Trial Information

Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification for Children With Standard Risk Acute Lymphoblastic Leukemia

OBJECTIVES:

- Compare the event-free survival and overall survival of children with standard-risk
acute lymphoblastic leukemia treated with escalating-dose IV methotrexate without
leucovorin calcium versus oral methotrexate during the interim maintenance phase of
therapy.

- Compare the event-free survival and overall survival of these patients after receiving
treatment in two delayed intensification phases versus one delayed intensification
phase.

- Compare the toxic effects of oral versus escalating-dose intravenous methotrexate in
these patients.

- Determine the prognostic significance of the rate of disappearance of peripheral
lymphoblasts and lymphocytes during the first week of treatment in these patients.

- Determine the prognostic significance of trisomies of chromosomes 4, 5, 10, and 17 and
early treatment response in patients treated with these regimens.

- Determine the prognostic significance of the TEL-AML1 fusion transcript and early
treatment response in patients treated with these regimens.

- Determine the minimal residual disease (MRD) by polymerase chain reaction in bone
marrow and cerebrospinal fluid at various stages of therapy in these patients.

- Determine the prognostic significance of MRD during various stages of therapy in these
patients.

- Determine whether a second delayed intensification therapy improves the prognosis of
patients who have MRD at the end of induction therapy.

OUTLINE: This is a randomized, multicenter study. Patients without CNS disease at diagnosis,
achieving a specified early marrow response profile and M1 marrow status of less than 5%
blasts in the bone marrow (regardless of the proportion of mature lymphocytes) by day 28 of
induction therapy, and remaining event free with favorable bone marrow status and
cytogenetics between day 21 and 28 of consolidation therapy are randomized to one of four
treatment arms. Patients with CNS disease at diagnosis are assigned to treatment arm II and
undergo cranial irradiation. Patients with any of the following unfavorable bone marrow
features and/or unfavorable cytogenetic features are assigned to the augmented treatment
regimen by day 21 of induction chemotherapy or at the beginning of consolidation
chemotherapy:

NOTE: All T-cell precursor patients that are not more than 4 months past completion of the
delayed intensification phase of therapy should be switched to the augmented regimen as of
3/8/2004. These patients may be switched to the augmented regimen. The protocol gives
specific instructions according to the phase of therapy the patients are actually in.

- Unfavorable marrow status:

- M2: 5-25% blasts in bone marrow at day 28 of induction chemotherapy (or at day 14
of induction chemotherapy if day 7 status is M3) OR

- M3: More than 25% blast cell in bone marrow, regardless of the proportion of
mature lymphocytes at day 14 of induction chemotherapy

- Unfavorable cytogenetics: Must have 1 of the following:

- t(9;22)(q34;q11)

- t(4;11)(q21;q23)

- Balanced t(1;19)(q23;p13)

- Hypodiploidy with less than 45 chromosomes

- Other 11q23 translocations involving MLL Patients receive standard induction
chemotherapy comprising cytarabine (ARA-C) intrathecally (IT) on day 0 or up to 72
hours before day 0; oral dexamethasone (DM) twice daily on days 0-27; vincristine
(VCR) IV on days 0, 7, 14, and 21; and pegaspargase (PEG-ASP) intramuscularly (IM)
once between days 3-5. Patients without CNS disease at diagnosis receive
methotrexate (MTX) IT on days 7 and 28. Patients with CNS disease at diagnosis
receive MTX IT on days 7, 14, 21, and 28.

Patients who have achieved M1 marrow status by day 28 of induction therapy and have
favorable early bone marrow response and cytogenetics proceed to standard consolidation
therapy once blood counts have recovered. Patients with M3 bone marrow status at day 28 of
induction therapy are taken off the protocol. All other patients are assigned to the
augmented treatment regimen.

Beginning on day 28 of induction chemotherapy, patients receive standard consolidation
chemotherapy comprising VCR IV on day 0 and oral mercaptopurine (MP) on days 0-27. Patients
without CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28. Patients with CNS
disease at diagnosis receive MTX IT on day 7 and cranial irradiation 5 days a week for 2
weeks. Patients with testicular disease receive bilateral testicular radiotherapy 5 days a
week for 1 week and then for 3 consecutive days during the next week.

NOTE: As of 3/8/2004, patients with T-cell disease who did not achieve M1 marrow status by
day 14 of induction OR who did not receive augmented induction and/or consolidation
(regardless of early marrow status) receive cranial irradiation.

- Arm I: Beginning on day 28 of consolidation chemotherapy, patients receive interim
maintenance I chemotherapy comprising oral DM twice daily on days 0-4 and 28-32; VCR IV
on days 0 and 28; oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49; oral MP on days
0-49; and MTX IT on day 28.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
intensification chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV
and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP IM on day
3; cyclophosphamide (CTX) IV over 20-30 minutes on day 28; oral thioguanine (TG) on days
28-41; ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38; and MTX IT on days 0
and 28.

