Trial Information

Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission

OBJECTIVES:

- Compare the duration of complete remission (CR) and survival in patients with acute
lymphoblastic leukemia in first remission treated with allogeneic or autologous stem
cell transplantation (SCT) vs conventional consolidation and maintenance chemotherapy.

- Compare the overall treatment outcomes in patients treated with these regimens.

- Determine the effect of imatinib mesylate given after induction therapy in Philadelphia
(Ph) chromosome-positive patients in CR.

- Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph
chromosome-positive patients.

- Determine the benefit of additional imatinib mesylate administered after allogeneic or
autologous SCT in Ph chromosome-positive patients.

- Determine the minimal residual disease in Ph chromosome-positive patients before and
after treatment with imatinib mesylate.

- Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene
amplification or mutation in Ph chromosome-positive patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age
(50 and under vs over 50), time to achieve complete remission (CR) (4 weeks or less vs more
than 4 weeks), and Philadelphia (Ph) chromosome status (positive vs negative).

- First induction therapy: Patients receive daunorubicin (DNR) IV over 15-30 minutes and
vincristine (VCR) IV over 3-5 minutes on days 1, 8, 15, and 22; oral prednisone (PRED)
once daily on days 1-28; and asparaginase (ASP) IV over 30 minutes or intramuscularly
on days 17-28. Patients with CNS leukemia at presentation also receive methotrexate
(MTX) intrathecally (IT) via an Ommaya reservoir weekly until the CSF is clear.
Patients without CNS leukemia at presentation receive MTX IT on day 23 only.

- Second induction therapy: Beginning immediately after first induction therapy, patients
receive cyclophosphamide (CTX) IV over 30 minutes on days 1, 15, and 29; cytarabine
(ARA-C) IV over 30 minutes on days 1-4, 8-11, 15-18, and 22-25; and oral mercaptopurine
(MP) once daily on days 1-28. Patients with CNS leukemia at presentation also undergo
concurrent craniospinal irradiation. Patients without CNS leukemia at presentation
receive MTX IT on days 1, 8, 15, and 22. Patients with Ph chromosome-positive status
receive oral imatinib mesylate once daily for at least 28 days (days 1-28).

Patients with Ph chromosome-positive status and CR after second induction therapy proceed to
group I for autologous or allogeneic stem cell transplantation (SCT). Patients with Ph
chromosome-negative status and CR after second induction therapy proceed to group II.

- Group I (Ph chromosome-positive patients):

- Autologous SCT: Patients receive high-dose consolidation/mobilization chemotherapy
comprising ARA-C IV over 3 hours on days 1-3 and mitoxantrone IV immediately after
ARA-C administration on days 1 and 2. Patients also receive filgrastim (G-CSF)
subcutaneously (SC) once daily beginning on day 5 and continuing until blood
counts recover.

Patients then undergo peripheral blood stem cell collection or bone marrow harvesting.

Patients receive preparative therapy comprising total body irradiation twice daily (5-10
hours apart) on days -6 to -4 and high-dose etoposide (VP-16) IV over 4 hours on day -3.
Male patients also undergo radiotherapy boost to the testes on day -6.

Patients undergo autologous SCT on day 0 and receive sargramostim (GM-CSF) SC once daily
beginning 6 hours after the completion of SCT and continuing until blood counts recover.

- Allogeneic SCT: Patients receive the preparative regimen as in autologous SCT and then
undergo allogeneic SCT on day 0. Patients receive GM-CSF as in autologous SCT.

- Post-SCT imatinib mesylate therapy: After recovery from autologous or allogeneic SCT,
patients receive oral imatinib mesylate once daily. Imatinib mesylate therapy continues
in the absence of disease progression or unacceptable toxicity.

- Group II (Ph chromosome-negative patients):

- Intensification therapy: Beginning 4 weeks after the completion of the second induction
therapy, patients receive high-dose MTX IV over 2 hours on days 1, 8, and 22;
leucovorin calcium IV every 6 hours for 4 doses and then orally every 6 hours for 12
doses beginning 22-24 hours after each MTX infusion; and ASP IV over 30 minutes on days
2, 9, and 23.

Patients who are ≤ 50 years of age with a histocompatible donor proceed to allogeneic SCT
and undergo allogeneic SCT as in group I. Patients who are ≤ 50 years of age without an
appropriate donor are randomized to 1 of 2 treatment arms.

- Arm I (conventional consolidation/maintenance therapy):

- Conventional consolidation therapy: During course 1, patients receive ARA-C IV
over 30 minutes and VP-16 IV over 1 hour on days 1-5; VCR IV on days 1, 8, 15, and
22; and oral dexamethasone on days 1-28. During course 2 (which begins 4 weeks
after initiation of course 1 or when blood counts recover), patients receive ARA-C
and VP-16 as in course 1. During course 3 (which begins 4 weeks after initiation
of course 2 or when blood counts recover), patients receive DNR IV on days 1, 8,
15, and 22; CTX IV over 30 minutes on day 29; ARA-C IV over 30 minutes on days
31-34 and 38-41; and oral thioguanine on days 29-42. During course 4 (which begins
8 weeks after initiation of course 3 or when blood counts recover), patients
receive treatment as in course 2.

- Maintenance therapy: Beginning 4 weeks after initiation of course 4 of
consolidation therapy or when blood counts recover, patients receive oral MP
daily; MTX orally or IV once weekly; VCR IV once every 12 weeks; and oral PRED for
5 days every 12 weeks. Maintenance therapy continues for 2.5 years after
initiation of intensification therapy.

- Arm II (autologous SCT): Patients undergo autologous SCT as in group I with the
exception of high-dose consolidation/mobilization chemotherapy.

Patients are followed every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 40 patients per year will be accrued for group I
(Philadelphia [Ph] chromosome-positive patients) of this study. Approximately 550 patients
will be accrued for group II (Ph chromosome-negative patients) of this study within 5 years.