional information.
12.7 METHOTREXATE (MTX, amethopterin)
NSC #000740/IND #4291
Source and Pharmacology: A folate analogue which inhibits the enzyme dihydrofolate reductase,
halting DNA, RNA, and protein synthesis. Initial IV half-life is about 1.2 hours, with a second phase of
10.4 hours. About 50% is bound to protein. Transport into the cell is carrier-mediated. Once in the
cell, MTX (Glu)n are formed, the number of which are related to the cytocidal effect. Once MTX
(Glu)n are formed, they do not pass back out of the cell unless converted back to MTX. After oral
administration, about 60% of a 30 mg/m2 dose is rapidly absorbed from the GI tract, with peak blood
levels at 1 hour. Above this dose, absorption decreases significantly. Absorption can be very erratic,
varying between 23% to 95%. A 20-fold difference between peak levels of drug has been reported (0.1
to 2mM). There is significant enterohepatic circulation of MTX: 9% of MTX is excreted in feces.
MTX is excreted unchanged in the urine, except at high doses when it is partially metabolized to
hydroxy-MTX and excreted.
Toxicity:
Immediate: Nausea, vomiting, anorexia, Dizziness, malaise, blurred vision,
Within 1-2 days of receiving allergic reaction, peeling, redness and
drug tenderness of the skin, especially the
soles and palms.
Prompt: Transaminase elevations Diarrhea, Alopecia, folliculitis, renal toxicity,
Within 2-3 weeks, prior to the myelosuppression, leukoencephalopathy1 (L), seizures1,
next course stomatitis, photosensitivity acute neurotoxicity
Delayed: Learning disability1 (L) Lung damage (L), hyperpigmentation,
Any time later during therapy, liver damage (L), osteoporosis (L),
excluding the above conditions osteonecrosis and soft tissue necrosis2.
Late: Progressive CNS deterioration
Any time after the completion
of therapy
Unknown Frequency and Timing: **Fetal and teratogenic toxicities and toxicities in breast-fed children
1
May be enhanced by HDMTX and/or cranial irradiation.
2
Concurrent use of methotrexate in head and neck cancer patients increased the incidence of osteonecrosis to 22% for
patients receiving 5000-5500 Gy of radiation therapy over 3 weeks. The median time of onset was 21 months after
radiation therapy (Radiotherapy and Oncology 1996;41:21-29). This adverse effect has not been reported with the lower
radiation doses used in leukemia patients.
**Methotrexate crosses the placenta to the fetus. Fetal toxicities and teratogenic effects of methotrexate (either alone or in
combination with other antineoplastic agents) have been noted in humans. The toxicities include: congenital defects,
chromosome abnormalities, malformation, severe newborn myelosuppression, pancytopenia, and low birth weight.
**Methotrexate is excreted into breast milk in low concentrations. However, because the drug may accumulate in neonatal
tissues, breast feeding is not recommended. Methotrexate is considered to be contraindicated during breast feeding because
of several potential problems, including immune suppression, neutropenia, adverse effects on growth, and carcinogenesis.
Intrathecal Therapy (Methotrexate Single Agent)
Toxicity: The following toxicities may occur when methotrexate alone is given intrathecally.
Happens to 21-100 Happens to 5-20 children Happens to <5 children out of
children out of every 100 out of every 100 every 100
Immediate: Headache, pleocytosis Vomiting, fever, rash,
Within 1-2 days of receiving somnolence, meningismus,
drug convulsions (L), paresis
Prompt: Somnolence, ataxia
Within 2-3 weeks, prior to the
next course
Delayed: Learning disability Leukoencephalopathy (L)
excluding the above condition
Late: Progressive CNS deterioration
treatment
High-dose administration may be associated with severe, acute toxicity, which is potentially lethal.
The conversion of MTX to hydroxy-MTX is enhanced with high-dose therapy. Renal failure will
markedly enhance the toxic effects and the serum creatinine should be <1.2 mg/dl (creatinine clearance
>50 ml/min/1.73m2) before starting therapy. The possibility of renal impairment is enhanced with
hydroxy-MTX because it is even less soluble than Methotrexate. The solubility of MTX and hydroxy-
MTX is as follows:
Urine pH MTX (in mg/L) HOMTX (in mg/L)

7 9 1.6
6 1.6 0.4
5 0.4 0.1
If a patient develops renal failure, very high doses of leucovorin are indicated. Leucovorin will not
reverse renal toxicity but will reverse the toxicity to bone marrow and mucosal cells. Leucovorin should
be continued until the level is <0.1mM. See section on leucovorin for LCV rescue guidelines.
Hemodialysis is not very effective for resolving renal damage; oral charcoal, bile drainage, induced
emesis, etc., have also been tried, but are not very effective. To prevent this complication, adequate
fluid intake (IV or PO >3000ml/m2) is indicated, with alkalinization (pH > 7) of urine using NaHC03.
Diamox may be used to supplement NaHC03 alkalinization of the urine. Check with specific protocol
for dose expected peak and clearance rates. Since MTX readily enters body fluids, patients with
effusion(s) can have sustained high levels and must be monitored carefully. Concomitant use of non-
steroidal anti-inflammatory agents, ASA and possibly other weak organic acids are associated with
increased toxicity (blocking binding of MTX to proteins) or prolonged elevated levels of MTX (by
decreased renal clearance). Other toxicities include those described on previous page under "Toxicity:"
for systemic administration. Two cases of anaphylaxis with MTX have been reported.
Formulation and Stability: Both the 2.5mg tablets and intact vials may be stored at room temperature
(22°-25°C) and are stable for at least 2 years or until date of expiration. INJECTABLE: Available in a
variety of forms, all prepared as the sodium salt (yellow powder), with or without preservatives. IT
MTX: Available in various dosages in preservative-free liquid, 25mg/ml in a 2ml vial, or as a
lyophilized powder. Reconstitute the powder with buffered saline solution. The Methotrexate solutions
may be further diluted with buffered saline or the patient's own CSF. After mixing it should be used
within 24 hours, since MTX contains no antibacterial preservative. HIGH-DOSE MTX: Available as a
1gm (30ml) vial which contains preservative-free lyophilized sodium MTX powder, for intravenous use
in high-dose therapy. When reconstituted with 19.4ml of 0.9% NaCl solution, or 5% D/W, or sterile
water, each ml will contain 50mg of Methotrexate. Note: MTX for high-dose administration is
chemically stable for 7 days at room temperature but should be used within 24 hours of dilution since it
contains no preservatives.
If a liquid formulation for oral methotrexate dose is needed, Jundt et al (J Rheumatology 1993;20:1845)
have documented bioavailability equivalent to tablets for a methotrexate formulation that also has
documented chemical stability for one month at refrigerated or room temperature. Refrigerated
temperatures would have less susceptibility to significant bacterial contamination. The formulation uses
a stock diluent prepared by measuring 250 mL of Diluent (0.05% saccharin in a cherry flavored
glycol/aqueous base--Roxane flavored Diluent*), 20 g of sodium bicarbonate, qs to 1000 mL with
distilled water. Methotrexate syrup 40 mg/20 mL can be made by using 1.6 mL MTX from a 50 mg/2
mL preservative-free vial, then qs to a total of 20 mL with the stock diluent solution.
Guidelines for Administration: No standardized method of delivery can be given for Methotrexate,
since so much of the dose and schedule is tied to pharmacology. Currently it is being used as continuous
24-hour infusion, a 4- to 6-hour infusion, as a round-the-clock PO dosage weekly, or weekly or every 2
weeks IM. Special Precautions: For high-dose therapy, support with leucovorin rescue. Observe
precautions with renal impairment. Note: All oral drugs should be given 30 minutes before meals or 2
hours after meals unless otherwise stated in the instructions.
Supplier: All forms of methotrexate are commercially available. See package insert for further
information.
12.8 MESNA (sodium 2-mercaptoethane sulfonate, MESNA)
NSC #113891
Source and Pharmacology: MESNA is a thiol compound with the capacity of inhibiting the urotoxicity
of the oxazaphosphorines, ifosfamide and cyclophosphamide. Within 1 hour of administration, MESNA is
completely oxidized to DiMESNA, a totally inert compound. After an 800mg dose the t½ for MESNA and
DiMESNA is 0.36 hours and 1.17 hours, respectively. There is little or no tissue penetration. Following
glomerular filtration DiMESNA is rapidly reduced in the renal tubules back to MESNA which inactivates
acrolein and the oxazaphosphamides, thus preventing bladder toxicity. After 3 hours, negligible amounts
of MESNA were present in the urine of rats given 100mg/kg by IV push.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out Happens to <5 children out
out of every 100 of every 100 of every 100
Immediate: Bad taste with oral use Nausea, vomiting, stomach Headache, pain in arms, legs,
Within 1-2 days of receiving drug pain and joints; fatigue, rash,
transient hypotension, allergy
Prompt: Diarrhea
Within 2-3 weeks, prior to the next course
Delayed:
Late:
Any time after completion of treatment
Young children receiving high doses of benzyl alcohol (> 99 mg/kg/day) may develop the gasping
syndrome manifested by gasping, metabolic acidosis and multiple organ system failure. Benzyl alcohol
is the preservative in multidose vials of MESNA.
Formulation and Stability: Available in 1000 mg/10mL multidose vials which contain 10.4 mg/mL of
benzyl alcohol* as a preservative, or in 200 mg/2 mL ampules without preservatives for neonates and
infants or patients with hypersensitivity to benzyl alcohol. In Canada, only the non-preserved ampules are
available. Store either product at controlled room temperature (15-30°C). MESNA is not light-sensitive,
but is oxidized to DiMESNA when exposed to oxygen. Non-preserved ampules should be used
immediately after opening, while benzyl alcohol-preserved vials may be stored and used for 8 days. After
further dilution for administration, either product is chemically stable for at least 24 hours. Lack of an
antimicrobial preservative suggests that the non-preserved product should be used within 6-8 hours after
diluted for administration. For IV administration, dilute to 20 mg/mL with any of the following fluids: 5%
dextrose, 5% dextrose in 0.45% sodium chloride, 0.9% sodium chloride or Lactated Ringer’s. MESNA
may be mixed with ifosfamide or cyclophosphamide.
*
The package insert for MESNA states that multidose vials contain benzyl alcohol 10.4 mg/mL (1%) as a
preservative, should not be used in neonates or infants, and should be used with caution in older pediatric
patients. A 200 mg/2 mL ampule remains available free of charge for pediatric patients less than 2 years
old and for patients with hypersensitivity to benzyl alcohol. It may be obtained in the U.S. by calling
Bristol-Myers Squibb Oncology at 1-800-437-0994.
The medical literature includes reports of gasping syndrome in premature infants receiving saline flushes
with benzyl alcohol at benzyl alcohol doses greater than 99 mg/kg/day. (Gershanik J, et al. N Engl J Med
1982;307:1384) There is also a report of metabolic acidosis occurring in a 5 year old girl receiving
continuous infusion diazepam which contained 180 mg/kg/day of benzyl alcohol. (Lopez-Herce, et al.
Ann Pharmacother 1995;29:632) The syndrome includes gasping respiration, severe metabolic acidosis,
and multiple organ system failure. It results from inability to adequately conjugate benzoic acid with
glycine, a metabolic pathway poorly developed under 8 weeks of age.
Even if the amount of benzyl alcohol in MESNA is not enough to cause problems in a patient, a number
of other drug products contain benzyl alcohol and therefore could add to the dose a patient is receiving.
Your pharmacist can check product contents and calculate the dose of benzyl alcohol any patient is
receiving.
Guidelines for Administration: IV. Can be given orally but has a foul taste. Total dose is usually 60%
of the oxazaphosphorine dose given in divided doses. Higher doses or continuous infusions are used with
high dose ifosfamide or cyclophosphamide, or in patients with a history of hemorrhagic cystitis.

12.9 VINCRISTINE SULFATE (VCR, Oncovin )
NSC #067574
Source and Pharmacology: Vincristine is an alkaloid isolated from Vinca rosea (periwinkle). It binds to
tubulin, disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic, with
initial, middle and terminal half-lives of 5 minutes, 1.3 hours, and greater than 24 hours , respectively. It is
excreted in the bile and feces. There is poor CSF penetration.
Toxicity:
Happens to 21-100 children Happens to 5-20 children Happens to <5 children out of every 100
out of every 100 out of every 100
Immediate: Local ulceration if Jaw pain
Within 1-2 days of receiving drug extravasated
Prompt: Hair loss Weakness, constipation Paralytic ileus, ptosis, vocal cord paralysis,
Within 2-3 weeks, prior to the next myelosuppression, CNS depression,
course inappropriate ADH, seizure
Delayed: Loss of deep tendon reflexes Numbness, tingling and
Any time later during therapy, clumsiness
Late:
treatment
Unknown Frequency and Timing: **Fetal and teratogenic toxicities
**Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other antineoplastic agents) have been
noted in humans. The toxicities include: chromosome abnormalities, malformation, pancytopenia, and low birth weight.
Formulation and Stability: Available in solutions of 1mg/1ml in 1, 2, or 5ml vials. Refrigerate and
protect from light. Once opened, it should be refrigerated and used within 10 days. Note: The drug is
light-sensitive.
Guidelines for Administration: IV push over <1 minute. Special Precautions: Avoid extravasation.
Decrease dose for infants (e.g., less than 10 kg, divide m2 dose by 30, multiply by weight in kg.
Alternatively, give 50% of calculated dose). Precaution: Concomitant radiation therapy to the liver may
enhance toxicity. Precaution: When dispensing vincristine in other than the original container, it is
imperative that it be packaged in the provided overwrap which bears the following statement: “Do not
remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”
12.10 IMATINIB MESYLATE (STI-571, Gleevec® ), (formerly CGP 57148)

NSC # 716051/IND #61135
Source and Pharmacology

STI571 is supplied by Navartis Pharmaceuticals and distrtibuted by the National Cancer Institute.
Imatinib mesylate is an inhibitor of the protein kinase inhibitor specific to Abl tyrosine kinase and the
receptor kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF) c-kit. It inhibits
Bcr-Abl dependent cellular proliferation, PDGF receptor and SCF receptor mediated biochemical
events. The drug is well-absorbed with a Cmax achieved within 2-4 hours after dosing. Mead absolute
bioavailability is 98%. CYP3A4 is the major enzyme responsible for metabolism. CYP1A2, CYP2D6,
CYP2C9, and CYP2C19 play minor roles in metabolism. Elimination is predominately in the feces.
Toxicity:
Known Toxicity, Dose-Limiting Toxicity (based on adult experience):
Happens to 21-100 children out of Happens to 5-20 children out of every Happens to <5 children out of
every 100 100 every 100
Immediate: Dyspepsia/heartburn, Fever, edema in limbs, face, Cerebral edema
Within 1-2 days of nausea/vomiting, headache periorbital area(L), weight gain,
receiving drug increased SGOT, SGPT, alkaline
phosphatase, bilirubin (L),
abdominal pain and cramping,
myalgia (L), arthralgia (L)
Prompt: Myelosuppression (L), fatigue Decreased bone marrow cellularity Melena/GI bleeding, anemia
Within 2-3 weeks, (L), lymphopenia (L), eczema (L), diarrhea, dysphagia,
prior to the next dermatitis, rash, muscle pain and esophagitis, odynophagia,
course cramping, anorexia hemorrhage/bleeding without
grade 3 or 4
thrombocytopenia
Delayed: Pigmentation changes (hypo-, Hepatotoxicity*(L)
Any time later during vitiligo)
therapy, excluding
Late:
Any time after the
completion of
treatment
*One patient with no known history of liver problems died on study due to liver failure. This patient was also taking acetaminophen (Tylenol®), also
known as paracetamol in European countries. Although no other patient taking acetaminophen has experienced liver-related side effects, it is
recommended as a precaution to adhere carefully to the instructions and warnings on the acetaminophen package label. Additionally, it is recommended
that any over-the-counter medications taken by the patient are carefully reviewed, as these may possibly contain combinations of drugs, including
acetaminophen or paracetamol.
OTHER REPORTED ADR’S – relationship to medication and timing/frequency is unknown at this time:
One patient has experienced pneumonitis/pulmonary infiltrates.
One patient developed progressive dyspnea after receiving 7 months of medication
The dose-limiting toxicity has not yet been determined in adults, but based on available clinical data
may prove to be myelosuppression.
Formulation and Stablility:

Description: STI571 is white to off-white to brownish or yellowish tinged powder.
How Supplied: STI571 is available in hard gelatin capsules which contain a common dry powder blend
filled in capsule shells of size 1 (100 mg dosage strength).
Storage: The capsules should be stored at room temperature not to exceed 25°C (77°).
Stability: Shelf life testing of the intact bottles is on-going. Current data support a shelf life of 3 years.
Route of Administration: Oral.
Guidelines for Administration: STI571 should be administered once daily with a meal to minimize G1
irritation. STI571 is a local irritant and must be taken in a sitting position with a large glass (or bottle,
for younger children) of water (250 ml/8 oz; at least 4 oz for children ≤ 3 years of age.) If the patient
cannot swallow the capsule whole, the following guidelines should be used. Pour the contents of a
capsule by small portions into 20 ml of milk. After addition of each portion, gently stir the mixture to
allow STI571 to dissolve. Note: The excipients used in the capsule will not dissolve. However, they are
white whilst the active substance is yellow. Thus if a white solid residue remains in the glass, it does not
matter as long as the capsule contents has been slowly added and well dispersed to allow the active
substance to dissolve during stirring. If a yellow residue is observed, it means that the active substance
was not completely dissolved and only a fraction of the dose has been swallowed.
If the patient vomits after taking the drug, the dose is replaced only if the pills can actually be seen and
counted. The number of pills counted is fully replaced. For younger children who take the drug
dissolved in milk, replace the dose only if the vomiting has occurred directly after swallowing, if the
amount appears substantial, and if all of the yellow material appears to be present.
Supplier /Drug Ordering:

NCI supplied agents may be requested by the Principal Investigator (or their authorized designee) at each
participating institution. Pharmaceutical Management Branch (PMB) policy requires that drug be shipped
directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents
between institutions (unless prior approval from PMB is obtained.) The CTEP assigned protocol number
must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each
participating institution must be registered with CTEP, DCTD, through an annual submission of FDA form
1572 and a CV. If there are several participating investigators at one institution, CTEP supplied
investigational agents for the study should be ordered under the name of one lead investigator at that
institution.
Drug may be requested by completing a Clinical Drug Request (NIH- 986) and mailing it to the
Pharmaceutical Management Branch, DCTD, NCI, EPN Room 7149, Bethesda, MD 20892 or faxing it
to (301) 480-4612. For questions call (301) 496-5725.
Drug Inventory Records - The investigator, or a responsible party designated by the investigator, must
maintain an accurate record of each shipment received, and all dispensing of study drug in a drug
accountability ledger. An accurate record of the date and amount of the study drug dispensed to each
patient must be available for inspection at all times. Copies of the drug accountability ledger will be
provided to Novartis at the end of the study. All drug supplies are to be used only for this protocol and
not for any other purpose. The investigator must not destroy any drug labels, or any partly-used, or
unused drug supply. At the conclusion of the study, and, as appropriate during the course of the study,
the investigator will return all used and unused drug containers, drug labels and a copy of the completed
drug disposition form to the Novartis monitor or to Novartis at the address given to the investigator.
12.11 ETOPOSIDE (VP-16, VePesid )

NSC #141540
Source and Pharmacology: A semisynthetic derivative of podophyllotoxin that forms a complex with
topoisomerase II and DNA which results in a single and double strand DNA breaks. Its main effect
appears to be in the S and G2 phase of the cell cycle. The initial t-½ is 1.5 hours and the mean terminal
half-life is 4 to 11 hours. It is primarily excreted in the urine. There is poor diffusion into the CSF. 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. Etoposide is well absorbed after oral administration, but a high degree of interpatient
variability has been reported (25 – 75% bioavailability).
Toxicity:
Happens to 21-100 children Happens to 5-20 children out of Happens to <5 children out of
out of every 100 every 100 every 100
Immediate: Nausea, vomiting Hypotension, anaphylaxis,
Within 1-2 days of skin rash
receiving drug
Prompt: Myelosuppression Alopecia (L) , enhanced damage Peripheral neuropathy,
Within 2-3 weeks, prior to due to radiation, diarrhea stomatitis
next course
Delayed:
Any time later during
therapy, excluding the
above conditions
Late: Secondary malignancy
Any time after completion
of treatment
Formulation and Stability: A yellow solution with a pH of 3 to 4, available in 100mg (5ml) or 500 mg
(25 ml) multiple-dose sterile vials containing 20mg/per ml etoposide. Unopened vials of VP-16 are stable
for 24 months at room temperature (25°C). Dilute with 0.9% sodium chloride injection or D5W. At room
temperature, the solution is thought to be stable for 48 hours at a concentration of 0.4mg/ml and for 96
hours at a concentration of 0.2mg/ml in both glass and plastic containers. At concentrations above
0.4mg/ml, the stability of the solution is highly unpredictable; therefore dilution to a concentration
>0.4mg/ml is not recommended. DO NOT REFRIGERATE SOLUTION: keep agitation to a minimum.
Also available in 50mg pink capsules. Store capsules under refrigeration, but do not freeze. For oral
administration in children too young to take the capsules, the parenteral product can be used orally. A 1:1
dilution (10 mg/mL) is stable for 3 weeks in Burron plastic oral syringes, and can be administered directly
to be followed by sour candy or gum, or can be further diluted immediately prior to administration with
fruit juice. Concentrations need to be 0.4 mg/mL or less to substantially enhance taste. At higher
concentrations in fruit juice, precipitation may occur in less than 3 hours.
Etopophos (etoposide phosphate) is a more-expensive but more water soluble prodrug of etoposide. It
is rapidly and completely dephosphorylated to etoposide in the plasma and has similar
pharmacokinetics. It is available commercially from Bristol-Meyers Squibb as single dose vials
equivalent to 100 mg of etoposide. Each vial should be reconstituted with 5 or 10 ml of diluent to made
a concentration equivalent to 20 or 10 mg/ml of etoposide. Sterile water for injection, 5% dextrose
injection, or 0.9% sodium chloride injection with or without benzyl alcohol as a bacteriostatic agent can
be used as diluents. Further dilution (if desired) for administration may be made with 5% dextrose
injection or 0.9% sodium chloride injection to concentrations as low as 0.1 mg/mL. These dilutions are
stable for 24 hours at room or refrigerated temperatures. When etoposide phosphate injection is used for
oral administration, bioavailability is about 70%, roughly 20% higher than when etoposide injection is
used
Guidelines for Administration: IV over 1 hour. Caution: severe hypotension may occur if the drug is
given in less than 30 minutes. SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS PUSH. Watch
for anaphylaxis.
Etopophos: For etoposide phosphate, infusion rates of 5-10 minutes have been recommended by the
manufacturer. Hypotensive and allergic reactions are less frequent than with plain etoposide, but can
still occur. It is not clear if these reactions are rate-related with etoposide phosphate. Drug
administration should be discontinued and appropriate treatment instituted should a reaction occur.