Beginning on day 56 of delayed intensification chemotherapy, patients receive interim
maintenance II chemotherapy identical to interim maintenance I chemotherapy except patients
receive MTX IT on days 0 and 28.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive maintenance
chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70,
and 77; and MTX IT on day 0.

- Arm II: Patients receive interim maintenance I chemotherapy, delayed intensification
chemotherapy, and interim maintenance II chemotherapy as in arm I. Beginning on day 56
of interim maintenance II chemotherapy, patients then receive a second course of
delayed intensification chemotherapy followed by maintenance chemotherapy as in arm I.

- Arm III: Beginning on day 28 of consolidation chemotherapy, patients receive interim
maintenance I chemotherapy comprising VCR IV; escalating doses of MTX IV on days 0, 10,
20, 30, and 40; and MTX IT on day 30. Patients then receive delayed intensification
chemotherapy as in arm I. Patients receive interim maintenance II chemotherapy as in
interim maintenance I chemotherapy, but with IV MTX starting at 2/3 of the maximum
tolerated dose (MTD) attained in interim maintenance I chemotherapy. Patients then
receive maintenance chemotherapy as in arm I.

- Arm IV: Patients receive interim maintenance I chemotherapy as in arm III, delayed
intensification chemotherapy as in arm I, interim maintenance II chemotherapy as in arm
III, delayed intensification II chemotherapy as in arm II, and maintenance chemotherapy
as in arm I.

- Augmented Treatment: Patients receive induction chemotherapy comprising daunorubicin IV
continuously for 48 hours beginning no later than day 21; oral DM twice daily on days
14-27; and VCR IV on days 14 and 21. Patients without CNS disease at diagnosis receive
MTX IT on days 21 and 35. Patients with CNS disease at diagnosis receive MTX IT on days
21 and 28.

NOTE: Patients with T-cell disease should re-start with augmented consolidation and proceed
as per the augmented regimen.

Beginning on day 35 of induction chemotherapy, patients receive consolidation therapy
comprising CTX IV over 20-30 minutes on days 0 and 28; oral MP on days 0-13 and 28-41; ARA-C
IV or SC daily on days 0-3, 7-10, 28-31, and 35-38; VCR IV on days 14, 21, 42, and 49; and
PEG-ASP IM on days 14 and 42. Patients without CNS disease at diagnosis receive MTX IT on
days 7, 14, and 21. Patients with CNS disease at diagnosis receive MTX IT on day 7 and
cranial irradiation as in the randomized treatment section. Patients with testicular
leukemia receive radiotherapy as in the randomized treatment section.

Beginning on day 63 of consolidation chemotherapy, patients receive interim maintenance I
chemotherapy comprising VCR IV on days 0, 10, 20, 30, and 40; escalating doses of MTX IV on
days 10, 20, 30, and 40; PEG-ASP IM on days 1 and 21; and MTX IT on days 0 and 30.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
intensification I chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV
on days 0, 7, 14, 42, and 49; DOX IV over 15 minutes to 2 hours on days 0, 7, and 14;
PEG-ASP IM on days 3 and 42; CTX IV over 20-30 minutes on day 28; oral TG on days 28-41;
ARA-C IV or SC daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

NOTE: Patients with T-cell disease who are in interim maintenance I chemotherapy with
escalating IV methotrexate should continue this phase and then proceed as per the augmented
regimen. If these patients are receiving conventional interim maintenance chemotherapy with
oral methotrexate, they should stop and restart the interim maintenance as per the augmented
regimen. These patients receive cranial irradiation starting on day 28 of delayed
intensification II chemotherapy.

Beginning on day 56 of delayed intensification I chemotherapy, patients receive interim
maintenance II chemotherapy as in interim maintenance I chemotherapy, but with IV MTX
starting at 2/3 of the MTD attained in interim maintenance I chemotherapy.

NOTE: Patients with T-cell disease who are in delayed intensification I chemotherapy proceed
with this phase, with the addition of 2 vincristine doses on days 42 and 49 and PEG-ASP on
day 42. These patients then proceed as per the augmented regimen with the addition of
cranial irradiation starting on day 28 of delayed intensification II chemotherapy.

NOTE: Patients with T-cell disease who are within 4 months of completing delayed
intensification I chemotherapy and have not received interim maintenance II chemotherapy
with escalating IV methotrexate or delayed intensification II chemotherapy receive a course
of interim maintenance chemotherapy and delayed intensification II chemotherapy according to
the augmented regimen. If these patients have received interim maintenance II chemotherapy
with escalating IV methotrexate, they receive delayed intensification II chemotherapy
according to the augmented regimen. These patients also receive cranial irradiation starting
on day 28 of delayed intensification II chemotherapy and then proceed to maintenance
therapy.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive delayed
intensification II chemotherapy as in delayed intensification I chemotherapy.

Beginning on day 56 of delayed intensification II chemotherapy, patients receive maintenance
chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70,
and 77; and MTX IT on day 0.

Patients are followed every 4-8 weeks for one year, every 3 months for one year, every 6
months for one year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,037 randomized patients will be accrued for this study
within 3.75 years.