Trial Information

International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic Leukemia

OBJECTIVES:

- Determine the outcome of induction chemotherapy followed by consolidation and
reinduction chemotherapy with or without late intensification chemotherapy followed by
a maintenance regimen or allogeneic bone marrow transplantation in infants with newly
diagnosed acute lymphoblastic leukemia.

- Determine the value of a late intensification course between reinduction and
maintenance therapy in these patients.

- Determine the prognostic value of age, immunophenotype, WBC, day 15 bone marrow status,
and MLL gene rearrangement in patients treated with these regimens.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified
according to risk (high vs standard).

Patients receive induction therapy comprising prednisone orally or IV three times a day on
days 1-7; dexamethasone orally or IV three times a day on days 8-35; vincristine IV on days
8, 16, 22, and 30; cytarabine IV over 30 minutes on days 8-21; daunorubicin IV over 60
minutes on days 8 and 9; asparaginase IV over 1 hour or intramuscularly (IM) on days 15, 18,
22, 25, 29, and 33; methotrexate intrathecally (IT) on days 1 and 29; and cytarabine IT on
day 15. Patients receive prednisolone IT in combination with any dose of intrathecal
chemotherapy. Patients with CNS involvement receive additional doses of methotrexate IT on
days 8 and 22 and then weekly after day 29 until there is no evidence of CNS leukemia.

After achieving complete remission, patients receive MARAM chemotherapy comprising oral
mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8; leucovorin
calcium orally or IV 36, 42, and 48 hours after beginning each dose of oral methotrexate;
methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice daily on days 15, 16, 22,
and 23; and asparaginase IV over 1 hour or IM on days 16 and 23. Patients receive
prednisolone IT in combination with any dose of intrathecal methotrexate.

At least 2 weeks after the completion of MARAM chemotherapy, patients receive OCTADD
chemotherapy comprising oral dexamethasone three times a day on days 1-21; oral thioguanine
daily on days 1-28 and 36-49; vincristine IV on days 2, 8, 16, and 22; daunorubicin IV over
60 minutes on days 1, 8, 15, and 22; cytarabine IV on days 2-5, 9-12, 16-19, 23-26, 37-40,
and 45-48; cytarabine IT on days 1 and 15; and cyclophosphamide IV over 1 hour on days 36
and 49. Patients receive prednisolone IT in combination with any dose of intrathecal
methotrexate.

Patients are randomized to one of two treatment arms for late intensification therapy.

- Arm I: Beginning at least 1 week after the completion of OCTADD chemotherapy, patients
receive VIMARAM chemotherapy comprising vincristine IV on days 1, 8, 15, and 22; oral
mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8;
leucovorin calcium orally or IV 36, 42, and 48 hours after the beginning of each dose
of oral methotrexate; methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice
daily on days 15, 16, 22, and 23; and asparaginase IV over 1 hour or IM on days 16 and
23. Patients receive prednisolone IT in combination with any dose of intrathecal
methotrexate. Patients then receive the appropriate maintenance therapy.

- Arm II: Patients do not receive VIMARAM chemotherapy but receive appropriate
maintenance therapy.

At least 2 weeks after the completion of the last course of chemotherapy, patients receive
maintenance therapy. Patients with a good response to initial therapy with prednisone
receive maintenance therapy comprising oral dexamethasone three times daily on weeks 1 and
2; vincristine IV on day 2 of weeks 1 and 2; oral mercaptopurine daily on weeks 1-14; and
oral methotrexate once weekly on weeks 1-14.

Patients with a poor response to initial therapy with prednisone receive maintenance therapy
comprising oral mercaptopurine daily for weeks 1-14; oral methotrexate once weekly for weeks
1-14; oral dexamethasone three times daily for weeks 1 and 2; vincristine IV on day 2 of
weeks 1 and 2; etoposide IV over 2 hours once weekly on weeks 8 and 9; and cytarabine IV
over 1 hour once weekly on weeks 8 and 9.

Treatment repeats in both maintenance therapy regimens every 14 weeks for a total of 3
courses. Patients also receive methotrexate IT on day 1 of the first and third course of
therapy and cytarabine IT on day 1 of the second course of therapy. Patients receive
prednisolone IT in combination with any dose of intrathecal chemotherapy.

Beginning after the completion of maintenance therapy, all patients receive continuing
maintenance therapy comprising oral mercaptopurine daily and oral methotrexate once a week.
Treatment continues until 104 weeks after initial diagnosis.

Patients with a poor response to initial therapy with prednisone may receive allogeneic bone
marrow transplantation if a donor is available. The patient undergoes transplantation
immediately after OCTADD chemotherapy rather than being randomized and receiving maintenance
therapy. These patients receive conditioning regimen comprising oral busulfan four times a
day on days -8 to -5, etoposide IV over 4 hours on day -4, methotrexate IT on day -3, and
cyclophosphamide IV over 1 hour on days -3 and -2. Allogenic bone marrow is transplanted on
day 0. Patients then receive cyclosporine orally or IV on days 1-180 as graft-versus-host
disease prophylaxis.

Patients are followed annually.

PROJECTED ACCRUAL: A total of 350 patients will be accrued for this study within 5 years.