12.12 IFOSFAMIDE (IFX, IFOS)
NSC #109724
Source and Pharmacology: Ifosfamide (IFOS) is a structural analogue of cyclophosphamide. Ifosfamide

requires hepatic microsomal activation for the production of the reactive 4-hydroxyoxazaphorine
intermediate which serves as a carrier molecule for the ultimate intracellular liberation of phosphoramide
mustard, an alkylating agent. The occurrence of another reactive metabolite, acrolein, is thought to be the
cause of the hemorrhagic cystitis, identical to that seen with cyclophosphamide. The metabolism of
ifosfamide is dose-dependent, with the terminal half-life varying between 7 and 16 hours at doses of 1.6-
2.4g/m² and 3.8-5 g/m², respectively. At 1.6-2.4g/m²/d, 12 to 18% of the dose was excreted in the urine,
whereas at 5g/m² single-dose, 61% was excreted in the urine. Evidence also exists to suggest that
metabolism is inducible, with more rapid clearance occurring in the second and later doses of fractionated
courses of 3-5 times daily. Unlike cyclophosphamide, as much as 50% of a large dose of ifosfamide may
be subject to alternative metabolic degradation, with the production of reactive but non-cytotoxic species.
Some of these products (chloracetaldehyde) are suggested as being the cause of ifosfamide neurotoxicity.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out of Happens to <5 children out of
out of every 100 every 100 every 100
Immediate: Nausea (L), vomiting (L), Somnolence, confusion, weakness, Encephalopathy (L),
Within 1-2 days of receiving drug anorexia (L) seizure, inappropriate ADH 1
Prompt: Myelosuppression, Hemorrhagic cystitis, cardiac
Within 2-3 weeks, prior to next course arrhythmia, EKG changes toxicities with arrythmias2,
2
myocardial necrosis
Delayed: Alopecia Fanconi’s renal syndrome Peripheral neuropathy, acute
Any time later during therapy, renal failure, pulmonary
excluding the above conditions fibrosis (L)
Late: Secondary malignancy,
Any time after completion of treatment bladder fibrosis
(12) Less common with lower doses
(12) Extremely rare at doses of < 10 g/m2/course
Formulation and Stability: Available in 1 g and 3 g vials of lyophilized white powder without
preservatives. Intact vials should be stored at room temperature and bear a stamped 5-year expiration date
from the manufacturer. Reconstitute with sterile water, 20ml/g, to produce a final solution of 50mg/ml
ifosfamide. Although the reconstituted product is stable for several days at room temperature, the absence
of preservatives mandates that all drug be used or discarded within 8 hours.
Guidelines for Administration: At <1.5g/m2 of IFOS, the following guidelines are suggested: Give IV
over 30 minutes/g/m2. Prehydrate with oral fluids beginning 6 hours prior to IFOS, 1000ml/m2. MESNA,
20% of IFOS dose, IV push should be given 15 minutes prior to IFOS, then repeated at 3 hrs and 6 hrs
after IFOS administration. Maintain continuous hydration of 1000ml/m2 D5W ¼ NS over 0 to 6 hrs.
Patients must receive either oral or IV hydration, at least 1500ml/m2 ending at hour 24. Patients should be
asked to void at least every 2 hours during the 12-hour period immediately following a dose of ifosfamide.
If more than 1.5g of IFOS is given, the time interval of administration of IFOS should be increased and the
dose of MESNA should be increased.
Supplier: The 1 g and 3g vials are commercially available. See package inserts for further information.
12.13 GRANULOCYTE COLONY-STIMULATING FACTOR,
(r-metHuG-CSF, G-CSF, Filgrastim, Neupogen®) NSC #614629
Source and Pharmacology: r-metHuG-CSF (produced in E. coli by recombinant DNA technology)
stimulates the production of neutrophils in the bone marrow and selected end-cell activation. The 175
amino acid protein (M.W. of 18,800 daltons) differs from the natural protein in that the N-terminal amino
acid is a methionine and it is not o-glycosylated. 3.45 ug to 11.5 ug of G-CSF administered
subcutaneously resulted in a maximum serum concentration of 4 ng/ml to 49 ng/ml within 2 to 8 hours.
The elimination half-life is similar for SQ and IV, approximately 3.5 hours.
Toxicity:
. Common Occasional Rare
Happens to 21-100 Happens to 5-20 children out of Happens to <5 children out of
children out of every 100 every 100 every 100
Immediate: Local irritation at the injection site Allergic reaction, low grade fever
Within 1-2 days of receiving drug
Prompt: Medullary bone pain, increased Subclinical splenomegaly,
Within 2-3 weeks, prior to the alkaline phosphatase, increased exacerbation of pre-existing skin
next course lactate dehydrogenase, increased rashes, alopecia
uric acid, thrombocytopenia
Delayed: Cutaneous vasculitis
Anytime later during therapy,
Late:
Anytime after completion of
treatment
Formulation and Stability: Supplied as a clear solution in 300 ug/ml (1 ± 0.6 x 108 U/mg) (1 ml or 1.6
ml) vials. Vials are preservative free and are intended to be single-use vials; do not reuse opened vials.
G-CSF must be stored between 2° and 8°C. Stability has been demonstrated for at least 24 months when
stored under these conditions. Boxes of Neupogen® contain an indicator which turns red when exposed to
freezing temperatures; medication should not be used in the event the indicator changes. Do not use if
discolored or if there is particulate matter. For IV use, dilute in D5W to concentrations > 15 ug/ml; G-
CSF is incompatible with normal saline. At dilutions from 5 ug/ml to 14 ug/ml, add human serum
albumin to a final albumin concentration of 2 mg/ml to protect against absorption of the G-CSF to
container walls (glass or plastic). G-CSF, when diluted as described above, is compatible with a number of
plastics commonly used in the manufacture of syringes, IV bags, infusion sets, and IV pump cassettes.
These include polyvinyl chloride, polyolefin, and polypropylene. Diluted G-CSF should be stored at 2° to
8° C and used within 24 hours. Do not shake or freeze.
Guidelines for Administration: Administer once daily, subcutaneously without dilution or if necessary
dilute with 5% dextrose in water, preferably to concentrations of 15 ug/ml or greater for IV administration.
Dilutions should be prepared as close to the time of administration as possible (up to 24 hours), since the
product is preservative-free. When diluting G-CSF to 5-14 ug/ml in D5W, it is necessary at all times to
add human serum albumin, to reach a final albumin concentration of 2 mg/ml. The suggested starting dose
is 5 ug/kg.
Although guidelines are not well documented in the literature, POG protocols typically recommend
stopping G-CSF if the following occurs:
ANC >5,000-10,000 after the nadir is reached (usually 10-14 days) or
ANC >1,500 on 2 consecutive days after nadir is reached
Generally, the ANC decreases by 50% in 24-48 hours
G-CSF should be stopped 48 hours before restarting chemotherapy.
12.14 LEUCOVORIN CALCIUM (LCV, Wellcovorin, citrovorum factor, folinic acid)
NSC #003590
Source and Pharmacology: Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition
of dihydrofolate reductase by Methotrexate (MTX). It competes with MTX for transport into the cells and
"rescues" cells from the adverse effects of MTX. It is stored in the cells as LCV polyglutamate. After a
20mg dose of leucovorin, the mean serum total reduced folate concentration was around 370mg/L,
regardless of whether given PO or parenterally. The peak levels were reached at 2 hours for the oral forms
and 1 hour for the parenteral form. The t½ of plasma 5-formyl-H4-folate was 1.5 hours and 3 hours for 5-
methyl-H4-folate. The apparent bioavailability of oral leucovorin for 25mg is 97%, for 50mg - 75%, and
for 100mg - 37%. For further discussion of pharmacokinetics and metabolism see drug insert. Both oral
and parenteral leucovorin raise the CSF folate levels.
Toxicity:
Happens to 21-100 children Happens to 5-20 children Happens to <5 children out of
out of every 100 out of every 100 every 100
Immediate: Allergic sensitization, rash
Within 1-2 days of receiving drug
Prompt:
Within 2-3 weeks, prior to the next course
Delayed:
Late:
Formulation and Stability: Available in ampules containing leucovorin in solution, 3mg/ml; in vials of
cryodessicated powder, 50mg, 100mg, and 350mg; and in tablet form, 5mg, 10mg, 15mg, and 25mg.
Reconstitute the cryodessicated powder with Bacteriostatic Water or sterile water to make a solution of
10mg/ml leucovorin calcium. When Bacteriostatic Water is used, the reconstituted solution is good for 7
days. If reconstituted with sterile water, use solution immediately. Intact vials are stable for at least 2
years at room temperature, but the reconstituted solution should be used as soon as possible as
precipitation occurs on prolonged standing.
Guidelines for Administration: If given PO, it should be administered 30 minutes before or 2 hours after
meals (may be mixed in juices). IV administration may be given as IV push. LCV should not be given
<24 hours after IT-MTX unless there are special circumstances.
Standard "rescue" criteria for mega doses of MTX (>100 mg/m2)
Time MTX Level Leucovorin

(hrs) (µM)* Rescue Comment
24» <1 Dose per protocol Stop monitoring
24» >1 Dose per protocol Continue to monitor
48 <0.2 5 mg/m2/6 hr x 5 PO Stop monitoring
48 >0.2 - 2 No change in leucovorin Continue to monitor
2
48 >2 - <20 10 mg/m /3 hr PO or IV Continue to monitor Check BUN & creatinine
48 >20 100 mg/m2/3 hr IV Continue to monitor Check BUN & creatinine
72 ** Continue dose used at hr 48 until MTX < 0.2 µM
* 1 µM = 10-6 molar concentration
** Continue to monitor every 24 hr; use 48-hr MTX levels as guidelines for further leucovorin
therapy. Contact Dr. Weitman (210) 567-5265, Dr. Kamen (214) 648-3896, or Dr. Winick (214)
640-6124 if >0.2 µM at 96 hours.
»
These levels are usually obtained after 12 to 15 gm/m2 HD MTX given as a 6-hour infusion the
day before.
« Time after start of infusion
Note that concomitant use of non-steroidal anti-inflammatory agents (e.g., ASA) and possibly other weak
organic acids are associated with increased toxicity (blocking binding of MTX to proteins) or prolonged
elevated levels of MTX (decreased renal clearance).

12.15 CYCLOSPORIN.
Source and Pharmacology: Cyclosporin (CSA) is a potent immunosuppressive agent which prolongs
survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine,
and lung. Current evidence suggests that cyclosporine selectively inhibits IL-2 stimulated proliferation of
activated T-lymphocytes. CSA has been shown in vitro to be a potent inhibitor of P-glycoprotein which
has been postulated to be a factor in multidrug resistance to various antineoplastic agents. The terminal
half-life of CSA is approximately 19 hours (range 10-27 hours). Ninety-nine percent of CSA is
metabolized. Elimination is primarily biliary with approximately 6% excreted in the urine. The volume of
distribution varies from 3.5 L/kg to 13 L/kg with higher concentrations of drug found in the liver,
pancreas, and fat. CSA clearance rates have been shown to be higher in pediatric patients and in patients
<25 years-old. Drugs which stimulate or inhibit hepatic p-450 enzymes may alter clearance of CSA.
Cyclosporin
Immediate Sudden redness of the face, high Headache (L), rapid heart rate Allergic reaction (possibly life-
blood pressure (L), reduced threatening), sneezing, seizure (L),
function of the immune system burning sensation on the palms of
(L) the hands and soles of the feet (L)
Prompt Increased amount of body hair Damage to kidney tissue (L), trembling Seizure, burning sensation on the
(L), low level of magnesium salts in the palms of the hands and soles of the
blood (L), high level of bilirubin in the feet (L), confusion (L), drowsiness,
blood (L) diarrhea
Delayed Swollen gums
Late abnormalities associated with the
increase of cells called lymphocytes
1
Cyclosporine A may cause side-effects of other anticancer medications to be worse
Formulation and Stability: CSA is available as a (50mg/ml) 5ml ampule in a polyoxyethylated castor oil
(chromophore) base for IV use. CSA is diluted 1ml (50mg) in 20 to 100ml of D5W or NS and is stable for
24 hours (in glass). Store ampules below 86°F and protect from light and freezing. (It is not necessary to
protect admixtures from light).
Guidelines for Administration: IV infusion in glass. Non PVC tubing should be used (as commonly
available for nitroglycerin infusions). Monitor closely for the first 30 minutes and at frequent intervals
thereafter for an acute allergic reaction. D5W is the preferred IV fluid, as normal saline results in a 7-8%
loss over 24 hours.
Supplier: Commercially available from Sandoz Pharmaceuticals. See package insert for further
information.
13.0 SUPPORTIVE CARE GUIDELINES
The following guidelines are intended to give general direction for optimal care and to encourage
uniformity in the treatment of this study population. Investigators should refer to the comprehensive
supportive care handbook Supportive Care of Children with Cancer (88). Initial evaluation at diagnosis
should be comprehensive and include such diagnostic studies as weight, blood pressure, serum electrolytes,
BUN, creatinine, calcium, phosphate, uric acid, prothrombin time, partial thromboplastin time, fibrinogen
and appropriate cultures in febrile patients. Investigators are requested to report unexpected or unusually
severe complications to Study Chair.
13.1 Blood Products
13.1.1 Irradiation
All blood products should be irradiated with at least 1500 cGy to avoid development of transfusion-
related graft versus host disease.
13.1.2 Red blood cells (RBCs)

RBC transfusion is indicated to correct severe or symptomatic anemia or acute blood loss. If RBC
transfusion becomes necessary during maintenance therapy due to severe anemia with reticulocytopenia,
investigators should consider evaluation for parvovirus with PCR and/or parvovirus IgM titers.
13.1.3 Platelets
Platelet transfusions are indicated for persistent bleeding due to thrombocytopenia, or platelet count <
10,000/µL in patients who have not developed platelet resistance. For patients on STI571 platelet
counts are to be maintained ≥20,000/µL. A platelet count of over 30,000 is required for an LP. Four
random donor units/m2 (or the equivalent amount as apheresed platelets) should provide a platelet count
increment of 40,000/µL. Leukodepletion of platelets is recommended to decrease development of
transfusion reactions and transmission of CMV. Some clinicians recommend prophylactic platelet
transfusions in any patient with < 20,000/µL platelets, particularly in patients with fever and
neutropenia.
13.1.4 White Blood Cells

White blood cell transfusions may be indicated in patients with documented gram negative sepsis and
severe neutropenia not responding to appropriate antibiotics. Published information is inadequate to
decide if white cell transfusions add any benefit to appropriate doses of appropriate antibiotics in other
settings. Unless given in an experimental setting, their use is discouraged.
13.1.5 Fresh Frozen Plasma

Fresh frozen plasma may be indicated to support coagulation factors in patients with a coagulopathy or
hepatic dysfunction.
13.1.6 CMV
Because some patients will receive an HSCT as part of the protocol and this population is at high risk
for relapse, it is recommended that CMV negative patients be transfused with CMV safe blood products
(either antibody screen or leukofiltered).
13.2 Infection Prophylaxis
13.2.1 Pneumocystis Carinii

All patients should receive trimethoprim/sulfamethoxazole (TMP-SMX) at a dose of TMP 5 mg/kg/day
(or 150 mg/m2/day) divided bid on two or three sequential days per week, starting first week of
Induction continuing for 3 months post Maintenance therapy.
Patients allergic to or experiencing excessive myelosuppression with TMP-SMX, should be treated with
prophylactic oral dapsone (2 mg/kg/day - max 100 mg/24 hours), intravenous pentamidine (4 mg/kg q 2-
4 wks), or aerosolized pentamidine (8 mg/kg for q 4 wks for patients < 5 years of age; 300 mg q 4 wks
for children ≥ 5 years of age).
13.2.2 Other bacterial infections

Other than TMP/SMX, no routine prophylactic antibacterial agents are to be used.
13.2.3 Fungal Infections

Mycostatin oral swish and swallow (5-10 ml BID) or clotrimazole troches (I BID, suck x 20 min) is
recommended for prevention of oral or esophageal candidiasis during treatment with steroids in
induction and delayed intensification. In certain situations, oral fluconazole may be appropriate. Use of
fluconazole concomitant with STI571, however, should be avoided, if possible.
13.2.4 Gammaglobulin
Some patients develop recurrent sinopulmonary infections in association with low levels of serum IgG
while on Maintenance therapy. Monthly replacement therapy with IV IgG (200-400 mg/kg/dose) may
be of benefit in such patients .
13.3 Varicella Exposure

Determination of varicella immunity status of patients newly diagnosed with leukemia may assist in the
future management.
13.3.1 Treatment for Exposed Non-immune Patients

Non-immune patients with significant exposure should be treated with varicella zoster immune globulin
(VZIG) 125 units (1 vial) per every 10 kg of body weight (rounded up to a full vial), with a maximum
recommended dose of 5 vials (625 Units) by deep intramuscular injection within 72-96 hours of
exposure. ZIG extends the incubation period from 21 to 28 days or longer.
13.3.2 Varicella Vaccine For Siblings

Non-immune siblings > 1 year old should receive varicella vaccination as soon as possible after diagnosis.
In the unlikely event (< 5% chance) that varicella develops in the sibling 10-21 days following vaccination,
the patient is unlikely to develop varicella but should receive ZIG.
13.3.3 Varicella Vaccine For Patients

Vaccination with varicella vaccine of patients on treatment for ALL is not encouraged. However, a non-
immune patient may receive varicella vaccine (2 injections ~ 2 months apart) during maintenance therapy at
the discretion of the individual investigator, provided that chemotherapy is not interrupted and the absolute
lymphocyte count (WBC/µl x % lymphs) is ≈ 700. A patient who develops rash (≈ 35% incidence) post
vaccination may be infectious and should be separated from susceptible patients. A patient who develops
rash may benefit from treatment with acyclovir. A post vaccination titer should be obtained 2 months after
the second vaccination on treatment, to verify antibody immunity.
13.3.4 Chemotherapy treatment during incubation after ZIG

During incubation (10-28 days after ZIG) the patient should be separated from other compromised hosts.
Chemotherapy (including steroids) should not be withheld during incubation but the CBC should be
followed to maintain counts within the protocol guidelines.
13.3.5 Treatment of active infection

If varicella occurs in a patient on treatment or within 3 months of chemotherapy completion, he/she should
be treated with acyclovir 500 mg/m2 IV q 8 hours. The usual course is 10 days but it appears that the drug
may be stopped when all lesions are scabbed and no new lesions are appearing. Changing from IV to oral
acyclovir (3000 mg/m2/day ÷ 4x/day) once no new pox have formed is probably safe practice although
published data are lacking.
13.4 Fever with Neutropenia (F and N)
13.4.1 All cases

For patients with ANC < 500/µL and temperature between 38.0°C and 38.5°C twice in 12 hours, or ≥
38.5°C, empiric parenteral broad spectrum antibiotics should be instituted after obtaining appropriate
cultures. Patients with shaking chills and no fever should be closely scrutinized with probable treatment for
presumed sepsis.
13.4.2 Persistent F and N

