Trial Information

Intensive Induction Therapy for Children With Acute Lymphoblastic Leukemia (ALL) Who Experience a Bone Marrow Relapse

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of using an intensified sequential induction regimen
to treat children with acute lymphoblastic leukemia (ALL), who experience an isolated, or
combined bone marrow relapse.

II. To determine the potential of this regimen to serve, as a backbone, for the future
testing of novel therapeutic agents.

SECONDARY OBJECTIVES:

I. To estimate the remission re-induction rates and four-month event-free survival (EFS) for
children, stratified by the duration of first remission.

II. To determine the feasibility of measuring minimal residual disease (MRD) quantitatively
in all patients at time points throughout re-induction, and to correlate post-remission
events with disease burden during induction.

III. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression
that predict treatment failure, and to compare gene expression profiles at the time of
relapse with those at the time of initial diagnosis to gain an understanding of the pathways
that may be involved in disease recurrence.

IV. To determine the feasibility of combining intensive re-induction therapy with imatinib
mesylate (STI571) for children with a relapse of Philadelphia chromosome positive (Ph+) ALL.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

Treatment Block 1: Patients receive cytarabine intrathecally (IT) on day 1 and methotrexate
IT on days 15 and 29. Patients also receive vincristine intravenously (IV) on days 1, 8, 15,
and 22; prednisone orally (PO) twice or thrice daily (BID or TID) on days 1-29; pegaspargase
intramuscularly (IM) on days 2, 8, 15, and 22; and doxorubicin IV over 15 minutes on day 1.
Ph-positive patients also receive imatinib mesylate PO on days 1-14.

Treatment Block 2: Patients receive methotrexate IT on days 1 and 22, cyclophosphamide IV
over 30 minutes and etoposide IV over 2 hours on days 1-5, and filgrastim (G-CSF)
subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Patients
also receive methotrexate IV over 24 hours on day 22 followed by leucovorin calcium IV every
6 hours on days 24 and 25. Ph-positive patients receive imatinib mesylate PO on days 1-14.

Treatment Block 3a (Ph-negative patients): Patients receive cytarabine IV over 3 hours every
12 hours on days 1, 2, 8, and 9, asparaginase IM on days 2 and 9, and G-CSF SC beginning on
day 10 and continuing until blood counts recover.

Treatment Block 3b (Ph-positive patients): Patients receive cytarabine IV over 3 hours every
12 hours on days 1 and 2, asparaginase IM on day 2, and G-CSF SC beginning on day 3 and
continuing until blood counts recover. Patients also receive imatinib mesylate PO on days
1-14.

ARM II:

Treatment Block 1: Patients receive cytarabine IT on day 1 and then methotrexate, cytarabine
and hydrocortisone IT (triple intrathecal therapy; TIT) on days 8, 15, 22, and 29.
Vincristine, prednisone, pegaspargase, doxorubicin, and imatinib mesylate are administered
as in arm I.

Treatment Block 3: Patients receive cytarabine, asparaginase, G-CSF, and imatinib mesylate
as in arm I.

Treatment Block 2: Patients receive TIT on days 1 and 22. Patients then receive
cyclophosphamide, etoposide, G-CSF, methotrexate IV, leucovorin calcium, and imatinib
mesylate as in arm I. After each block is completed, disease is assessed. The next block is
started on day 36 if blood counts have recovered and marrow during block 1 is at least
M2/M3. Patients are removed from protocol therapy if disease progresses, unacceptable
toxicity occurs, marrow is M2/M3 at day 15 of the second administered block of treatment, or
cerebrospinal fluid blasts persist after 6 weekly doses of TIT.

After completion of study treatment, patients are followed up for 4 months.

PROJECTED ACCRUAL: A total of 63-126 patients will be accrued for this study within 14
months.