In all cases, if fever and neutropenia persist in the neutropenic patient, systemic antifungal therapy with
amphotericin should be initiated after 3-7 days.
In the absence of positive cultures and clinical source of infection, antibiotics should be continued until
the patient is afebrile (T < 38.0°C) for at least 24 hours and CBC shows early sings of bone marrow
recovery. Lung CT scan maybe helpful for the diagnosis of pneumonia in a patient with cough or
unexplained hypoxemia.
13.5 Use of Growth Factors

Routine G-CSF should be administered only as given in the protocol. G-CSF may be given at an
individual investigator's discretion for severe myelosuppression in the face of a life-threatening
infection.
13.6 Nausea and Vomiting

Antiemetics should be given as needed. The use of high-dose corticosteroids for control of vomiting may
influence outcome of this study and is discouraged.
13.7 Nutrition
An emphasis is placed on maintenance of good nutritional status rather than on correction of the
malnourished state. Active measures should be employed to prevent weight loss > 10% of the premorbid
body weight. Enteral feeding is preferred to parenteral.
13.8 Venous Access

Repeated venous access is needed for all patients. Central venous catheters (CVCs) offer reliable access
and improved patient comfort at the risk of increased likelihood of infection. Tunneled CVCs (double
lumen) may be preferred to subcutaneous devices for the continuous, repetitive, and/or multiport access
characteristically needed for this patient population.
13.9 Hepatic Veno-Occlusive Disease (VOD)
Notify Study Chair of presumed VOD and to discuss supportive care. The following studies are
recommended for diagnosis and management of VOD: 1) CBC 2) liver function tests: AST, ALT, total
and fractionated bilirubin, albumin, alkaline phosphatase; 3) abdominal ultrasound with doppler
evaluation of hepatic and portal venous flow, 4) PT, PTT, fibrinogen, and DIC screen with D-dimer, 5)
hepatitis serology (A, B, C, CMV, EBV). Serial CBC's and liver function tests are indicated. If weight
gain and ascites are present, fluid and salt restriction, furosemide and/or spironolactone should be
considered. For hypoalbuminemia and ascites, albumin infusions and furosemide may be of benefit.
Thrombocytopenia (presumably secondary to platelet consumption from endothelial damage and
chemotherapy-induced myelosuppression) and anemia should be corrected with transfusions to keep
platelet count ≥ 20,000/µL. Liver biopsy is not recommended if the diagnosis of VOD can be made by
clinical and radiographic criteria, as bleeding can be a serious complication.
One patient receiving STI571 in a phase 1 study and with no known history of liver problems died on
study due to liver failure. This patient was also taking acetaminophen (Tylenol®), also known as
paracetamol in European countries. Although no other patient taking acetaminophen has experienced
liver-related side effects, it is recommended as a precaution to adhere carefully to the instructions and
warnings on the acetaminophen package label. Additionally, it is recommended that any over-the-
counter medications taken by the patient are carefully reviewed, as these may possibly contain
combinations of drugs, including acetaminophen or paracetamol.
13.10 Bleeding disorders associated with STI571

One patient on the POG phase 1 STI571 pediatric study had an intracranial hemorrhage. He was also
receiving enoxaparin, 70 mg subcutaneous bid (1 mg/kg). In addition, and specifically for coumadin, a
68 year old patient experienced hematuria and central nervous system hemorrhage at a time when he
was taking both STI571 and coumadin. His coumadin dose was increased 3 weeks before he presented
with an intracerebral hematoma. Investigators are therefore warned to carefully monitor therapeutic
anti-coagulation in patients receiving STI571, and, more specifically, to maintain adequate platelet
counts above 20,000/ul in such patients.
14.0 REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Contact Study Chair prior to removing any patient from protocol therapy for toxicity.
14.1 Criteria for Removal from Protocol Therapy
14.1.1
M2 or M3 (>5% blasts) bone marrow at the end of Consolidation block 2.
14.1.2
Relapse at any site.
14.1.3
Secondary malignancy.
14.1.4
Refusal of further protocol therapy.
14.2 Off Study Criteria
14.2.1
Confirmed as lost to follow-up.
14.2.2
Withdrawal of informed consent for further follow-up.
14.2.3
Entry into another COG therapeutic study.
14.2.4
Death.
15.0 SURGICAL GUIDELINES
15.1 Biopsy Of The Clinically Enlarged Testis

Testicular biopsy to confirm overt testicular leukemia should be made through the most convenient scrotal
incision which overlies the testicular mass and allows minimal scrotal dissection. In the case of overt
testicular enlargement, the median raphe is not necessarily the incision of choice because it is necessary to
biopsy only the involved testis. The biopsy should be oriented in whichever direction will produce the
maximal tumor tissue for the given incision. The specimen should be sufficient for routine histology,
electron microscopy, and cell surface marker analysis. A minimum size is probably 3x5 mm.
16.0 RADIATION THERAPY GUIDELINES
16.1 Indications for Radiation

(CNS involvement, testicular involvement, or total body irradiation as part of HSCT).
16.1.1 CNS involvement at diagnosis:

CNS leukemia is defined as an elevated CSF WBC (≥ 5 cells/µL) and a cytocentrifuge preparation
demonstrating lymphoblast cells (CNS 3). CNS leukemia may also be diagnosed when the CSF WBC is
normal, but clinical signs of CNS leukemia such as facial nerve palsy or hypothalamic syndrome are
present. Patients who have less then 5 cell/µL and a positive cytospin will not be considered to be CNS
positive.
16.1.2 Testicular involvement at diagnosis:

Patients with biopsy-proven testicular involvement will receive testicular irradiation
16.1.3
Patients treated on the hematopoietic stem cell transplantation (HSCT) arm will receive Total Body
Irradiation (TBI) as part of the preparatory regimen.
16.1.4
Separate guidelines are not included for patients who present with eye, parenchymal brain or spinal cord
involvement. In these rare cases please contact the RT Study Coordinator (see 16.2.9.3 of protocol for
contact information) to discuss radiation treatment.
16.1.5
No other patient will receive irradiation. Prophylactic cranial radiation therapy is NOT used on this
protocol.
16.2 Cranial Irradiation

No Routine Spinal Irradiation Will Be Used On This Protocol.
16.2.1 Patients
Patients with CNS-3 leukemia or cranial nerve palsy/hypothalamic syndrome at diagnosis (see 16.1.1) and
who will not undergo total body irradiation will receive cranial radiation at the start of cycle 5 of the
maintenance chemotherapy. Patients with CNS involvement who receive TBI will receive a cranial
radiation “boost” just prior to the TBI.
Patients who develop CNS leukemia while receiving therapy are off protocol therapy.
16.2.2. Equipment
16.2.2.1 Modality:
X-ray beams with a nominal energy between 4 and 6 MV.
16.2.2.2 Calibration:
The calibrations of therapy units used in this protocol shall be verified by the Radiological Physics
Center.
16.2.3 Cranial Target Volume
16.2.3.1 Cranial Irradiation:

The target volume consists of the entire brain and meninges, including the frontal lobe as well as the
posterior halves of the globes of the eyes, with the optic disk and nerve superior to the vertex and
posterior to the occiput. The caudal border shall be below the skull base at the C2 vertebral level.
16.2.3.2 Localization:
The target volume shall be defined by means of a CT simulator or conventional simulator. Care must be
taken to avoid shielding the posterior orbit and cribriform plate. Radio-opaque markers should be
placed on the surface of the fleshy canthus to aid in localizing this point.
16.2.4 Cranial Target Dose
16.2.4.1 Prescription Point:

The prescription point in the cranial volume is at or near the center1. Note: Regardless of the location
of the central axis, the dose should be prescribed at the center of the cranial volume (midway between
the maximum separation).
16.2.4.2 Dose Definition:

The absorbed dose is specified below in centigrays (cGy)-to-muscle.
1
This follows the recommendations of ICRU Report 50. If your institution’s practice differs, a conversion may be necessary. For
instance, if you prescribe to a certain isodose line, adjust this (departmental) prescription so that the (protocol) prescribed dose is
given to the (protocol) prescription point. Contact QARC if assistance is needed.
16.2.4.3 Tissue heterogeneity:
No corrections for bone attenuation shall be made. Institutions that customarily correct for
heterogeneities must calculate monitor units without this option.
16.2.5 Patient NOT receiving TBI - Prescribed cranial dose and fractionation
16.2.5.1 Daily Dose:

The daily dose to the prescription point for the cranial volume shall be 180 cGy.
16.2.5.2 Total Dose:

The total dose to the prescription point shall be 1800 cGy in 10 treatments .
16.2.5.3 Fractionation:
All the radiation fields shall be treated once each day. The treatment shall be given 5 days a week.
16.2.5.4 Timing:
Cranial irradiation should start within 4 days of the beginning of cycle #5 of maintenance chemotherapy
unless the absolute granulocyte count is less than 750/µl, the platelet count is less than 75,000/µl, or there is
evidence of sepsis. When treatment is delayed because of a low granulocyte count or low platelet count,
radiotherapy should start as soon as the granulocyte count is recovering and has exceeded 750/µl. Patients
who have their radiotherapy delayed because of sepsis or suspected sepsis may start treatment as soon as
they have been afebrile for 72 hours and are asymptomatic.
16.2.5.5 Interruption of Therapy:

Patients who develop sepsis during radiotherapy should have radiotherapy stopped. If protraction of the
course is necessary due to treatment interruption, the total dose, fraction size, and number of fractions
should not be altered.
16.2.6 TBI Patient

Prescribed dose and fractionation of Cranial “boost” are as follows:
16.2.6.1 Daily Dose:

The daily dose to the prescription point for the cranial volume shall be 200 cGy.
16.2.6.2 Cranial “Boost” Total Dose:

The total dose to the prescription point shall be 600 cGy in 3 treatments.
16.2.6.3 Fractionation:
All the radiation fields shall be treated once each day.
16.2.6.4 Timing:
The 3 weekdays preceding TBI.
16.2.7 Treatment Interruptions

No corrections shall be made for treatment interruptions less than three days. For interruptions greater
than three days, please contact the Radiation Oncology Coordinator.
16.2.8 Treatment Technique
16.2.8.1 Patient Position:

It is recommended that the patient be treated supine with immobilization appropriate for the child such
as a face mask.
16.2.8.2 Beam Configuration:

The cranial volume is treated with two lateral, equally weighted photon beams. The fields shall extend
at least 1 cm beyond the periphery of the scalp.
16.2.8.3 Field Shaping:

Blocks: Field-shaping shall be done with blocks which are at least 5 HVL thick. Multileaf collimation is
permitted.
Eye Protection: A simple method to minimize lens irradiation, while irradiating the posterior halves of
the eyes, is to have the central axes of the horizontal cranial beams go through both orbits. The anterior
edges of the beams are defined by an external block or by an independently controlled collimator and
meet at a point 1 cm anterior to the frontal lobe meninges. Shielding blocks cover the anterior halves of
the eyes and protect the nose and mouth. Essentially the same geometry can be achieved with the
central axes through the center of the head by angling the lateral fields so that the rays through the eyes
lie in the same horizontal plane . It is acceptable to use a parallel-opposed beam-pair, without such
angling, with shielding blocks that cover the anterior half of the proximal eye . The dose to the
contralateral lens will then increase, however.
16.2.9 Quality Assurance Documentation For Cranial And/Or Testes RT:
16.2.9.1 QARC Post Treatment Review: Patients receiving Cranial or Testes RT on this study will have
a simple review of the treatment delivered. There is no on-treatment review in this study. There is no
film review required. Within one week of the completion of radiotherapy, the following data shall be
submitted.
The “RT-2 Radiotherapy Total Dose Record” form.

• A copy of the patient’s radiotherapy record including the prescription, and daily and
cumulative doses.
These data should be sent to:
T.J. Fitzgerald, MD Director
Quality Assurance Review Center
825 Chalkstone Avenue
Providence, RI 02908-4735
Telephone: (401) 456-6500
Fax: (401) 456-6550
e-mail: tjfitzgerald@qarc.org
16.2.9.2 Questions regarding the dose calculations or documentation should be directed to:
COG Protocol Dosimetrist
Telephone: (401) 456-6500
Fax: (401) 456-6550
16.2.9.3 Questions regarding the radiotherapy section of this protocol should be directed to the radiation
oncology study coordinator:
Rob Rutledge, MD FRCPC
Nova Scotia Cancer Center
5820 University Ave
Halifax, Nova Scotia
Canada, B3H 3Y6
Work: (902) 473-6096
Fax: (902) 473-7205
Email: ccrrr@qe2-hsc.ns.ca
16.2.9.4 Definitions Of Deviation In Protocol Performance
Prescription Dose
Minor Deviation:
The dose to the prescription point differs from that in the protocol by between 6% and 10%.
Major Deviation:
The dose to the prescription point differs from that in the protocol by more than 10%.
16.3 Testes
16.3.1 Patients:
All patients with biopsy-proven testicular leukemia at diagnosis will receive testicular radiation (24Gy
in 12 fractions) during the first consolidation phase. Patients who develop testicular leukemia while
receiving therapy are off protocol therapy.
16.3.2 Equipment
16.3.2.1 Modality:
High-energy photon or electron beams. The selection of energy is determined by the dose uniformity
criterion, and with electrons, the lowest possible energy should be used to spare tissues outside the target
volume.
The calibrations of therapy machines used in this protocol shall be verified by the Radiological Physics
Center.
16.3.3 Target Volume
The target volume consists of the testes in the scrotal sac. (N.B. Cremasteric reflex may move testes
high up in the inguinal canal.)
16.3.4 Target Dose

The prescription point is at or near the center of the planning target volume2.
16.3.4.2 Dose definition:

The absorbed dose is specified as centigrays (cGy)-to-muscle.
16.3.4.3 Prescribed Dose and Fractionation:

The total dose to the prescription point shall be 2400 cGy in 12 fractions. The patient shall be treated
with one fraction per day of 200 cGy (5 days per week). If the patient is known to be going on to the
HSCT arm with TBI, the dose to the prescription point shall be 12Gy in 6 fractions.
16.3.4.4 Timing:
Testicular irradiation should start within 4 days of the beginning of the first consolidation chemotherapy
unless the absolute granulocyte count is less than 750/µl, the platelet count is less than 75,000/µl, or there is
evidence of sepsis. When treatment is delayed because of a low granulocyte count or low platelet count,
radiotherapy should start as soon as the granulocyte count is recovering and has exceeded 750/µl. Patients
who have their radiotherapy delayed because of sepsis or suspected sepsis may start treatment as soon as
they have been afebrile for 72 hours and are asymptomatic.
16.3.4.5 Interruption of Therapy:

Patients who develop sepsis during radiotherapy should have radiotherapy stopped. If protraction of the
course is necessary due to treatment interruption, the total dose, fraction size, and number of fractions
should not be altered.
16.3.4.6 Dose Uniformity:

The variations of dose within the planning target volume shall be within +7%, -5% of the dose to the
prescription point3. The uniformity requirement can in general be met with an electron beam of
appropriate energy provided bolus is used, which is the simplest technique. Bolus may also be needed
for photon beams to fulfill the dose uniformity requirement.
2
This follows the recommendations of ICRU Report 50. If your institution’s practice differs, a conversion may be necessary.
For instance, if you prescribe to a certain isodose line, adjust this (departmental) prescription so that the (protocol) prescribed
dose is given to the (protocol) prescription point. Contact QARC if assistance is needed.
3
In accordance with the ICRU Report 50, small high-dose volumes can be excluded from the evaluation of the dose uniformity but not
small low-dose volumes.
16.3.5.1 Patient Position:

The patient shall be treated in the supine position.
16.3.5.2 Field-shaping:
Field shaping can be done with blocks of at least 5 HVL thick for photon beams. Multileaf collimation
is permitted.
16.3.6 Normal Tissue Sparing
16.3.6.1 Perineum:
The testes shall be supported posteriorly and, if possible, extended caudally in order to minimize
perineal irradiation. The field shall not be angled towards the perineum.
16.3.6.2 Penis:
The penis shall be excluded from the field by fixing it to the skin over the symphysis pubis.
16.3.7 Quality Assurance Documentation And Definitions Of Deviation In Protocol Performance

Refer to section 16.2.9 for submission requirements, contact names, and deviation definitions.
16.4 Total Body Irradiation Section
16.4.1 Patients
Every patient who will be undergoing hematopoietic stem cell transplantation will receive total body
irradiation as part of the preparatory regimen. The treatment dose will be 1200 cGy given over three
consecutive treatment days (days -7, -6, -5) at 200cGy twice per day. The interval between TBI fractions
will be at least four hours.
Patients undergoing TBI and who had CNS involvement at diagnosis will receive an additional “boost” of
cranial radiation of 6 Gy in 3 daily fractions on the weekdays just preceding the TBI (see section 16.2 for
details). Modifications of the testicular radiation are also required for patients with testicular involvement
who are undergoing TBI (see section 16.3 for details).
16.4.2 Institutional Requirements

Centers are required to satisfactorily complete the QARC TBI benchmark prior to any patient receiving
TBI on this protocol. Contact QARC to receive the required material (see section 16.4.7.4). For advice
about developing a TBI technique institutions may contact Dr Art Olch, Children’s Hospital of Los
Angeles, 323-669-5406, aolch@chla.usc.edu
16.4.3 Equipment
16.4.3.1 Modality:
High-energy photons with energy greater than or equal to Cobalt 60. Although there is no upper limit on
the energy as long as the skin dose requirements can be met, it is recommended that 18MV or lower be
used.. The selection of energy is determined by the dose uniformity criterion.
The calibrations of therapy machines used in this protocol shall be verified by the Radiological Physics
Center.
16.4.4 Target Volume

The entire body including skin.
16.4.5 Target Dose

The prescription point is at the midplane at the level of the umbilicus.
16.4.5.2 Dose definition:

The absorbed dose is specified as centigrays (cGy)-to-muscle.
16.4.5.3 Prescribed Dose and Fractionation and timing:

The total dose to the prescription point shall be 1200 cGy in 6 fractions, given 200cGy BID over 3 days,
minimum 6-hour interval between fractions, given on days –7, -6,-5 of the preparatory regimen. All
fields should be treated at each fraction.
16.4.5.4 Dose Rate:

A mid-plane dose rate of between 4 and 15cGy per minute is required.
16.4.5.5 Dose Uniformity:

The objective is to keep the dose throughout the body, defined to extend to within 2 mm of the skin surface,
to at least 90% of the prescription dose. In addition, the lung and brain dose shall not exceed 107% of the
prescription dose. For AP/PA treatments, partial transmission lung blocks should be used to compensate for
the higher transmission of lung tissue compared to muscle. Caution should be used when treating with
opposed laterals with the arms at the side to avoid having part of the arm block tissues inferior to the lungs.
The dose at the midpoint of the thickest part of the body while in the treatment position should be
determined and if necessary, modifications made to the treatment to raise the dose in this region to at least
90% of the prescription dose.
In order to satisfy the requirement that the skin dose at a depth of 2 mm is within at least 90% of the
prescription dose, beam spoilers or other equally effective devices should be used.
The field size shall be such that no part of the patient extends into the portion of the penumbra region where
the dose is less than 90% of the central axis dose.

Any treatment technique and patient position that meets the criteria for dose, dose rate and dose uniformity
is acceptable. Typically, AP/PA fields with partial transmission lung blocks to compensate for the lung
transmission or opposed laterals with the arms at the patient's side to provide the lung transmission
compensation are used.
16.4.6.1 Dose calculation for the Prescription Point

The calculation of the treatment time or the monitor units for the prescribed dose can be carried out using
standard techniques. However, TBI presents special problems relative to the routine treatment situation in
that the field sizes are much larger and the treatment distances much longer. The TBI percent depth dose
(PDD) or Tissue Maximum Ratio (TMR) and output factors should be measured under TBI treatment
conditions for a range of phantom sizes to establish the database for TBI beam-on time calculations or to
validate the calculation methodology. Typically, a calculation methodology will be adopted which uses
PDD or TMR and output factors measured under standard conditions but then modified to account for the
larger treatment distance. For example, modified values for inverse square corrected percentage depth dose
or tissue-air ratios and tissue-phantom ratios are necessary for some treatment units when the patient is
positioned at a long distance from the photon source and near the floor or one wall of the room. Also, some
deviation from an exact inverse square decrease with distance has been demonstrated for certain
geometries. Measurements of dose at the center of a phantom about the size of the typical patient should be
performed and compared to the calculated dose. If differences are found, additional correction factors
should be introduced to the calculation method.
Provided an agreement between measurements and calculations is established, the following technique is
used to find the monitor units or treatment time.
Example calculation for a given SSD (central axis prescription point).
MU = D / {PDD(A,d) x OPF(A) x CF(A) x U}

MU = monitor units for linear accelerator
D = prescribed dose per field
PDD = percent depth dose for patient area A and depth d
A = the area of the entrance surface presented by the patient's trunk
D = depth to midline at level of umbilicus
OPF(A) = output factor for patient area A
CF(A) = patient size correction factor for patient area A
U = the treatment unit calibration in units of cGy/monitor unit
Similar calculations can be written for time-on for Co60 treatment machines. Either the Percentage depth
Dose (PDD), Tissue Maximum Ratio (TMR) or Tissue Air Ratio (TAR) can be used in the above
formalism. These factors must be determined for a depth equal to the half-separation at the level of the
umbilicus and for the scattering area of the patient in the treatment position. For opposed lateral treatments,
this scattering area is the equivalent square area found from the torso length in one direction and the AP
thickness at the umbilicus for the other dimension. For AP/PA treatments, the area is found from the torso
length in one direction and the lateral width at umbilicus level for the other dimension.
16.4.6.2 Critical Organ Dose Points

The acceptable dose ranges for the various organs are outlined in Table 16.1. The midline dose at these
locations should be recorded on the TBI Data Capture Form. In addition, the dose to the thickest part of the
patient (typically the hip) must be assessed to determine if there is an under-dosage. A number of methods
can be used to determine the dose to the various organs:
1) The dose can be calculated based on the thickness at each location and factors appropriate to the TBI
treatment conditions.
2) Typical values can be measured using phantoms which simulate different patient sizes, or
3) Entrance and exit TLD’s or diodes can be placed on the patient at each required dose assessment
location. The midline dose can be calculated from these measurements making the appropriate
corrections to the readings and then averaging the corrected values.
16.4.6.3 Lung dose points
The optimal dose distribution to the lung would limit the dose to any part of the lung to ≤ 100% of the
prescribed dose.
The dose to lung shall be measured. Entrance and exit TLD’s or diodes can be placed on the patient at the
midlung level. Care must be taken to assure that the detectors are positioned over the middle of the lung.
This can be done by taking a port film with the detectors in place. If lung blocks are used, port films will
also verify that they are placed in the shadow of these blocks. The midline dose can be calculated from
these measurements making the appropriate corrections to the readings and then averaging the corrected
values. The lung dose will be reported on the TBI summary form.
If the dose to lung or brain is found to be outside the 90-107% range, either adjustments to the beam on-
time should be made (if all other dose reference points would remain within acceptable limits).
TABLE 16.1 DOSE GUIDELINES FOR TOTAL BODY IRRADIATION BY TISSUE

The dose is prescribed at the mid-separation at the umbilicus (100%).
Organ Minimum dose Maximum dose
Lung 1080 (90%) 1284 (107%)*
Abdomen and Pelvis 1080 (90%) 1320 (110%)
Brain 1080 (90%) 1284 (107%)
Limbs 1080 (90%) 1440 (120%)
* The maximum dose to any point in the lung should not exceed 107% of the prescribed dose. The
optimal distribution would limit the dose to all of the lung volume to ≤ 100%.
16.4.7 QA Documentation For Total Body Irradiation
16.4.7.1
Centers are required to satisfactorily complete the QARC TBI benchmark prior to any patient receiving TBI
on this protocol. Contact QARC to receive the required material.
16.4.7.2 QARC Post Treatment Review:

Patients receiving RT on this study will have a simple review of the treatment delivered. There is no on-
treatment review in this study. There is no film review required.
16.4.7.3 Within one week of the completion of radiotherapy, the following data shall be submitted.
• Radiotherapy Summary Form for Total Body Irradiation.
• A copy of the patient’s radiotherapy record including the prescription, and daily and
cumulative doses.
• If a technique other than the technique in the approved benchmark is utilized for this patient,
a new benchmark must be completed and approved.
These data should be sent to:

T.J. Fitzgerald, MD
Director
Telephone: (401) 456-6500
Fax: (401) 456-6550
e-mail: tjfitzgerald@qarc.org
16.4.7.4 Questions regarding the dose calculations or documentation should be directed to:
COG Protocol Dosimetrist
Telephone: (401) 456-6500
Fax: (401) 456-6550
16.4.7.5 Questions regarding the radiotherapy section of this protocol should be directed to the radiation
oncology study coordinator (see section 16.2.9.3)
16.4.7.6 Definitions Of Deviation In Protocol Performance

Prescription Dose
Minor Deviation:
The dose to the prescription point differs from that in the protocol by between 6% and 10%.
Major Deviation:
The dose to the prescription point differs from that in the protocol by more than 10%.
17.0 PATHOLOGY AND SPECIMEN GUIDELINES (APPLIES TO FORMER CCG
INSTITUTIONS)
17.1 FAB Morphology
Table 8.1 FAB Classification (105-107)

Cytological Feature L1 L2 L3
Amount of cytoplasm Scanty* Mod. Abundant* Mod. abundant

(< 20% of surface area) ( ≥ 20% of surface area)
Vacuolation Variable Variable Prominent, 3+/cell*
Basophilia of cytoplasm Slight Slight Deep*
Nucleoli 0-1, small* 1+/cell, prominent* 1+/cell, prominent
Nuclear membrane contour Round*, Uniform* convoluted,* Round

or with narrow clefts* or round
Cell size Small* Large* Large

(< 2 RBC diameters) (≥ 2 RBC diameters)
% L1 cells 90-100% < 90% < 74%
*Distinguishing features of subgroup.
17.2 Diagnostic CSF Cytospin Samples for Morphology

1) Centrifuge all available spinal fluid. Sample can be centrifuged in the large collection tube
in a centrifuge (5 mins @ 2500 rpm) or decanted into a 10 x 75 mm test tube and
centrifuged in a bench top centrifuge (i.e., Serofuge) for 3 minutes.
2) Remove supernatant leaving an estimated 8-10 drops of spinal fluid on the sediment.
3) Add two drops of 22% bovine albumin to the tube to reduce cell distortion during
cytocentrifugation. (Addition of albumin is not needed if the cytospin slides have been
commercially prepared with albumin.)
4) Prepare cytocentrifuge slide from the pre-spun spinal fluid, as per manufacturer's directions.
17.3 Cytogenetics Studies

For patients enrolled on CCG ALL studies, the institutional cytogeneticist MUST be informed that the
patient will be on a CCG study AT THE TIME THE DIAGNOSTIC SAMPLE IS SENT FOR
CYTOGENETIC STUDIES. At the time the patient is diagnosed, he/she will be eligible for either
CCG-1961 or CCG-1991. For review, a completed CCG Cytogenetics Reporting Form and 2
karyotypes of each abnormal clone must be sent to Dr. Heerema directly via overnight courier, or they
may be sent electronically.
(For requirements for Cytogenetic Studies in CCG-1961, see Section 26.3 of the CCG-1961 protocol.
For requirements for Cytogenetic Studies in CCG-1991, see Section 14.3 of the CCG-1991 protocol.
The requirements are identical for both studies.)
Patients enrolled on POG studies will be identified as eligible for AALL0031 by RT-PCR in the Biology
Reference Laboratory in Albuquerque, New Mexico, or by DNA index in the Baltimore, Maryland,
Immunophenotyping Reference Laboratory. Cytogenetics for review from approved institutional
cytogenetics laboratories are sent to Dr. Andrew Carroll to confirm the RT-PCR or DNA index results.
No additional requirements will be necessary for patients initially enrolled on POG Studies.
17.4 Specimens to the COG ALL Biology Reference Laboratory

See section 10.8 for specimen submission at the time of relapse.
18.0 STATISTICAL CONSIDERATIONS
18.1 Accrual and Disease Outcome
The COG accrual for newly diagnosed ALL is about 1900 patients per year. Among the large cohort of
1880 non-infant children with accepted cytogenetic data treated on CCG trials conducted between 1989
and 1995, the incidence rate for patients with Ph+ ALL was 2.3%. Similar 81,82 or higher rates83-87 of
Ph+ ALL were reported in other studies. The incidence of Ph+ ALL on recent POG studies is
approximately 4% (Camitta, B, personal communication), so the preceding estimate of 2.3% might be an
underestimate. The incidence of hypodiploidy with ≤ 44 chromosomes and induction/consolidation
failures on the CCG studies conducted between 1989 and 1995 were 1.2% and 0.7%, respectively (see
VHR patient identification, Preliminary Results, above). After correcting for some overlap of the three
categories, we estimate that the VHR group comprises approximately 4% of the overall ALL population.
Approximately 76 patients per year (6 patients per month) would meet these VHR criteria. We estimate
that approximately 10% of these VHR patients will not be eligible for study entry due to 1) lack of
successful cytogenetic or molecular genetic data; 2) relapse prior to study entry; 3) achievement of M1
marrow status at the end of extended induction (POG) or consolidation (CCG). Thus, we estimate that
68 patients per year will be eligible for study entry.
The primary goal of the current study is to determine if patient accrual is sufficiently high and toxicity is
adequately low to demonstrate the feasibility of conducting a randomized Phase III clinical trial for
VHR patients. As a target goal, we wish to enroll at least 80% of the potential available patients, giving
about 54 patients per year. Insufficient accrual and/or excessive toxicity will be cause for examining
whether the study should continue. Based on the estimates for the patient subsets we expect that about
50-65% of patients will be in the Ph+ group. Thus, we anticipate 27-35 Ph+ ALL patients per year. The
accrual duration for this pilot study will be based on accruing adequate numbers (N=84) to complete the
dose escalation study of STI571 (see below) in the Ph+ subset. The planned study duration should be no
more than three years, although if enrollment is close to the maximum number available, the study may
be completed sooner.
Past disease outcome experience in the VHR patient subsets that are eligible for this study has been very
poor and relapses occur quite early. Data from a recent CCG series of studies indicates that from initial
diagnosis, 1-year EFS was approximately 50% for Ph+ patients and 75% for patients with ≤ 44
chromosomes. Two-year EFS for these patients was about 45%. By three years the EFS outcome was
less than 40% and by five years it was in the neighborhood of 30%. A secondary goal of this pilot study
is to compare EFS for the VHR cohort treated with the intensive regimen, with or without STI571,
versus appropriate historical controls from recent CCG and POG studies.
18.2 Statistical Design and Toxicity Monitoring
Since the intensified post-induction therapy in this study and the use of STI571 have never been examined
extensively in this population, we wish to establish that patients are able to successfully complete the
therapy blocks, and that severe toxicity or other major complications do not occur at an excessive rate. For
this reason, STI571 will be studied in a dose-escalation scheme for successive cohorts of Ph+ patients (as
also described in Sections 5 and 7 of the protocol). Each of these cohorts will enroll 12 patients. Some
patients will be found to have sibling donors (approximately 20-25%) and will receive HSCT following
consolidation block #1, and others might have early relapse which removes them from the study. Enrolling
12 patients in each cohort should provide an adequate number who will receive several courses that include
STI571, and should provide an opportunity to judge the toxicity of the agent at each dose level in
combination with the chemotherapy being given. Although a subsequent cohort of patients can begin
enrollment at an escalated dose upon conclusion of patient entry to a prior cohort, the data will be
monitored in an ongoing continuous manner as described below to permit suspension of entry if
accumulating data from a previous cohort(s) suggests a toxicity problem.
The use of STI571 as given in combination with other agents in a particular cohort will be considered
feasible initially if 5 or more of the first 6 evaluable patients complete the phase(s) without evidence of
grade 3 or 4 non-hematologic toxicity. If 2 or more are found to have this level of dose limiting toxicity
(DLT) in the first six evaluable patients, the dose will be reduced by 30%. If the first group of six evaluable
patients in the cohort does not have an excessive level of toxicity, the remaining patients in the cohort will
still be included in the evaluation of toxicity with the cumulative percentage of DLT being continually
reassessed. If at any time the percentage of DLT reaches 33% or greater for the full cohort, that would be
considered excessive and the dose would have to be reduced or appropriate modifications made. Cohorts 1-
3 use STI571 in only one of the three early components of therapy (either in consolidation #1, in
reinduction #1 and #2, or in intensification #1 and #2). Cohorts 4-6 will involve the use of STI571 in
various combinations for two of the three early components, but only if each of those components was
demonstrated during cohorts 1-3 to not have DLT at the prescribed dose. Cohort 7 would involve the use of
STI571 in all three early components of therapy, but only if each of cohorts 4-6 have shown no evidence of
DLT at the prescribed dose. Evaluation of STI571 toxicity in maintenance therapy will require combining
data from multiple cohorts because of the relatively long time to reach some of the maintenance courses and
the expected attrition due to the high rate of relapse which may occur in these patients. Similar to the earlier
therapy blocks, maintenance therapy will be continually reassessed beginning with the first group of 6
evaluable patients. If at any time the level of DLT reaches 33% for any course of maintenance therapy, that
would be evidence that the dose must be reduced or other modifications made.
Experience in previous COG studies suggest that remission deaths (RD) in these categories of VHR patients
occur primarily in the first 18 months of therapy and is in the neighborhood of 10%. This outcome index
will be monitored by comparing the current study population outcome to the historical control using life
table methods twice each year following the regular updates of the study data. A one-sided test will be used
with a higher Type I error than typically chosen (alpha = 0.10) in order to provide better power to detect an
increase in the RD rate for the patients on this study.
HSCT is the intended treatment for patients with a related donor who are in remission after the second
consolidation block (approximately 6 weeks from starting the study). Patients on the study without a
suitable donor will continue on the intensive chemotherapy arm. A secondary goal of the study is to assess
the feasibility of administering HSCT after the second consolidation block for patients in first remission
with suitable related donors. Although patient numbers will be insufficient to provide a definitive
assessment of the role of HSCT, outcome of the HSCT patients will be compared to the chemotherapy
patients who also achieve an initial remission and maintain it through the second consolidation block. To
reduce the chance of selection bias and other associated analytic problems in comparing transplant to non-
transplant groups, this analysis will put primary emphasis on a biologic “intent-to-treat” comparison
(comparing subsequent outcome for those who have a related donor versus those who do not among
patients who were in remission at the end of the second consolidation block). This comparison will also be
examined separately in the primary patient subsets (Ph+, hypodiploid, induction failures). Toxicity of
STI571 for the Ph+ patients receiving it in consolidation post-HSCT will be evaluated in the manner
described above for the other Ph+ patients (i.e., requiring DLT to be remain below 33% for this group of
patients once the initial group of 6 evaluable patients is obtained). Remission deaths post-transplant will be
evaluated using life table analysis by contrasting the HSCT RD rate to the historical control experience.
Analyses will also examine the actual length of time required to complete the various phases of therapy
relative to the nominal length of time for the phases. This will be done for the patients receiving STI571,
those receiving only chemotherapy without STI571, and the HSCT patient subsets. We will judge
consolidation blocks 1 and 2 to be feasible if 75% or more of patients in an STI571 cohort successfully
complete blocks 1 and 2 in clinical remission and within 8 weeks of beginning therapy on the study.
Reinduction blocks 1 and 2 and intensification blocks 1 and 2 will be judged feasible if 65% or more of the
entrants in a cohort are still in clinical remission and complete the 22 weeks of scheduled therapy in less
than 27 weeks. Similar criteria will be used for the entire non- Ph+ subset who receive the chemotherapy
without STI571.
18.3 Statistical Power to Detect Differences
The primary goal of this study is to establish the safety of STI571 when given in combination with the other
chemotherapy, and also to provide some preliminary assessment of efficacy by determining that adequate
percentages of patients remain in remission and complete the various phases of the study as described above
in Section 18.2 . The monitoring rules for toxicity and completion of therapy blocks have been described in
the previous section. In regard to general disease outcome, the results for these patients will be contrasted
with a historical control population obtained from recent series of CCG and POG ALL studies for those
patients who fall in the same very high risk group categories. Using the studies initiated since
approximately 1996 will provide a large group of such patients treated with recent therapeutic strategies.
While this may not permit a definite conclusion in regard to the therapeutic effect of the regimen including
STI571 for the Ph+ patients or for the chemotherapy regimen used in the non- Ph+ subsets, it should still
provide useful information about the potential efficacy of the treatment strategies being investigated.
An important secondary aim of the study is to examine the prognostic effect of MRD assays in this patient
population. MRD assessment will be done as many as five times for those patients who remain in
remission with the treatment given in the study. Suppose that approximately half of the patients may be
MRD positive at the first assessment occurring prior to consolidation block 1. Allowing for an overall EFS
of 45% at two years, suppose that the MRD negative group has a 2-year EFS of 60% and the MRD positive
group has a 2-year EFS of 30%. With an accrual duration of two years and adequate follow-up thereafter,
one would have approximately 91% power to detect such a difference (one-sided test of proportions, alpha
= 0.05 test). In the case that a higher percentage is MRD positive at this baseline assessment, the power
would be reduced somewhat (depending on the assumptions about EFS outcomes), but would still provide a
reasonable opportunity to judge the prognostic effect. For example, suppose 70% are MRD positive with a
two year EFS of 37.5%, and suppose that 30% who are MRD negative have a two year EFS of 62.5%
(these relative mixing proportions of MRD positive and negative patients giving an overall EFS of 45%).
In this case the power for comparing the 2- year EFS outcomes would be 71%. Since several MRD
assessments are available for analysis, the data will be examined for various patterns of MRD positivity that
are prognostic (e.g., patients who show persistent MRD positivity at more than one of the early assessments
versus those who do not present with MRD or show rapid clearance). Detailed analysis of the MRD data
will utilize Cox regression methods for time-dependent covariates which allows examination of the
predictive effect using the entire profile of each patient’s MRD assessments.
19.0 ADVERSE EVENT REPORTING REQUIREMENTS
Adverse event collection and reporting is a routine part of every clinical trial. The first step is to identify
the event using the Common Toxicity Criteria (CTC).
A copy of the current version of the CTC can be downloaded from the CTEP home page
(http://ctep.info.nih.gov). All appropriate treatment areas should have access to a copy of the
current CTC.
19.1 Expedited Reporting Requirements for Protocols Utilizing Investigational Agents Supplied
by the National Cancer Institute (NCI)
As of January 1, 2001, certain adverse events experienced on protocols using NCI-sponsored

investigational agents supplied through the NCI require expedited reporting to CTEP using its Web-
based AdEERS. This study requires expedited adverse event reporting using AdEERS. NCI’s
guidelines for expedited adverse event reporting for protocols using NCI investigational agents can be
found at: http://ctep.cancer.gov/reporting/adeers.html
19.1.1 AdEERS Requirements

NCI-sponsored investigational agent: STI571 (Gleevec), IND# 61135
ADVERSE EVENT
ATTRIBUTION
GRADE 3 GRADE 4 GRADE 5∀
GRADE 1 GRADE 2 and/or and/or
❋ ❋
Hospitalization Hospitalization
UNEXPECTED EXPECTED UNEXPECTED EXPECTED UNEXPECTED EXPECTED UNEXPECTED EXPECTED UNEXPECTED EXPECTED
UNRELATED ❋ ❋ AdEERS AdEERS AdEERS AdEERS
UNLIKELY ❋ ❋ AdEERS AdEERS AdEERS AdEERS
AdEERS AdEERS ❋ AdEERS AdEERS AdEERS AdEERS

POSSIBLE

PROBABLE

DEFINITE
❋ For Hospitalization Only – Any medical event equivalent to CTC Grade 3, 4, or 5 which precipitated hospitalization (or
prolongation of existing hospitalization) must be reported regardless of requirements for Phase of study, expected or
unexpected and attribution.
∀ All deaths within 30 days of the last dose of treatment with an investigational agent require expedited reporting,
regardless of attribution within 7 working days. Any late death attributed to the agent (possible, probable or definite)
requires expedited reporting within 7 working days.
Expedited reports are to be submitted using AdEERS or the AdEERS paper templates available at http://ctep.info.nci.gov
within 7 working days.
Expedited reporting may not be appropriate for certain protocols where an adverse event is expected. Exceptions to the
above table for AALL0031 are provided below.
Expedited Reporting for Phase 2 and Phase 3 Studies

UNEXPECTED EVENT EXPECTED EVENT
GRADES 2-3 GRADES 4 and 5 GRADES 2-3 GRADES 4 and 5
Attribution of Possible, Regardless of Attribution Regardless of Attribution Regardless of Attribution
Probable or Definite
Report by phone to IDB (301-230- Grade 2: Adverse Event Expedited Expedited report, including Grade
Grade 2-3: Expedited report within 2330) and the Study Chair within Reporting NOT required. 5 Aplasia in leukemia patients,
7 working days. 24 hrs. Expedited report to follow within 7 working days.
within 7 working days. Grade 3: Adverse Event Expedited
Reporting dependent on This includes all deaths within
associated hospitalization and 30 days of the last dose of
This includes all deaths within 30 protocol exceptions. treatment with an investigational
days of the last dose of treatment agent regardless of attribution.
with an investigational agent
Grade 3 regardless of attribution. Any late death attributed to the
Regardless of Attribution agent (possible, probable, or
definite) should be reported
Any late death attributed to the within 7 working days.
agent (possible, probable, or
Adverse Event Expedited definite) should be reported within Grade 4 Myelosuppression or
Reporting dependent on 7 working days. other Grade 4 events that do not
associated hospitalization and require expedited reporting will
protocol exceptions be specified in the protocol.
19.1.2 AdEERS Reporting Exceptions

The following adverse events do NOT require expedited AdEERS reporting
For this protocol the expected toxicities listed in Section 12.0 and the exceptions listed below do not
require expedited reporting.
The following adverse events do NOT require expedited AdEERS reporting for this protocol.
Grade 3 hemoglobinemia, leukopenia, neutropenia or thrombocytopenia with hospitalization
Grade 3 infection with hospitalization
Grade 3 mucositis with hospitalization
Grade 3 fever/neutropenia with hospitalization
Grade 3 transfusion with hospitalization
Grade 3 diarrhea or gastritis with hospitalization
Grade 4 fever/neutropenia +/- hospitalization
Grade 4 hemoglobinemia, leukopenia, neutropenia or thrombocytopenia +/- hospitalization
19.1.3 Additional Protocol Specific AdEERS Requirements
Intracranial hemorrhage, unexplained hemorrhage with platelet > 10,000, and hepatotoxicity are of special
concern with STI571. Expedited reporting rules apply to patients experiencing Intracranial hemorrhage,
unexplained hemorrhage with platelet > 10,000, and hepatotoxicity after receiving STI571. The Study
Chair should also be notified immediately of patients experiencing hemorrhage adverse event as specified
in protocol Section 12.10.
NOTE: Whether or not an adverse event is reported via AdEERS, it should be reported as prescribed by the
protocol using the appropriate end-of-phase and other reporting forms.
19.2 Expedited Reporting For Investigational Agent(S) Used In A Clinical Trial Involving A
Commercial Agent(S)
19.2.1 Investigational Agent(s) and the Commercial Agent(s) on Separate Arms

An expedited adverse event report should be submitted using AdEERS for an investigational agent(s)
supplied by the NCI used in a clinical trial involving a commercial agent(s) on a separate arm only if the
event is specifically associated with the investigational agent(s). Reporting of adverse events occurring on
the arm using commercial agent(s) require MedWatch submission as described in the Section 19.3.
19.2.2 Investigational Agent(s) and the Commercial Agent(s) used in Combination

When an investigational agent(s) supplied by the NCI is used in combination with a commercial agent(s),
the combination should be considered investigational. Expedited adverse event reporting is required using
AdEERS regardless of attribution.
19.2.3 Investigational Agent(s) used as a Treatment “Window” with Commercial Agents used in
Subsequent Treatment Courses
An expedited adverse event report should be submitted using AdEERS for an investigational agent(s)
supplied by the NCI used in a clinical trial as a treatment window during the administration of the agent and
for 30 days following the “window”. During subsequent courses, adverse events considered to be
specifically attributed (possibly, probably or definitely-related) to the commercial agent(s) should be
reported using the MedWatch form as described in the Section 19.3.
19.3 Adverse Event Reporting For Commercial Agents

Commercial agents are those agents not provided under an IND but obtained instead from a commercial
source. In some cases an agent obtained commercially may be used for indications not included in the
package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in
these cases, the agent is still considered to be a commercial agent and the following procedures should be
followed:
19.3.1 What To Report:

Any life-threatening (Grade 4) or fatal (Grade 5) adverse event with an attribution of possible, probable
or definite to a study drug that is also unexpected (not listed in the package label).
19.3.2 When To Report:

These events should be reported within ten (10) working days.
19.3.3 Where To Report:

These adverse events with commercial agents must be reported to the FDA and a copy provided to the
NCI using the MedWatch form. A copy of the MedWatch form can be obtained from the FDA’s
MedWatch Web site (see below) or the CTEP home page in Appendix 12 of the Investigator’s
Handbook. The MedWatch report can be sent by the following mechanisms:
To the FDA: NCI: COG

On Line: Copy Copies
Www.fda.gov/medwatch
Mail: Mail: Operations Center::
MedWatch Investigational Drug Branch
5600 Fishers Lane P.O. Box 30012 Fax: 626-445-4334
Rockville, MD 20852-9787 Bethesda, MD 20824
Fax: 1-800-332-0178 Fax: 301-230-0159 Data Center:
Fax: 352-392-8162
19.4 Reporting Secondary AML/MDS
19.4.1 What To Submit:

Within two weeks of an AML/MDS diagnosis following treatment for cancer on NCI-sponsored trials,
submit the following:
• a completed NCI/CTEP Secondary AML/MDS Report Form;
• a copy of the pathology report confirming the AML/MDS; and
• a copy of the cytogenetic report (if available).
Submit instead of the MedWatch Form (FDA #3500)
19.4.2 Where To Send:

NCI COG (Copies)
Mail: Mail:
Investigational Drug Branch AER Coordinator
P.O. Box 30012 104 N Main St, Suite. 600
Bethesda, MD 20824 Gainesville, FL 32601-3330
20.0 RECORDS AND REPORTING
20.1 Categories or Research Records

Research records for this study can be divided into three categories:
1. Reference Labs, Biopathology Reviews, and QARC data. These data accompany submissions to
these centers, who forward their data electronically to the COG Research Data System.
2. Non-computerized information: Roadmaps, Pathology Narrative Reports, Surgical Reports. These
forms are faxed to the Research Data Center at (352) 392-8162.
3. Computerized Information supplied after Registration. All other computerized data will be entered
on the COG Remote Data Entry System with the aid of schedules and worksheets (essentially paper
copies of the RDE screens) as provided in the data form packet. See separate Data Form Packet
which includes submission schedule.
20.2 CDUS
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and
October 31. This is not a responsibility of institutions participating in this trial.
20.3 Clinical Trials Agreement

The agent(s) (hereinafter referred to as Agent(s)), STI571, used in this protocol is/are provided to the
NCI under a Clinical Trials Agreement (CTA) or a Cooperative Research and Development Agreement
(CRADA) between Novartis Pharmaceuticals (hereinafter referred to as Collaborator(s)) and the NCI
Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines apply to
the use of the Agent(s) in this study:
1. Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be transferred or
licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are
confidential and proprietary to Collaborator(s) and should be maintained as such by the
investigators.
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different CTAs or CRADAs , the access to
and use of data by each Collaborator shall be as follows (data pertaining to such combination use
shall hereinafter be referred to as "Multi-Party Data.):
a. NCI must provide all Collaborators with written notice regarding the existence and nature
of any agreements governing their collaboration with NIH, the design of the proposed
combination protocol, and the existence of any obligations which would tend to restrict
NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial
by any other Collaborator to the extent necessary to allow said other Collaborator to
develop, obtain regulatory approval or commercialize its own investigational Agent.
c. Any Collaborator having the right to use the Multi-Party Data from these trials must
agree in writing prior to the commencement of the trials that it will use the Multi-Party
Data solely for development, regulatory approval, and commercialization of its own
investigational Agent.
3. The NCI encourages investigators to make data from clinical trials fully available to
Collaborator(s) for review at the appropriate time (see #5). The NCI expects that clinical trial
data developed under a CTA or CRADA will be made available exclusively to Collaborator(s),
and not to other parties.
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI,
who will then notify the appropriate investigators (Group Chair for cooperative group studies, or
PI for other studies) of Collaborator's wish to contact them.
5. Any data provided to Collaborator(s) must be in accordance with the guidelines and policies of
the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial should be provided to CTEP for
immediate delivery to Collaborator(s) for advisory review and comment prior to submission for
publication. Collaborator(s) will have 30 days from the date of receipt for review. An additional
30 days may be requested in order to ensure that confidential and proprietary data, in addition to
Collaborator(s) intellectual property rights, are protected. Copies of abstracts should be provided
to Collaborator(s) for courtesy review following submission, but prior to presentation at the
meeting or publication in the proceedings. Copies of any manuscript and/or abstract should be
sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI

Executive Plaza North, Room 7111
Bethesda, Maryland 20892
FAX 301-402-1584
The Regulatory Affairs Branch will then distribute them to Collaborator(s).

21.0 STUDY COMMITTEE
STUDY CHAIR Bruce Camitta, M.D.

Kirk R. Schultz, M.D. Ped. Hematology-Oncology
British Columbia's Children's Hospital Midwest Children's Cancer Center
Div of Pediatric Hem-Onc 8701 Watertown Plank Road
4480 Oak St, Rm A119D Milwaukee, WI 53226
Vancouver, BC V6H 3V4 Phone: (414) 456-4106
Canada Fax: (414) 456-6543
Phone: (604) 875-2316 E-mail: bcamitta@mcw.edu
Fax: (604) 875-2911
E-mail: kschultz@interchange.ubc.ca William L. Carroll, M.D.
Hematology/Oncology
VICE CHAIR Mount Sinai Medical Center
Paul Bowman, M.D. Chief: Division of Hematology/Oncology
Cook Children's Medical Center One Gustave Levy Place
901 Seventh Avenue Suite 220 Box 1208
Fort Worth, TX 76104 New York, NY 10029
Phone: (817) 885-4006 Phone: (212) 241-6031
Fax: (817) 810-1712 Fax: (212) 360-6921
E-mail: pbowman@cookchildrens.org E-mail: bill.carroll@mssm.edu
STATISTICIAN Stella M. Davies, M.B.B.S.

Harland Sather, Ph.D. HSCT
Children's Oncology Group University of Minnesota Cancer Center
P.O. Box 60012 Dept of Pediatrics Box 422
Arcadia, CA 91066-6012 425 E. River Road, Suite 554
Phone: (626) 447-0064 Minneapolis, MN 55455
Fax: (626) 445-4334 Phone: (612) 626-2786
e-mail: hsather@childrensoncologygroup.org Fax: (612) 626-4842
E-mail: davie008@tc.umn.edu
Alexander Aledo, MD
Ped. Hematology/Oncology Tammie Eslinger, C.C.R.P.
New York Hospital-Cornell Univ Medical Center Clinical Research Associate
525 E. 68th Street Rm P-603 Mountain States Tumor Institute
New York, NY 10021-4873 Clinical Research
Phone: (212) 746-3447 100 East Idaho St.
Fax: (212) 746-8609 Boise, ID 83712
E-mail: aaledo@med.cornell.edu Phone: (208) 381-2774
Fax: (208) 381-3124
Dana Bond, R.N. E-mail: eslinget@slrmc.org
Nursing
University of Texas Southwestern Medical School Paul S. Gaynon, M.D.
Children's Medical Center Hematology/Oncology
Center for Cancer & Blood Disorders Childrens Hospital Los Angeles
1935 Motor Street Division of Hem-Onc, MS #54
Dallas, TX 75235 4650 Sunset Blvd.
Phone: (214) 456-5413 Los Angeles, CA 90027
Fax: (214) 456-6133 Phone: (323) 669-2163
E-mail: dbond@childmed.dallas.tx.us Fax: (323) 660-7128
E-mail: pgaynon@chla.usc.edu
Nyla Heerema, Ph.D. CONTACT PERSON FOR DATA

Cytogeneticist SUBMISSION/ENTRY
1645 Neil Avenue http://members.childrensoncologygroup.org/
Hamilton Hall Room 167 GOC Telephone: (626) 447-0064
Columbus, OH 43210-1228 RDC Telephone: (352) 392-5198
Phone: (614) 292-7815
Fax: (614) 292-7072
E-mail: heerema-1@medctr.osu.edu
Dean Jorstad, R.Ph.

Pharmacist
Midwest Children's Cancer Center
Children's Hospital of Wisconsin
9000 West Wisconsin Avenue
Milwaukee, WI 53226
Phone: (414) 266-2425
Fax: (414) 266-2426
E-mail: djorstad@chw.org
Robert Rutledge M.D. F.R.C.P.

Radiation/Oncology
Nova Scotia Cancer Center
5820 University Avenue
Halifax,Nova Scotia B3H 1V7 NS B3H 3Y6
Canada
Phone: (902) 473-6096
Fax: (902) 473-7205
E-mail: ccrrr@qe2-hsc.ns.ca
William Birdsall Slayton MD

Hematology/Oncology
Primary Childrens Medical Center
Pediatrics/Hematology-Oncology
100 North Medical Drive
Suite # 1400
Salt Lake City UT 84113
Phone: (801) 588-2680
Fax: (801) 588-2662
E-mail: bslayton@hci.utah.edu
Michael Trigg MD
Hematology/Oncology
Christiana Care Health Services/A.I. duPont Inst.
Chief, Div. Blood and BMT
P.O. Box 269
Wilmington DE 19899
Phone: (302) 651-5565
Fax: (302) 651-5575
E-mail: mtrigg@nemours.org
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES
PERFORMANCE STATUS CRITERIA

Karnofsky and Lansky performance scores are intended to be multiples of 10
ECOG (Zubrod) KARNOFSKY LANSKY*
Score Description Score Description Score Description
100 Normal, no complaints, no 100 Fully active, normal.

evidence of disease
Fully active, able to carry on all
0 pre-disease performance
without restriction. 90 Able to carry on normal 90 Minor restrictions in physically
activity, minor signs or strenuous activity.
symptoms of disease.
80 Normal activity with effort; 80 Active, but tires more quickly

Restricted in physically some signs or symptoms of
strenuous activity but disease.
ambulatory and able to carry
1
out work of a light or sedentary
nature, e.g., light housework, 70 Cares for self, unable to carry 70 Both greater restriction of and
office work. on normal activity or do active less time spent in play activity.
work.
60 Required occasional assistance, 60 Up and around, but minimal

but is able to care for most of active play; keeps busy with
Ambulatory and capable of all his/her needs. quieter activities.
self-care but unable to carry out
2 any work activities. Up and
about more than 50% of waking 50 Requires considerable 50 Gets dressed, but lies around
hours assistance and frequent much of the day; no active play,
medical care. able to participate in all quiet play
and activities.
40 Disabled, requires special care 40 Mostly in bed; participates in

Capable of only limited self- and assistance. quiet activities.
care, confined to bed or chair
3
more than 50% of waking 30 Severely disabled, 30 In bed; needs assistance even for
hours. hospitalization indicated. quiet play.
Death not imminent.
20 Very sick, hospitalization 20 Often sleeping; play entirely

Completely disabled. Cannot indicated. Death not imminent. limited to very passive activities.
4 carry on any self-care. Totally
confined to bed or chair. 10 Moribund, fatal processes 10 No play; does not get out of bed.
progressing rapidly.
*
The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.
AALL0031 Page 122
(#1) SAMPLE INFORMED CONSENT DOCUMENT FOR PATIENTS ENROLLED ON A FRONT
LINE CCG, POG, OR COG STUDY.
AALL0031, A Children’s Oncology Group Pilot Study for the Treatment of Very High Risk Acute
Lymphoblastic Leukemia in Children and Adolescents
WHAT IS THIS STUDY ABOUT?

This study is a clinical trial (a research study involving human patients). Clinical trials only include patients who
choose to take part. Please take your time to make your decision. Discuss your decision with your friends and
family.
This study is being carried out by the Children’s Oncology Group (COG). COG is an international research group
that consists of more than 200 hospitals that treat children with cancer in the USA, Canada and Australia. It is
common medical practice to treat children with leukemia on national research studies like this one.
You are being asked (to allow your child) to take part in this study because you (your child) has a type of cancer
called acute lymphoblastic leukemia (ALL), a cancer of white blood cells called lymphocytes. The particular type
of ALL with which you (your child) has been diagnosed has not responded well to therapies used in the past. You
(your child) is eligible for this study because your (your child’s) leukemia did not respond well enough to the first
round of treatment already given or because of a genetic indicator.
This clinical trial is a pilot study of a proposed new treatment for patients with your (your child’s) type of ALL. A
pilot study is an introductory study to test whether a certain treatment plan is workable before it is developed into
a larger study.
This clinical trial studies the use of a new intensive chemotherapy (treatment with anti-cancer drugs) plan. All
patients will be given chemotherapy treatment and some patients may receive a stem cell transplant (if an
appropriate donor is available). Stem cells can be young cells derived from bone marrow, peripheral blood or
umbilical cord blood, which create other kinds of blood cells, such as red blood cells, white blood cells (infection
fighting cells), and platelets (blood clotting cells). A stem cell transplant is a procedure where you are (your child
is) given some of another person’s healthy stem cells. Patients that do not have a suitable stem cell donor will be
given more chemotherapy treatment instead.
Additionally, certain patients that carry a particular genetic indicator, called Philadelphia chromosome positive
(Ph+), will be given an additional drug called STI571 throughout treatment. STI571 has been studied as a single
agent for use in the treatment of ALL patients that are Ph+ but not in combination with other chemotherapy agents
as used in this protocol.
WHY IS THIS STUDY BEING DONE?

The goals of this study are:
• To determine the workability of giving this intensive chemotherapy treatment to children and
adolescents with very high risk ALL.
• To determine the side effects* of the drug STI571 when given in combination with other
chemotherapy drugs in children with the Philadelphia chromosome positive leukemia.
*A side effect is an unintended result of the drug treatment that is not related to the reason the
drug is being used.
• To measure the effectiveness of this treatment when compared to the effectiveness of treatments
used in the past.
• To look at the workability and effectiveness of performing a stem cell transplant after the new
chemotherapy treatment being given on this study.
• To study patients’ blood at different points during treatment to find out if there are ways to
predict how well a patient will respond to treatment.
AALL0031 Page 123
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
There will be about 170 patients participating in this study.
WHAT WILL HAPPEN TO ME (MY CHILD) ON THIS STUDY?

Specimens
A portion of the first bone marrow aspirate and any relapse bone marrow will be sent to a central research
laboratory for each patient on study. Any remaining sample will be banked for future research. Researchers will
not know your child’s name or identity.
Methods for Giving Drugs

Various methods will be used to give the drugs to your child. Some drugs will be given by tablet or liquid through
the mouth. Some drugs will be given using a needle inserted into the muscle. The drugs used to treat the brain
and spinal cord will be given using a needle inserted into the fluid surrounding your child’s spinal column (this
procedure is called a spinal tap). Other drugs will be given using a needle inserted into a vein.
Central Line
For drugs to be given by vein, your doctor will likely recommend that you (your child) have a central venous line
placed. A central line is a special type of tubing inserted into a large vein in the chest by a surgeon during a short
operation. You (your child) would be anesthetized for this procedure and receive pain medication afterwards to
keep you (your child) comfortable. The central line is used to administer chemotherapy drugs and to withdraw
small amounts of blood for testing during treatment. The risks associated with central lines will be explained to
you and all of your questions will be answered. If you are (your child is) to have a central line inserted, you will
be given a separate informed consent document to read and sign.
Patients treated on this study will receive multiple drugs all designed to kill leukemia cells. Patients that have an
appropriate donor will be given a stem cell transplant. Those without an appropriate donor will continue on with
more chemotherapy. Patients with high levels of cancer cells in the spinal fluid will also receive radiation to the
brain. Boys with leukemia cells in the testes will receive radiation to the testes. Patients receiving a stem cell
transplant will also be given radiation to the entire body before their transplant. Patients will be hospitalized for
about three months during treatment.
An outline of treatment is provided below.
• Consolidation Block 1 (3 weeks)

Patients that have an acceptable stem cell donor will be given preparative chemotherapy and transplant,
as described to the right.**
Patients not receiving a stem cell transplant will
continue with the treatment plan described below.
• Reinduction Block 1 (3 weeks) • Transplant Preparation Treatment (1 week)
• Intensification Block 1 (8 weeks) • Stem Cell Transplant
• Reinduction Block 2 (3 weeks) • Maintenance- only for patients that are Ph+ or
• Intensification Block 2 (8 weeks) have evidence of disease remaining (6 months)
• Maintenance Cycles 1-4 (8-week cycles)
**IF YOU ARE (YOUR CHILD IS) TO RECEIVE A BONE MARROW TRANSPLANT, YOU WILL BE
GIVEN A SEPARATE INFORMED CONSENT TO READ AND SIGN. THE SEPARATE CONSENT WILL
EXPLAIN THE THERAPY TO BE GIVEN AND THE RISKS THAT ARE ASSOCIATED WITH IT.
AALL0031 Page 124
A more detailed calendar of Consolidation Blocks 1 and 2 and the treatment for patients not receiving transplant
is provided at the end of this consent. A detailed calendar of treatment for patients receiving transplant after
Consolidation Block 2 is provided in the separate consent.
Radiation
Most patients on this study will not receive radiation. However, if your child has a lot of leukemic cells in the
spinal fluid at the time of diagnosis, he/she will receive radiation to treat the brain. If your son has enlarged testes,
the physician will recommend that a biopsy be done. If leukemic cells are found in the testes, your son will
receive radiation to treat both testes. Patients who are receiving a stem cell transplant will be given radiation to
their entire body as part of the transplant preparation treatment. The timing of radiation therapy is shown in the
Calendar of Therapy at the end of the consent.
Additional Medicines
Your child will receive some additional medications, such as antibiotics, to help prevent infection. Other
medications may be given to reduce the side effects of chemotherapy.
Spinal Taps
Whether treated on this study or not, patients will have a number of spinal taps performed to look for leukemia in the
spinal fluid or to inject medications to treat or prevent leukemia in the spinal fluid. In most cases, patients will get
medications to numb the pain and blur the memory. A small area of skin over the back will be cleaned and numbed
with Emla cream and/or lidocaine. A small needle will be inserted between the spine bones and into the spinal fluid.
Two teaspoons of spinal fluid will be collected and medication will be injection. Sometimes doing spinal taps on
small infants is difficult. Rarely, babies have stopped breathing when “crunched” around for a spinal tap. Spinal taps
may cause headache. The test is painful and has a small risk of infection or bleeding. The pain usually gets better
within seconds to hours. Many children find the experience frightening.
Tests on the Bone Marrow

(Bone marrow is the soft tissue in the hollow of flat bones of the body that produces new blood cells.)
Whether treated on this study or not, patients with ALL have occasional bone marrow aspirates to make the
diagnosis of leukemia and to check the amount of leukemia still present. In most cases, infants will get
medications by vein to numb the pain and blur the memory. A small area of skin over the pelvis will be cleaned
and numbed with Emla cream or lidocaine and a teaspoon of marrow withdrawn with a needle. The test is painful
and has some small risk of infection or bleeding. The pain normally lessens within seconds to hours. Many
children find the experience frightening.
Standard Medical Tests

Before treatment on this study begins, and while receiving treatment, you (your child) will receive a series of
standard medical tests:
• Physical exam • Various scans

• Blood tests# • Tests of lung and heart function
• Bone marrow tests • Urine tests
• Spinal taps (at least 7 times during treatment) • Pregnancy test*
* Given to females of childbearing age prior to treatment.
# In addition to routine blood tests, your child will have 10 cc (2 teaspoons) of blood drawn 6 times during
treatment (for a total of 4-5 tablespoons). These additional blood draws will be taken when your child is already
having blood drawn for routine purposes. The blood samples will be shipped to a central lab for detection of
cancer cells.
AALL0031 Page 125
HOW LONG WILL I (MY CHILD) BE ON THIS STUDY?
You (your child) will be treated on this study for about 2 1/2 years. However, patients will continue to have
physical exams and blood tests for a few years after treatment so that researchers can continue to observe any
effects of treatment.
The researchers may decide to take you (your child) off the study if your (your child’s) cancer gets worse or you
(your child) experiences side effects from the treatment that are considered too severe.
You can leave (remove your child from) the study at any time. However, if you consider leaving (removing your
child from) the study, we encourage you to talk to your (your child’s) regular physician and to the research
physician before making a final decision.
WHAT ARE THE RISKS OF THE STUDY?
Chemotherapy agents are drugs that, in addition to killing tumor cells, can damage normal tissue. These drugs,
however, have been in use long enough so that severe problems can usually be avoided. Side effects are usually
reversible when medication is stopped but occasionally can persist and cause serious complications. The common
side effects from cancer treatment include nausea, vomiting and hair loss. Drugs may be given to prevent or
counteract nausea and vomiting but sometimes these symptoms may be severe enough that you (your child) will
need to have fluid given directly into the vein to replace the fluid loss. Hair loss is usually temporary but on rare
occasions it may be permanent. The more serious side effect from cancer treatment is depression of the number of
blood cells resulting in anemia, increased chance of infection and bleeding tendency. These complications can
sometimes be fatal. Bone marrow aspirates, biopsies, blood work and laboratory tests will be done to monitor
your (your child's) progress. In addition, when chemotherapy drugs are combined the side effects can be
increased. It is possible that the experimental drug STI571 when combined with chemotherapy, will produce
severe side effects that have not previously been seen with STI571 given alone. Finally, a few patients who
survive leukemia develop a second form of cancer. In this study, prolonged depression of the number of blood
cells, skin rashes and sores in the mouth and intestines are anticipated.
STI571 has not been used in combination with high doses of chemotherapy before. It is possible that
unanticipated severe toxicity may result with the combination of STI571 with chemotherapy.
You (your child) may receive all or some of the following drugs in this protocol. The following kinds of side
effects may be observed from the drugs used in this protocol:
Frequency of Side Effects When Side Effects Typically Occur

Common = 21-100 patients per 100 patients Immediate = Within 1-2 days of receiving drug.
Occasional = 5-20 patients per 100 patients Prompt = Within 2-3 weeks (prior to the next course).
Rare = 1-4 patients per 100 patients Delayed = Any time later during therapy.
Late = Any time after completion of treatment.
Asparaginase
Immediate Local allergic reactions Rash Allergic reaction (possibly severe and life-threatening),
nausea, vomiting, drowsiness, feeling tired, headaches,
seizures (L), increased uric acid levels, excessive
amounts of protein breakdown products in the blood,
decreased urine production
Prompt High level of ammonia High blood sugar, Inflammation of the pancreas (L); seizures (L), bleeding
or ammonia salts in the abnormal liver function (L), loss of appetite, lack of oxygen to the brain, kidney
blood (L), decreased test results damage, fluid build-up in tissues which causes swelling,
production of protein blockage of an artery or vein from a clot, decreased
in the body (L) blood counts, irritability, depression, confusion, brain
test changes, hallucinations
Delayed
Late
AALL0031 Page 126
Cyclophosphamide
Immediate Loss of appetite (L), nausea (L), Metallic taste (L), abnormal Temporary blurred vision1, heart
vomiting (L) hormone function affecting damage with abnormal heart
levels of salt in the blood and rhythms1, decay of muscle tissue in
urine, causing too much or too the heart2
little urine1
Prompt Decrease in the number of red and Bleeding and inflammation of
white blood cells and platelets made the urinary bladder (L)
in the bone marrow, hair loss
Delayed decreased ability of the body to fight Damage/scarring of lung tissue 3 (L)
infection or disease, absence of
sperm or stopped monthly periods,
inability to have children(L)
Late A new cancer or leukemia resulting
from this treatment, damage/scarring
of bladder tissue
1
2
3
Risk increased in someone who has had chest radiation.
Cytarabine
Immediate Nausea, vomiting, loss of Flu-like symptoms with Rash (L), poor brain function1(L), uncoordinated
appetite (L), eye fever (L) movements1, unsteady walk (L)
1
irritation/soreness
Prompt Decrease in the number of red Diarrhea Damage to the liver1 (L), blockage within the
and white blood cells and liver1(L), leakage of fluid into the lungs resulting
platelets made in the bone in severe difficulty breathing1
marrow, mouth sores, hair loss
Delayed Inflammation of the lungs
Late Absence of sperm or stopped monthly periods

1
Daunorubicin
Immediate Abnormal heart rhythm1, nausea, vomiting, Allergic reaction
worsening of side effects due to radiation (sometimes life-
treatments, pink or red color to urine, damage threatening), rash
to the skin if the medication leaks from a vein
Within 2-3 wks Decrease in the number of red and white Mouth sores (L), damage to the Rash
blood cells and platelets made in the bone liver (L)
marrow (L), decreased ability of the body to
fight infection and disease, hair loss (L)
Delayed Low number of white blood cells and Weakness of the heart muscle,
platelets (L), reduced function of the immune the chance of which is higher
system, hair loss with higher doses2 (L)
Late A new cancer or leukemia
resulting from this
treatment
1
Rarely causes a problem.
2
AALL0031 Page 127
Dexamethasone
Immediate Poor wound healing, Inflammation of the pancreas, which
stomach upset produces insulin and digestive enzymes (L),
abnormal levels of certain salts in the body
(like sodium and potassium) (L), bleeding in
the stomach and intestines (L), increased
pressure within the eye
Prompt Overeating, decreased ability of high blood sugar high blood pressure
the body to fight infection and
disease, slowed growth,
pimples (L), personality
changes
Delayed muscle weakness, Stomach ulcer, slowed growth (L), stretch
inflammation of the marks (L), decreased bone density (L)
stomach
Late Cataracts
Etoposide
Immediate Nausea, vomiting Low blood pressure, allergic
reaction (sometimes life-
threatening) skin rash
Prompt Decrease in the number of red and Hair loss, worsens side Numbness, tingling, clumsiness,
white blood cells and platelets effects due to radiation mouth sores
made in the bone marrow treatments, diarrhea
Delayed
resulting from this treatment
G-CSF
Immediate Local irritation at injection site Allergic reaction, low fever
Prompt Ache or pain inside the bones, Enlargement of the spleen,
increased levels of liver enzymes worsening of pre-existing skin
and uric acid in the blood, low rashes, hair loss
number of platelets in the blood
Delayed Inflammation of a blood vessel in the
skin
Late
Ifosfamide:
anorexia (L) seizure, inappropriate ADH 1
arrhythmia, EKG changes toxicities with arrythmias2,
2
myocardial necrosis
Delayed: Alopecia Fanconi’s renal syndrome Peripheral neuropathy, acute renal
failure, pulmonary fibrosis (L)
fibrosis
1
Less common with lower doses
2
Extremely rare at doses of < 10 g/m2/course
AALL0031 Page 128
Leucovorin
Immediate Allergic reaction (rash, hives, itching,
wheezing)
Within 2-3 wks
Delayed
Late
Mercaptopurine
Immediate Loss of appetite, Blood in the urine1, life threatening allergic
nausea, vomiting, reaction, passage of crystals in the urine causing
diarrhea kidney irritation1, hives
Prompt Decrease in the number of red and Mouth sores
white blood cells and platelets
made in the bone marrow
Delayed Scarring of liver tissue, high level of bilirubin in the
blood
Late
1
Mesna
Immediate Bad taste when taken by Nausea, vomiting, stomach pain Headache, pain in arms, legs, and joints; tired
mouth feeling, rash, temporary low blood pressure, allergic
reaction
Prompt diarrhea
Delayed
Late
Methotrexate
Immediate Headache, abnormally high Vomiting, fever, rash, drowsiness, stiff neck,
number of cells in the spinal irritation of tissues in the brain/spinal cord,
fluid seizures (L), partial paralysis
Prompt Drowsiness, unsteady walk
Delayed Learning disability Damage to brain tissue (L)
Late Increasingly poor nervous system function
AALL0031 Page 129
Vincristine
Immediate Damage to nearby tissue if the Jaw pain
medication leaks from a vein
Prompt Hair loss Weakness, constipation Absent intestinal activity resulting in intestinal
blockage, drooping eyelid, hoarseness, decrease in
the number of red and white blood cells and
platelets made in the bone marrow, reduced function
of the brain, abnormal hormone function affecting
levels of salt in the blood and urine, causing too
much or too little urine, seizures
Delayed Loss of deep tendon reflexes Numbness, tingling and
clumsiness
Late
STI571 (Gleevec)
Immediate: Heartburn, nausea, Fever, fluid retention in the arms, legs, Swelling of the brain
vomiting, headache face, or around the eyes (L), increase in
liver enzymes (SGOT, SGPT) and bilirubin
(L), abdominal pain/cramping, muscle and
joint pain (L)
Prompt: Decrease in numbers of red Decreased number of bone marrow cells Dark, bloody bowel movements, low
and white blood cells and (L), low numbers of a type of blood cell level of red blood cells (L), diarrhea,
platelets made in bone called a lymphocyte (L), scaly and/or itchy inflammation of the passage between the
marrow (L), feeling of rash, rash, muscle pain and cramping, loss throat and stomach, pain during
extreme tiredness of appetite swallowing, bleeding, vomiting blood
Delayed: Skin color changes, usually lighter patches Liver Damage (L)*
Late:
(L) Side effect may also occur later
* One patient with no known history of liver problems died on study due to liver failure. This patient was also taking acetaminophen (Tylenol®), also
known as paracetamol in European countries. Although no other patient taking acetaminophen has experienced liver-related side effects, it is recommended
as a precaution to adhere carefully to the instructions and warnings on the acetaminophen package label. Additionally, it is recommended that you carefully
review any over-the-counter medications you take, as these may possibly contain combinations of drugs, including acetaminophen or paracetamol.
OTHER REPORTED Adverse Drug Reactions – be aware that it is unknown whether the medication caused these side effects and if it did it is unknown at
this time as to when this side effect might occur and how often it might occur:
One patient has experienced inflammation of the lung tissue and lung tissue changes.
One patient developed progressive difficulty breathing after receiving 7 months of medication
Radiation Risks
Radiation therapy may produce the following side effects: Nausea, vomiting, diarrhea, generalized redness or
dryness of the skin, bone marrow failure (absent blood counts resulting in increased risk of infection, weakness,
and bleeding), loss of hair (which may take 6 months or more for full re-growth), parotitis (swelling of salivary
glands) causing jaw pain and swelling, damage to major body organs which may include the brain, eyes, heart,
lung, liver, and kidneys, and reddening of the skin. There is also the risk of temporary worsening of neurological
symptoms, such as weakness or loss of sensation. Some children experience a week or two of low grade
temperature and extreme sleepiness six to eight weeks after radiation therapy has been completed. Sterility has
been associated with testicular radiation.
Possible late effects may include: shortened height (growth retardation), back bone change of shape (vertebral
deformities), difficulty with vision (cataracts), changes in endocrine function (low hormones), inability to have
children (sterility), learning disabilities or brain damage, and increased risk of developing another cancer.
AALL0031 Page 130
Reproductive Risks
Because the drugs in this study can affect an unborn baby, you/your child should not become pregnant or father a
baby while on this study. You (Your child) should not nurse your baby while on this study. Ask about counseling
and more information about preventing pregnancy.
Since this is a new, experimental treatment for children, other presently unknown side effects may be
encountered. Your child will be watched closely and the drugs will be discontinued if serious side effects develop.
WILL MY CHILD BENEFIT FROM THIS STUDY?

There may or may not be direct medical benefits to your child from taking part in this study. It is hoped that the
information learned from this study may help future ALL patients.
ARE THERE OTHER TREATMENT OPTIONS?

Yes, there are other options.
• The standard treatment for high risk ALL.

• Another experimental treatment (if available).
• No further treatment and comfort care only.
Please discuss these options with your regular doctor as well as other trusted personal and family advisors.
WILL MY (MY CHILD’S) RECORDS BE CONFIDENTIAL?

You may read your (your child’s) medical record. The records are available to those caring for you (your child) at
this hospital. Organizations that may inspect and /or copy your (your child’s) research records for Quality
Assurance and data analysis include:
• The Children’s Oncology Group
• The National Cancer Institute
• The Food and Drug Administration
• The Institutional Review Board of this hospital
• Representatives from the pharmaceutical company Novartis, which supplies the drug STI571
The named groups are all involved in monitoring for any toxicity and the outcome of you/your child as a result
from participation in this study.
Names of participants or material identifying participants (except as described above) will not be released without
written permission, unless required by law. The above groups will access for quality assurance and data analysis.
WILL I (MY CHILD) HAVE TO PAY FOR THIS TREATMENT?

Taking part in this study may lead to added costs to your insurance company. Please ask about any expected
added costs or insurance problems.
In the case of injury or illness resulting from this study, emergency medical treatment is available but will be
provided at the usual charge. No funds have been set aside to compensate you (your child) in the event of injury.
You or your insurance company will be charged for continuing medical care and/or hospitalization.
You will receive no payment for taking part in this study.
The Division of Cancer Treatment and Diagnosis, NCI, will provide you with the investigational agent free of
charge for this study. Every effort has been made to ensure adequate supplies of the investigational agent, free of
charge, for all participants. If, however, the investigational agent becomes commercially available while you are
being treated, there is a possibility that you would be asked to purchase subsequent supplies.
AALL0031 Page 131
WHAT ARE MY (MY CHILD’S) RIGHTS AS A STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose (for your child) not to participate in this study. If you
decide not to (let your child) participate, you (your child) will not be penalized and you (your child) will still
receive the standard treatment.
If you choose to (allow your child to) participate, you may discontinue your (your child’s) participation in the
study at any time. If you discontinue participation in the study, physicians and hospital personnel will still take
care of you (your child).
You also have the right to know about new information that may affect your (your child’s) health, welfare, or
your willingness to (let him/her) participate in the study. You (your child) will be provided with this information
as soon as it becomes available.
Whether you participate or not, you (your child) will continue to get the best medical care this hospital can
provide.
WHAT IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or an injury related to the research, please call
____________________ ___________________
NAME at TELEPHONE NUMBER
For questions about you (your child) rights as a study participant, please call
______________________________________________________
NAME OF INSTITUTIONAL REVIEW BOARD REPRESENTATIVE*
___________________
at TELEPHONE NUMBER
*The Institutional Review Board is a group of people who review the research study to protect your rights.
WHERE CAN I GET MORE INFORMATION?

• Call the National Cancer Institute’s Cancer Information Service:
1-800-4-CANCER (1-800-422-6237) OR
1-800-332-8615 (for the hearing impaired)
• You will be given a copy of this protocol (complete study plan) upon request.
• Visit the National Cancer Institute’s Web sites:
CancerTrials: http://www.nci.nih.gov/cancer_information/
This site provides comprehensive clinical trials information.
CancerNetTM: http:/cancernet.nci.nih.gov
This site provides accurate cancer information including the Physicians Data Query (PDQ). The PDQ is the
National Cancer Institute’s comprehensive cancer database. It contains peer-reviewed summaries on cancer
treatment, screening, prevention, and supportive care; a registry of about 1,700 open and 10,300 closed cancer
clinical trials from around the world; and directories of physicians, genetic counselors, and organizations that
provide cancer care.
• You will be given a copy of this consent form.

AALL0031 Page 132
STATEMENT OF CONSENT
I have already read the above information. I have asked all my questions and I have gotten answers. I agree
to enroll (my child) in this study.
A copy of this consent form will be provided to me
PATIENT NAME ________________________________________
_____________________________________ _______________
SIGNATURE OF PATIENT DATE
_____________________________________ _______________
SIGNATURE OF PARENT OR GUARDIAN DATE
____________________________________ ______________
SIGNATURE OF PHYSICIAN OR DATE
RESPONSIBLE INVESTIGATOR
AALL0031 Page 133
TREATMENT CALENDAR FOR AALL0031
CONSOLIDATION BLOCK 1
Drug Method Schedule
Day 1 2 3 4 5 6-15 21
Etoposide By needle inserted X X X X X
into vein or central
line for 1 hour
Ifosfamide By needle inserted X X X X X
line for 1 ½ hour
MESNA By needle inserted X X X X X
line for 15 minutes
Methotrexate # By spinal tap, for 1-2 X
minutes
G-CSF By injection (1 X
injection daily)
STI571* By mouth X
Testicular radiation** 8 visits, 10-15 min. X
each
* Only for patients with Ph+ ALL assigned to receive STI571 with this chemotherapy combination.
** Only patients with testicular leukemia at diagnosis will receive testicular radiation therapy.
# Patients classified as CNS 2 or those with traumatic taps that have not received 2 additional intrathecal
methotrexate doses in induction, will receive 2 additional IT MTX doses on days 8 and 15.

Day 1 2 3 4-13
Methotrexate By needle inserted into vein or central X
line for 24 hours
Methotrexate By spinal tap, for 1-2 minutes X
Leucovorin By needle inserted into vein or central X X
line every 6 hours (6 total doses)
Cytarabine By needle inserted into vein or central X X
G-CSF By injection (1 injection daily) X
AALL0031 Page 134
REINDUCTION BLOCK 1
Day 1 2 3 4 5 6 7 8 10 12 14 15 17 19 21
Vincristine By needle inserted X X X
line
Daunorubicin By needle inserted X X
line over several
minutes
Cyclophosphamide By needle inserted X X
line for 30 minutes
(4 total doses)
Pegaspargase By needle inserted X
into the muscle
Methotrexate By spinal tap, for X X
1-2 minutes
Dexamethasone By mouth, 2 times X X
a day daily
G-CSF By injection X
(1 injection daily)
STI571* By mouth X
INTENSIFICATION BLOCK 1
Day 1 2 3 8 9 10 15 19 20 29 36 37 42 56
Methotrexate By needle inserted into vein X X
or central line for 24 hours
Leucovorin By needle inserted into vein X X X X
or central line (6 total
doses)
Methotrexate By spinal tap, for 1-2 X X
minutes
Cyclophosphamide By needle inserted into vein X
or central line
Etoposide By needle inserted into vein X
or central line
MESNA By needle inserted into vein X
G-CSF By injection –1 daily X
injection
Cytarabine By needle inserted into vein X X
(4 total doses)
L-asparaginase By needle inserted into the X
muscle
STI571* By mouth X
*Only for patients with Ph+ ALL assigned to receive STI571 with this chemotherapy combination.
AALL0031 Page 135
REINDUCTION BLOCK 2

Day 1 2 3 4 5 6 7 8 10 12 14 15 21
Vincristine By needle inserted into X X X
vein or central line
Daunorubicin By needle inserted into X X
vein or central line over
several minutes
Cyclophosphamide By needle inserted into X X
vein or central line for
30 minutes every 12
hours (4 total doses)
Pegaspargase By needle inserted into X
the muscle
Methotrexate By spinal tap, for 1-2 X
minutes
Dexamethasone By mouth, 2 times a X X
day daily
injection daily)
STI571* By mouth X
+
*Only for patients with Ph ALL assigned to receive STI571 with this chemotherapy combination.
AALL0031 Page 136

Day 1 2 3 8 9 10 15 19 20 29 36 37 42 56
Methotrexate By needle inserted X X
line for 24 hours
Leucovorin By needle inserted X X X X
line (6 total doses)
minutes
Cyclophosphamide By needle inserted X
line
Etoposide By needle inserted X
line
MESNA By needle inserted X
line for 4 hours
injection daily)
Cytarabine By needle inserted X X
line for 3 hours every
12 hours (4 total
doses)
L-asparaginase By needle inserted X
into the muscle
STI571* By mouth X
AALL0031 Page 137
MAINTENANCE BLOCK (Cycles 1-4)
Day 1 2 3 5 8 15 22 28 29 33 36 37 40 41 42 50
Methotrexate By needle inserted into X
24 hours
Leucovorin By needle inserted into X X
vein or central line (6
total doses)
minutes
Vincristine By needle inserted into X X
Dexamethasone By needle inserted into X X

2 hours
Mercaptopurine By mouth X
Methotrexate By mouth X X X
Etoposide By needle inserted into X

2 hours
Cyclophosphami By needle inserted into X
de vein or central line for
30 minutes
injection daily)
STI571* By mouth X
*Only for Ph+ patients.

Day 1 5 8 15 22 29 33 36 42 43 50 56
Methotrexate By spinal tap, for X
1-2 minutes
Vincristine By needle inserted X X
line
Dexamethasone By mouth X X
Methotrexate By mouth X X X X X X X
STI571* By mouth X X
Cranial 10 visits, 10-15 X
radiation** min. each
** Only patients with leukemia in the spinal fluid at diagnosis will receive cranial radiation therapy with cycle 5.
AALL0031 Page 138
(#2) SAMPLE INFORMED CONSENT DOCUMENT FOR PATIENTS NOT ENROLLED ON A FRONT
LINE CCG, POG, OR COG STUDY.
If this is the first time that you (your child) will be treated on a Children’s Oncology Group clinical trial, we will
need to collect information about the treatment you have (your child has) been given up to this point. We will
also need to collect the results from laboratory or genetic tests done during past treatment.

family.
This study is being carried out by the Children’s Oncology Group (COG). COG is an international research group
that consists of more than 200 hospitals that treat children with cancer in the USA, Canada and Australia. It is
common medical practice to treat children with leukemia on national research studies like this one.
You are being asked (to allow your child) to take part in this study because you (your child) has a type of cancer
called acute lymphoblastic leukemia (ALL), a cancer of white blood cells called lymphocytes. The particular type
of ALL with which you (your child) has been diagnosed has not responded well to therapies used in the past. You
(your child) is eligible for this study because your (your child’s) leukemia did not respond well enough to the first
round of treatment already given or because of a genetic indicator.
This clinical trial is a pilot study of a proposed new treatment for patients with your (your child’s) type of ALL. A
pilot study is an introductory study to test whether a certain treatment plan is workable before it is developed into
a larger study.
This clinical trial studies the use of a new intensive chemotherapy (treatment with anti-cancer drugs) plan. All
patients will be given chemotherapy treatment and some patients may receive a stem cell transplant (if an
appropriate donor is available). Stem cells can be young cells derived from bone marrow, peripheral blood or
umbilical cord blood, which create other kinds of blood cells, such as red blood cells, white blood cells (infection
fighting cells), and platelets (blood clotting cells). A stem cell transplant is a procedure where you are (your child
is) given some of another person’s healthy stem cells. Patients that do not have a suitable stem cell donor will be
given more chemotherapy treatment instead.
Additionally, certain patients that carry a particular genetic indicator, called Philadelphia chromosome + (Ph+),
will be given an additional drug called STI571 throughout treatment. STI571 has been studied as a single agent
for use in the treatment of ALL patients that are Ph+ but not in combination with other chemotherapy agents as
used in this protocol.

The goals of this study are:
• To determine the workability of giving this intensive chemotherapy treatment to children and
adolescents with very high risk ALL.
• To determine the side effects* of the drug STI571 when given in combination with other
chemotherapy drugs in children with the Philadelphia chromosome positive leukemia.
*A side effect is an unintended result of the drug treatment that is not related to the reason the
drug is being used.
• To measure the effectiveness of this treatment when compared to the effectiveness of treatments
used in the past.
• To look at the workability and effectiveness of performing a stem cell transplant after the new
chemotherapy treatment being given on this study.
AALL0031 Page 139
• To study patients’ blood at different points during treatment to find out if there are ways to
predict how well a patient will respond to treatment.

There will be about 170 patients participating in this study.

Specimens
A portion of the first bone marrow aspirate and any relapse bone marrow will be sent to a central research
laboratory for each patient on study. Any remaining sample will be banked for future research. Researchers will
not know your child’s name or identity.
Methods for Giving Drugs

Various methods will be used to give the drugs to your child. Some drugs will be given by tablet or liquid through
the mouth. Some drugs will be given using a needle inserted into the muscle. The drugs used to treat the brain
and spinal cord will be given using a needle inserted into the fluid surrounding your child’s spinal column (this
procedure is called a spinal tap). Other drugs will be given using a needle inserted into a vein.
Central Line
For drugs to be given by vein, your doctor will likely recommend that you (your child) have a central venous line
placed. A central line is a special type of tubing inserted into a large vein in the chest by a surgeon during a short
operation. You (your child) would be anesthetized for this procedure and receive pain medication afterwards to
keep you (your child) comfortable. The central line is used to administer chemotherapy drugs and to withdraw
small amounts of blood for testing during treatment. The risks associated with central lines will be explained to
you and all of your questions will be answered. If you are (your child is) to have a central line inserted, you will
be given a separate informed consent document to read and sign.
Patients treated on this study will receive multiple drugs all designed to kill leukemia cells. Patients that have an
appropriate donor will be given a hematopoietic stem cell transplant. Those without an appropriate donor will
continue on with more chemotherapy. Patients with high levels of cancer cells in the spinal fluid will also receive
radiation to the brain. Boys with leukemia cells in the testes will receive radiation to the testes. Patients receiving
a stem cell transplant will also be given radiation to the entire body before their transplant. Patients will be
hospitalized for about three months during treatment.
An outline of treatment is provided below.

Patients that have an acceptable stem cell donor will be given preparative chemotherapy and transplant,
as described to the right.**
Patients not receiving a stem cell transplant will
continue with the treatment plan described below.
• Reinduction Block 1 (3 weeks) • Transplant Preparation Treatment (1 week)
• Intensification Block 1 (8 weeks) • Stem Cell Transplant
• Reinduction Block 2 (3 weeks) • Maintenance- only for patients that are Ph+ or
• Intensification Block 2 (8 weeks) have evidence of disease remaining (6 months)
AALL0031 Page 140
**IF YOU ARE (YOUR CHILD IS) TO RECEIVE A HEMATOPIOETIC STEM CELL TRANSPLANT, YOU
WILL BE GIVEN A SEPARATE INFORMED CONSENT TO READ AND SIGN. THE SEPARATE
CONSENT WILL EXPLAIN THE THERAPY TO BE GIVEN AND THE RISKS THAT ARE ASSOCIATED
WITH IT.
A more detailed calendar of Consolidation Blocks 1 and 2 and the treatment for patients not receiving transplant
is provided at the end of this consent. A detailed calendar of treatment for patients receiving transplant after
Consolidation Block 2 is provided in the separate consent.
Radiation
Most patients on this study will not receive radiation. However, if your child has a lot of leukemic cells in the
spinal fluid at the time of diagnosis, he/she will receive radiation to treat the brain. If your son has enlarged testes,
the physician will recommend that a biopsy be done. If leukemic cells are found in the testes, your son will
receive radiation to treat both testes. Patients who are receiving a stem cell transplant will be given radiation to
their entire body as part of the transplant preparation treatment. The timing of radiation therapy is shown in the
Calendar of Therapy at the end of the consent.
Additional Medicines
Your child will receive some additional medications, such as antibiotics, to help prevent infection. Other
medications may be given to reduce the side effects of chemotherapy.
Spinal Taps
Whether treated on this study or not, patients will have a number of spinal taps performed to look for leukemia in the
spinal fluid or to inject medications to treat or prevent leukemia in the spinal fluid. In most cases, patients will get
medications to numb the pain and blur the memory. A small area of skin over the back will be cleaned and numbed
with Emla cream and/or lidocaine. A small needle will be inserted between the spine bones and into the spinal fluid.
Two teaspoons of spinal fluid will be collected and medication will be injection. Sometimes doing spinal taps on
small infants is difficult. Rarely, babies have stopped breathing when “crunched” around for a spinal tap. Spinal taps
may cause headache. The test is painful and has a small risk of infection or bleeding. The pain usually gets better
Tests on the Bone Marrow

(Bone marrow is the soft tissue in the hollow of flat bones of the body that produces new blood cells.)
Whether treated on this study or not, patients with ALL have occasional bone marrow aspirates to make the
diagnosis of leukemia and to check the amount of leukemia still present. In most cases, infants will get
medications by vein to numb the pain and blur the memory. A small area of skin over the pelvis will be cleaned
and numbed with Emla cream or lidocaine and a teaspoon of marrow withdrawn with a needle. The test is painful
and has some small risk of infection or bleeding. The pain normally lessens within seconds to hours. Many
children find the experience frightening.
Standard Medical Tests

Before treatment on this study begins, and while receiving treatment, you (your child) will receive a series of
standard medical tests:

• Blood tests# • Tests of lung and heart function
• Spinal taps (at least 7 times during treatment) • Pregnancy test*
* Given to females of childbearing age prior to treatment.
# In addition to routine blood tests, your child will have 10 cc (2 teaspoons) of blood drawn 6 times during
treatment (for a total of 4-5 tablespoons). These additional blood draws will be taken when your child is already
having blood drawn for routine purposes. The blood samples will be shipped to a central lab for detection of
cancer cells.
AALL0031 Page 141
You (your child) will be treated on this study for about 2 1/2 years. However, patients will continue to have
physical exams and blood tests for a few years after treatment so that researchers can continue to observe any
effects of treatment.
The researchers may decide to take you (your child) off the study if your (your child’s) cancer gets worse or you
(your child) experiences side effects from the treatment that are considered too severe.
You can leave (remove your child from) the study at any time. However, if you consider leaving (removing your
child from) the study, we encourage you to talk to your (your child’s) regular physician and to the research
physician before making a final decision.
Chemotherapy agents are drugs that, in addition to killing tumor cells, can damage normal tissue. These drugs,
however, have been in use long enough so that severe problems can usually be avoided. Side effects are usually
reversible when medication is stopped but occasionally can persist and cause serious complications. The common
side effects from cancer treatment include nausea, vomiting and hair loss. Drugs may be given to prevent or
counteract nausea and vomiting but sometimes these symptoms may be severe enough that you (your child) will
need to have fluid given directly into the vein to replace the fluid loss. Hair loss is usually temporary but on rare
occasions it may be permanent. The more serious side effect from cancer treatment is depression of the number of
blood cells resulting in anemia, increased chance of infection and bleeding tendency. These complications can
sometimes be fatal. Bone marrow aspirates, biopsies, blood work and laboratory tests will be done to monitor
your (your child's) progress. In addition, when chemotherapy drugs are combined the side effects can be
increased. It is possible that the experimental drug STI571 when combined with chemotherapy, will produce
severe side effects that have not previously been seen with STI571 given alone. Finally, a few patients who
survive leukemia develop a second form of cancer. In this study, prolonged depression of the number of blood
cells, skin rashes and sores in the mouth and intestines are anticipated.
STI571 has not been used in combination with high doses of chemotherapy before. It is possible that
unanticipated severe toxicity may result with the combination of STI571 with chemotherapy.
You (your child) may receive all or some of the following drugs in this protocol. The following kinds of side
effects may be observed from the drugs used in this protocol:
Asparaginase
Immediate Local allergic reactions Rash Allergic reaction (possibly severe and life-threatening),
nausea, vomiting, drowsiness, feeling tired, headaches,
seizures (L), increased uric acid levels, excessive
amounts of protein breakdown products in the blood,
decreased urine production
Prompt High level of ammonia High blood sugar, Inflammation of the pancreas (L); seizures (L), bleeding
or ammonia salts in the abnormal liver function (L), loss of appetite, lack of oxygen to the brain, kidney
blood (L), decreased test results damage, fluid build-up in tissues which causes swelling,
production of protein in blockage of an artery or vein from a clot, decreased blood
the body (L) counts, irritability, depression, confusion, brain test
changes, hallucinations
Delayed
Late
AALL0031 Page 142
Cyclophosphamide
Immediate Loss of appetite (L), nausea (L), Metallic taste (L), abnormal Temporary blurred vision1, heart
vomiting (L) hormone function affecting damage with abnormal heart
levels of salt in the blood and rhythms1, decay of muscle tissue in
urine, causing too much or too the heart2
little urine1
Prompt Decrease in the number of red and Bleeding and inflammation of
white blood cells and platelets made the urinary bladder (L)
in the bone marrow, hair loss
Delayed decreased ability of the body to fight Damage/scarring of lung tissue 3 (L)
infection or disease, absence of
sperm or stopped monthly periods,
inability to have children(L)
Late A new cancer or leukemia resulting
from this treatment, damage/scarring
of bladder tissue
1
2
3
Risk increased in someone who has had chest radiation.
Cytarabine
Immediate Nausea, vomiting, loss of Flu-like symptoms with Rash (L), poor brain function1(L), uncoordinated
appetite (L), eye fever (L) movements1, unsteady walk (L)
1
irritation/soreness
Prompt Decrease in the number of red Diarrhea Damage to the liver1 (L), blockage within the
and white blood cells and liver1(L), leakage of fluid into the lungs resulting
platelets made in the bone in severe difficulty breathing1
marrow, mouth sores, hair loss
Delayed Inflammation of the lungs
Late Absence of sperm or stopped monthly periods

1
Daunorubicin
Immediate Abnormal heart rhythm1, nausea, vomiting, Allergic reaction
worsening of side effects due to radiation (sometimes life-
treatments, pink or red color to urine, damage threatening), rash
to the skin if the medication leaks from a vein
Within 2-3 wks Decrease in the number of red and white Mouth sores (L), damage to the Rash
blood cells and platelets made in the bone liver (L)
marrow (L), decreased ability of the body to
fight infection and disease, hair loss (L)
Delayed Low number of white blood cells and Weakness of the heart muscle,
platelets (L), reduced function of the immune the chance of which is higher
system, hair loss with higher doses2 (L)
resulting from this
treatment
1
Rarely causes a problem.
2
AALL0031 Page 143
Dexamethasone
Immediate Poor wound healing, Inflammation of the pancreas, which
stomach upset produces insulin and digestive enzymes (L),
abnormal levels of certain salts in the body
(like sodium and potassium) (L), bleeding in
the stomach and intestines (L), increased
pressure within the eye
Prompt Overeating, decreased ability of high blood sugar high blood pressure
the body to fight infection and
disease, slowed growth,
pimples (L), personality
changes
Delayed muscle weakness, Stomach ulcer, slowed growth (L), stretch
inflammation of the marks (L), decreased bone density (L)
stomach
Late Cataracts
Etoposide
Delayed
G-CSF
Immediate Local irritation at injection site Allergic reaction, low fever
Prompt Ache or pain inside the bones, Enlargement of the spleen,
increased levels of liver enzymes worsening of pre-existing skin
and uric acid in the blood, low rashes, hair loss
number of platelets in the blood
Delayed Inflammation of a blood vessel in the
skin
Late
Ifosfamide:
anorexia (L) seizure, inappropriate ADH 1
arrhythmia, EKG changes toxicities with arrythmias2,
2
myocardial necrosis
Delayed: Alopecia Fanconi’s renal syndrome Peripheral neuropathy, acute renal
failure, pulmonary fibrosis (L)
fibrosis
1
Less common with lower doses
2
Extremely rare at doses of < 10 g/m2/course
AALL0031 Page 144
Leucovorin
Immediate Allergic reaction (rash, hives, itching,
wheezing)
Within 2-3 wks
Delayed
Late
Mercaptopurine
Immediate Loss of appetite, Blood in the urine1, life threatening allergic
nausea, vomiting, reaction, passage of crystals in the urine causing
diarrhea kidney irritation1, hives
Prompt Decrease in the number of red and Mouth sores
white blood cells and platelets
made in the bone marrow
Delayed Scarring of liver tissue, high level of bilirubin in the
blood
Late
1
Mesna
Immediate Bad taste when taken by Nausea, vomiting, stomach pain Headache, pain in arms, legs, and joints; tired
mouth feeling, rash, temporary low blood pressure, allergic
reaction
Prompt diarrhea
Delayed
Late
Methotrexate
Immediate Headache, abnormally high Vomiting, fever, rash, drowsiness, stiff neck,
number of cells in the spinal irritation of tissues in the brain/spinal cord,
fluid seizures (L), partial paralysis
Prompt Drowsiness, unsteady walk
Delayed Learning disability Damage to brain tissue (L)
Late Increasingly poor nervous system function
AALL0031 Page 145
Vincristine
Immediate Damage to nearby tissue if the Jaw pain
medication leaks from a vein
Prompt Hair loss Weakness, Absent intestinal activity resulting in intestinal
constipation blockage, drooping eyelid, hoarseness, decrease in the
number of red and white blood cells and platelets made
in the bone marrow, reduced function of the brain,
abnormal hormone function affecting levels of salt in
the blood and urine, causing too much or too little
urine, seizures
Delayed Loss of deep tendon reflexes Numbness, tingling
and clumsiness
Late
STI571 (Gleevec)
joint pain (L)
Late:
*One patient with no known history of liver problems died on study due to liver failure. This patient was also taking acetaminophen (Tylenol®), also known
as paracetamol in European countries. Although no other patient taking acetaminophen has experienced liver-related side effects, it is recommended as a
precaution to adhere carefully to the instructions and warnings on the acetaminophen package label. Additionally, it is recommended that you carefully
Radiation Risks
lung, liver, and kidneys, and reddening of the skin. There is also the risk of temporary worsening of neurological
been associated with testicular radiation.
Possible late effects may include: shortened height (growth retardation), back bone change of shape (vertebral
deformities), difficulty with vision (cataracts), changes in endocrine function (low hormones), inability to have
children (sterility), learning disabilities or brain damage, and increased risk of developing another cancer.
AALL0031 Page 146
Reproductive Risks
baby while on this study. You (Your child) should not nurse your baby while on this study. Ask about counseling
Since this is a new, experimental treatment for children, other presently unknown side effects may be
encountered. Your child will be watched closely and the drugs will be discontinued if serious side effects develop.
WILL MY CHILD BENEFIT FROM THIS STUDY?

There may or may not be direct medical benefits to your child from taking part in this study. It is hoped that the
information learned from this study may help future patients ALL.

Yes, there are other options.
• The standard treatment for high risk ALL.

• Another experimental treatment (if available).
• No further treatment and comfort care only.
Please discuss these options with your regular doctor as well as other trusted personal and family advisors.

this hospital. Organizations that may inspect and /or copy your (your child’s) research records for Quality
The named groups are all involved in monitoring for any toxicity and the outcome of you/your child as a result
from participation in this study.
WILL I (MY CHILD) HAVE TO PAY FOR THIS TREATMENT?

provided at the usual charge. No funds have been set aside to compensate you (your child) in the event of injury.
The Division of Cancer Treatment, and Diagnosis, NCI, will provide you with the investigational agent free of
AALL0031 Page 147
your willingness to (let him/her) participate in the study. You (your child) will be provided with this information
as soon as it becomes available.
provide.

____________________ ___________________
For questions about you (your child) rights as a study participant, please call
______________________________________________________
___________________
at TELEPHONE NUMBER

1-800-4-CANCER (1-800-422-6237) OR
CancerTrials: http://www.nci.nih.gov/cancer_information/

AALL0031 Page 148
PATIENT NAME ________________________________________
_____________________________________ _______________
_____________________________________ _______________
____________________________________ ______________
AALL0031 Page 149
TREATMENT CALENDAR FOR AALL0031
Day 1 2 3 4 5 6-15 21
Etoposide By needle inserted X X X X X
line for 1 hour
Ifosfamide By needle inserted X X X X X
line for 1 ½ hour
MESNA By needle inserted X X X X X
line for 15 minutes
Methotrexate # By spinal tap, for 1-2 X
minutes
injection daily)
STI571* By mouth X
Testicular radiation** 8 visits, 10-15 min. X
each
* Only for patients with Ph+ ALL assigned to receive STI571 with this chemotherapy combination..
** Only patients with testicular leukemia at diagnosis will receive testicular radiation therapy.
# Patients classified as CNS 2 or those with traumatic taps that have not received 2 additional intrathecal
methotrexate doses in induction, will receive 2 additional IT MTX doses on days 8 and 15.

Day 1 2 3 4-13
Methotrexate By needle inserted into vein or central X
line for 24 hours
Methotrexate By spinal tap, for 1-2 minutes X
Leucovorin By needle inserted into vein or central X X
Cytarabine By needle inserted into vein or central X X
G-CSF By injection (1 injection daily) X
AALL0031 Page 150
REINDUCTION BLOCK 1
Day 1 2 3 4 5 6 7 8 10 12 14 15 17 19 21
Vincristine By needle inserted X X X
line
Daunorubicin By needle inserted X X
line over several
minutes
Cyclophosphamide By needle inserted X X
line for 30 minutes
(4 total doses)
Pegaspargase By needle inserted X
into the muscle
Methotrexate By spinal tap, for X X
1-2 minutes
Dexamethasone By mouth, 2 times X X
a day daily
G-CSF By injection X
(1 injection daily)
STI571* By mouth X
Day 1 2 3 8 9 10 15 19 20 29 36 37 42 56
Methotrexate By needle inserted into vein X X
Leucovorin By needle inserted into vein X X X X
or central line (6 total
doses)
minutes
Cyclophosphamide By needle inserted into vein X
or central line
Etoposide By needle inserted into vein X
or central line
MESNA By needle inserted into vein X
G-CSF By injection –1 daily X
injection
Cytarabine By needle inserted into vein X X
(4 total doses)
L-asparaginase By needle inserted into the X
muscle
STI571* By mouth X
AALL0031 Page 151
REINDUCTION BLOCK 2

Day 1 2 3 4 5 6 7 8 10 12 14 15 21
Vincristine By needle inserted into X X X
Daunorubicin By needle inserted into X X
vein or central line over
several minutes
30 minutes every 12
hours (4 total doses)
Pegaspargase By needle inserted into X
the muscle
Methotrexate By spinal tap, for 1-2 X
minutes
Dexamethasone By mouth, 2 times a X X
day daily
injection daily)
STI571* By mouth X
*Only for patients with Ph+ AL assigned to receive STI571 with this chemotherapy combination.
AALL0031 Page 152

Day 1 2 3 8 9 10 15 19 20 29 36 37 42 56
Methotrexate By needle inserted X X
line for 24 hours
Leucovorin By needle inserted X X X X
line (6 total doses)
minutes
Cyclophosphamide By needle inserted X
line
Etoposide By needle inserted X
line
MESNA By needle inserted X
line for 4 hours
injection daily)
Cytarabine By needle inserted X X
line for 3 hours every
12 hours (4 total
doses)
L-asparaginase By needle inserted X
into the muscle
STI571* By mouth X
AALL0031 Page 153
Day 1 2 3 5 8 15 22 28 29 33 36 37 40 41 42 50
Methotrexate By needle inserted into X
24 hours
Leucovorin By needle inserted into X X
vein or central line (6
total doses)
minutes
Vincristine By needle inserted into X X
Methotrexate By mouth X X X
Etoposide By mouth X
Cyclophospha- By needle inserted into X

mide vein or central line for
30 minutes
injection daily)
STI571* By mouth X

Day 1 5 8 15 22 29 33 36 42 43 50 56
Methotrexate By spinal tap, for X
1-2 minutes
Vincristine By needle inserted X X
line
Methotrexate By mouth X X X X X X X
STI571* By mouth X X
Cranial 10 visits, 10-15 X
radiation** min. each
** Only patients with leukemia in the spinal fluid at diagnosis will receive cranial radiation therapy with cycle 5
AALL0031 Page 154
(#3) SAMPLE CONSENT DOCUMENT FOR MINIMUM RESIDUAL DISEASE SPECIMENS

family.
You are being asked (to allow your child) to take part in this study because you are (your child is) being treated
for acute lymphoblastic leukemia (ALL) on the Children’s Oncology Group Study # AALL0031.
In addition to standard bone marrow tests done as part of treatment on AALL0031, researchers would like to take
additional bone marrow samples from you (your child) for highly specialized tests that detect the presence of
leukemia cells. These kinds of tests are called tests for minimum residual disease (MRD). Researchers want to
study whether results of MRD tests can be used to predict how well patients will respond to treatment and which
patients are at a higher risk of relapse.
We are asking your permission to take extra samples of you (your child’s) bone marrow to perform MRD studies.
These additional bone marrow tests are for research purposes only and are not necessary for treatment. You will
not be given the test results and test results will not impact the treatment that you (your child) is given.

The goal of this study is to look at whether tests of MRD on bone marrow can predict how well patients will
respond to treatment and which patients are at a higher risk of relapse.

About 170 patients will take part in this study.

If you agree to (allow your child to) participate in the additional bone marrow tests, we will be testing bone
marrow collected from you (your child) at 5-6 time points during treatment. If you (your child) relapses (the
cancer comes back), we would like to obtain a sample of bone marrow at that time as well.
Whenever possible, the marrow for MRD tests will be taken when marrow is collected for other purposes, so its
use and collection has no additional risks.
In most cases, infants will get medications by vein to numb the pain and blur the memory. A small area of skin
over the pelvis will be cleaned and numbed with Emla cream or lidocaine and a teaspoon of marrow withdrawn
with a needle. The test is painful and has some small risk of infection or bleeding. The pain normally lessens
Each bone marrow sample for these tests will measure about 3 ml, which is about 1/2 teaspoon. The total amount
of bone marrow taken for the 5-6 samples is 21 ml (about 4 teaspoons). A schedule of the bone marrow samples
for MRD tests is listed below. Since some patients will be given a stem cell transplant as part of treatment on
AALL0031 and some will be given chemotherapy only, the schedule outlines time points for both groups of
patients.
AALL0031 Page 155
Schedule of Bone Marrow Collections for Tests of MRD
Course Day
At Study Entry
Consolidation 2 Day 1
Reinduction 1/Before stem cell transplant Day 1
Reinduction 2/ After stem cell transplant Day 1/24 weeks post HSCT (or before start of ST1571)
Maintenance 1/ After stem cell transplant Day 1/48 weeks post HSCT(or at the end of STI571)
At relapse (if patient relapses)

You (your child) will be treated on this study as long as you are (your child is) being treated on AALL0031. Once
the bone marrow samples are obtained, you (your child) will not have any additional procedures performed as part
of this study. In the event of relapse, however, we will request a sample of your (your child’s) bone marrow as
part of this study.

The risks of marrow collection are minimal local pain, bruising and infection. In the rare situations when bone
marrow is collected for research purposes only, there is the additional risk of conscious sedation, which is used so
that the procedure can be done with minimal discomfort. Conscious sedation is done with drugs given through a
vein or by mouth and will cause you (your child) to be sleepy. When you (your child) is very sleepy there is a risk
of shallow breathing and aspirating food or liquid into the lungs. For this reason, your (child's) breathing, heart
rate and blood pressure will be monitored during and after the procedure. You (your child may) also be given a
drug through a vein or by mouth that will decrease pain.
WILL I (MY CHILD) BENEFIT FROM THIS STUDY?

This study will not benefit you (your child) or your family directly. However, this study may help doctors better
diagnose and treat patients with ALL in the future.
ARE THERE OTHER OPTIONS?

Yes, you are free to choose not to (allow your child to) participate in this research study. This is not a treatment
study and choosing not to participate in this study will not affect the care you (your child) will receive.

You may read your (your child’s) medical record. Unfortunately, absolute confidentiality cannot be guaranteed.
Information about you (your child) may be disclosed if required by law. Your (your child’s) name will not be
used when the research results are published.
Organizations that may inspect/or copy your (your child’s) research records for quality assurance and data
analysis include:
WILL I HAVE TO PAY FOR THIS TREATMENT?

Your family will not be charged for the tests and procedures required specifically for research purposes. Tests,
procedures and office visits required for routine medical care of you (your child) will be billed to you or to a third
party in the usual manner.
AALL0031 Page 156
provided at the usual charge. No funds have been set aside to compensate you in the event of injury.

Taking part in this study is voluntary. You may choose not to (allow your child to) participate in this study. If you
(your child) participate(s), you may discontinue your (your child’s) participation in the study at any time. If you
discontinue participation, physicians and hospital personnel will still take care of you (your child).
Whether you (your child) participate(s) or not, you (your child) will continue to get the best medical care this
hospital can provide.

For questions about your rights as a study participant, please call
______________________________________________________
___________________
at TELEPHONE NUMBER

1-800-4-CANCER (1-800-422-6237) OR
cancerTrials: http://www.nci.nih.gov/cancer_information/

AALL0031 Page 157
to (allow my child to) participate in these additional bone marrow tests.
PATIENT NAME ________________________________________
_____________________________________ _______________
_____________________________________ _______________
____________________________________ ______________
AALL0031 Page 158
(#4) SAMPLE INFORMED CONSENT DOCUMENT FOR STEM CELL TRANSPLANT
Previous studies have shown that stem cell transplant can be curative in some children with very high-risk leukemia.
First, high-dose chmotherapy and radiation therapy (the use of high-dose x-rays to kill cancer cells) are given to
destroy any remaining cancer cells in the patient’s bone marrow. Then, stem cells from another person are given to
rescue the patient’s bone marrow from the deadly side effects of the chemotherapy and radiation. The stem cells from
a donor (another person) will be infused through your child’s central line so that he or she will grow new health stem
cells.
WHY IS THE TRANSPLANT PART OF THE STUDY BEING DONE?

Many believe that stem cell transplant is a good treatment option for very high risk ALL. We wish to find out how
well stem cell transplant works when given after Consolidation Blocks 1 and 2 on this study.
HOW MANY CHILDREN WILL TAKE PART IN THE TRANSPLANT PART OF THE STUDY?
There will be about 120 patients enrolling on the study. Only some of these patients will receive a stem cell
transplant.
WHAT WILL HAPPEN TO ME (MY CHILD) DURING TRANSPLANT?

After you (your child) receive Consolidation Blocks 1 and 2 of chemotherapy, your (your child’s) doctor may
recommend stem cell transplant. This is a decision between you and your doctor. The study allows, but does not
require stem cell transplant. If you and your doctor choose to go to stem cell transplant, you (your child) will
receive chemotherapy and radiation over a period of seven days as per the study protocol.
An outline of the treatment given prior to transplant is below:
TRANSPLANT PREPARATION TREATMENT

Day -7 -6 -5 -4 -3 -2 -1 transplant
Total Body 3 days, given twice X X X
Irradiation each day
Etoposide By intravenously, for 1- X
2 hours
Rest X
Before and after the bone marrow infusion, the patient will be started on the drug cyclosporine (starts day –1 and
continues after transplantation). Cyclosporine will be given twice a day by needle inserted into the central line
until the patient can take it by mouth.
Antibiotics will also be given to prevent or treat infection.
High dose chemotherapy and radiation, in addition to destroying your (your child's) leukemia, will also destroy
normal marrow. This will result in low blood counts that will increase the risk of infection or bleeding during the
first three to four weeks (or longer) and could lead to death. During this time you (your child) will stay in an
isolated room with special care attempted at reducing the chance of infection. You (your child) will need
intravenous fluids and feeding, medication for infection, and transfusions of red blood cell and platelets. Your
(your child's) doctors will try to prevent and correct any medical problem. After marrow function is recovered, the
likelihood of developing an infection or bleed is decreased but will continue as a risk for several months. You
(your child) will spend about 3 months in the hospital.
AALL0031 Page 159
CONSOLIDATION FOR SOME TRANSPLANT PATIENTS

Following transplant, patients with Ph+ ALL and patients with evidence of disease after transplant will take the
drug STI571 by mouth daily for 6 months. STI571 is an experimental drug that will be closely monitored for
possible toxicity.
You (your child) will undergo the following medical tests before, during and after transplant:
• Blood tests • Tests of lung and heart function
• Spinal taps
After transplant, children will be seen regularly by their doctors to look for signs of relapse and late side effects.
WHAT ARE THE POSSIBLE RISKS OF TRANSPLANT?

The new stem cells may not grow, or they may fail to produce necessary blood cells including red blood cells to
carry oxygen, white blood cells to fight infection and platelets to prevent bleeding. If the stem cells fail to grow it
may be necessary to give additional medications and/or to collect additional stem cells from the same or another
donor. Some children with poor blood cell recovery die from infection or bleeding.
Once the new stem cells start to grow in your (your child's) body, you (your child) may develop graft versus host
disease (GVHD). The new stem cells react against your (your child's) body, causing damage to the skin, gut, liver
and other organs. In the skin, you (your child) may develop a rash, which may progress to blisters and peeling of
the skin. The gut disease can present as vomiting, watery diarrhea sometimes with blood and severe stomach
cramping. If there is liver disease you (your child) will be tired, weak and jaundiced (yellow in the eyes). Acute
GVHD may lead to death. The doctors will try to prevent GVHD with a medication called Cyclosporine that will
be started the day before the transplant (day –1), and continued for several months. If you (your child) develop(s)
GVHD, the doctors will attempt to control it with other medication that may or may not be successful. You (your
child) may develop chronic GVHD (after more than 3 months) which may result in long-term damage to the skin,
gut, liver and other organs. If you (your child) develop(s) chronic GVHD, you (your child) may have to remain on
therapy for a long time. Some children die from chronic GVHD after many months of illness.
Since you have (your child has) received chemotherapy in the past, your (his/her) body organs may be weakened
and this may increase the chance for damage from the radiation and high dose chemotherapy. You (your child)
may develop significant damage to any of your (his/her) organs that could result in death. Unexpected
complications may occur, which may result in permanent damage to any of your (your child's) organs including
the brain, so that you (your child) may not be able to function normally either physically (of body parts) or
mentally (of the brain).
Side effects can be expected as listed below. Additional side effects may happen, either immediately or weeks,
months or years after the transplant. The specific side effects of the drugs are listed below:

AALL0031 Page 160
Cyclophosphamide
Immediate Loss of appetite (L), nausea (L), Metallic taste (L), Temporary blurred vision1, heart
vomiting (L) abnormal hormone damage with abnormal heart
function affecting levels of rhythms1, decay of muscle tissue
salt in the blood and urine, in the heart2
causing too much or too
little urine1
Prompt Decrease in the number of red and Bleeding and
white blood cells and platelets made inflammation of the
in the bone marrow, hair loss urinary bladder (L)
3
Delayed decreased ability of the body to fight Damage/scarring of lung tissue
infection or disease, absence of sperm (L)
or stopped monthly periods, inability
to have children(L)
resulting from this treatment,
damage/scarring of bladder tissue
1
2
3
Risk increased in someone who has had chest radiation..
Cyclosporine
Immediate Sudden redness of the face, Headache (L), rapid heart rate Allergic reaction (possibly life-
high blood pressure (L), threatening), sneezing, seizure
reduced function of the immune (L), burning sensation on the
system (L) palms of the hands and soles of
the feet (L)
Prompt Increased amount of body hair Damage to kidney tissue (L), Seizure, burning sensation on the
trembling (L), low level of palms of the hands and soles of
magnesium salts in the blood (L), the feet (L), confusion (L),
high level of bilirubin in the drowsiness, diarrhea
blood (L)
Delayed Swollen gums
Late abnormalities associated with the
increase of cells called
lymphocytes
1
Cyclosporine may cause side-effects of other anticancer medications to be worse
Etoposide
Delayed
AALL0031 Page 161
STI571 (Gleevec)
joint pain (L)
Late:
*One patient with no known history of liver problems died on study due to liver failure. This patient was also taking acetaminophen (Tylenol®), also known
as paracetamol in European countries. Although no other patient taking acetaminophen has experienced liver-related side effects, it is recommended as a
precaution to adhere carefully to the instructions and warnings on the acetaminophen package label. Additionally, it is recommended that you carefully
Radiation Risks
lung, liver, and kidneys, and reddening of the skin; There is also the risk of temporary worsening of neurological
been associated with testicular radiation. With radiation therapy there is also the small chance that a second
tumor (for example a brain tumor) may appear years later at the site of treatment.
Possible late effects which may include: shortened height (growth retardation), back bone change of shape
(vertebral deformities), difficulty with vision (cataracts), changes in endocrine function (low hormones), inability
to have children (sterility), learning disabilities or brain damage, and increased risk of developing another cancer.
Reproductive Risks
baby while on this study. You/Your child should not nurse your baby while on this study. Ask about counseling
Side Effects of Marrow Infusion

Allergic reactions (may develop rash, hives, trouble breathing), emboli (clot) to lungs (may cause difficulty with
breathing), fever, bacterial infection.
Relapse
Leukemia may return (relapse) despite bone marrow transplantation.
WILL I (MY CHILD) BENEFIT FROM STEM CELL TRANSPLANT?

You (your child) may be cured by stem cell transplant. However, some children may die from transplant
complications and leukemia may come back after transplant. We do not know whether outcome after transplant is
better than that obtained with chemotherapy. It is hoped that the information learned from this study may help
future patients with ALL.
AALL0031 Page 162

Yes. You (your child) may continue on planned chemotherapy. You and your physician may choose transplant
employing a regimen different from the one outlined here.

this hospital. Organizations that may inspect and/or copy your (Your child’s) research records for Quality

WILL I HAVE TO PAY FOR THIS TRANSPLANT?

provided at the usual charge. No funds have been set aside to compensate you in the event of injury.
The Division of Cancer Treatment, and Diagnosis, NCI, will provide you with the investigational agent free of

your willingness to (let him/her) participate in the study. You will be provided with this information as soon as it
becomes available.
provide.
AALL0031 Page 163
____________________ ___________________
For questions about your (your child’s) rights as a study participant, please call
______________________________________________________
___________________
at TELEPHONE NUMBER

1-800-4-CANCER (1-800-422-6237) OR
cancerTrials: http://www.nci.nih.gov/cancer_information/

AALL0031 Page 164
PATIENT NAME ________________________________________
_____________________________________ _______________
_____________________________________ _______________
____________________________________ ______________

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AALL0031 Page 1

Open to Entry: October 14, 2002

CHILDREN'S ONCOLOGY GROUP

A CHILDREN’S ONCOLOGY GROUP PILOT STUDY FOR THE TREATMENT OF VERY

A PHASE III GROUP-WIDE PILOT STUDY

Kirk R. Schultz, M.D.

NOTE REQUIREMENT FOR

FORMER CCG INSTITUTIONS - Central review is required for:

FORMER POG INSTITUTIONS FORMER CCG INSTITUTIONS

1.1 Specific Aims

3. To conduct a preliminary evaluation of the feasibility and efficacy of following intensive

5. To evaluate whether MRD detected by PCR at post-intensification time points is prognostically

2. The chemotherapy regimen will have acceptable toxicity.

Consolidation Block 1 (3 weeks)

Consolidation Block 2 (3 weeks)

Patients Meeting Transplant Criteria* Patients Not Receiving Transplants

Preparative Regimen (1 week) Reinduction Block 1 (3 weeks)

MRD Intensification Block 1 (8 weeks)

Intensification Block 2 (8 weeks)

Maintenance (8-week cycles) Maintenance (8-week cycles)

2.2.2.1 Frontline Induction

2.2.2.2. VHR Therapy

Consolidation Block 1 (3 weeks)

Consolidation Block 2 (3 weeks)

Reinduction Block 1 (3 weeks)

Reinduction Block 2 (3 weeks)

Intensification Block 2 (8 weeks)

Maintenance (8-week cycles): Cycles 5-12

3.2 Rationale for Chemotherapy

Treatment of the Central Nervous System (CNS)

Traumatic Spinal Taps and CNS-2 at diagnosis

CCG 1800’s std, CCG 1922 # of pts 2896

CCG 1952, CCG 1962 # of pts 2035

3.3 Rationale for Use of HSCT for VHR Patients

3.4 Rationale for Use of STI571 for Ph+ Patients

3.5 Rationale for Studies of Minimal Residual Disease (MRD) in ALL

3.6 Identification of a VHR Subset of Patients with ALL

3.7 Chemotherapy: NYII Induction

3.9 Chemotherapy: STI571 Phase I trial

4.0 ELIGIBILITY CRITERIA, STUDY ENTRY, AND DEFINITIONS

4.1 Eligibility Criteria

FORMER POG INSTITUTIONS – Central review is required for:

FORMER CCG INSTITUTIONS - Central review is required for:

FORMER POG INSTITUTIONS FORMER CCG-INSTITUTIONS

4.1.1.1 Patients in Remission

4.1.1.2 Patients not in Remission

4.1.3 Prior Therapy Restrictions

4.1.4 Informed Consent

a) Consent for COG AALL0031

4.2.2 Recording IRB Approval

4.2.3 Study Enrollment

4.3.1 Absolute Neutrophil Count (ANC)

4.3.2 Absolute Blast Count

4.3.3 Central Nervous System (CNS ) Disease at Diagnosis

CSF WBC > 2X Blood WBC

60 = 0.04 > 2x 46000 = 0.015

4.3.4 Overt Testicular Leukemia at Diagnosis

4.3.5 Bone Marrow Status

M3: > 25% blasts in a bone marrow aspirate.

5.0 TREATMENT PLAN

5.1 Frontline Induction

5.2 Consolidation Block 1 (3 weeks)

5.2.4 Filgrastim (G-CSF)

5.2.5 Intrathecal Methotrexate: