Two Combination Chemotherapy Regimens in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia

OBJECTIVES:

Primary

• Compare the incidence of marrow suppression with 2 methods of maintenance treatment in children with acute lymphoblastic leukemia.
• Compare the incidence of liver toxicity with 2 methods of maintenance treatment in these patients.

Secondary

• Determine any difference in infection rates and related hospitalizations in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (high vs intermediate vs standard), age in years (0 to 5 vs 6 to 9 vs 10 to 17), and sex.

• Patients with standard-risk disease:

• Induction therapy: Patients receive prednisolone IV or orally three times daily on days 1-7; oral dexamethasone three times daily on days 8-28; asparaginase IV over 1 hour or intramuscularly once on days 8, 11, 14, 17, 20, 23, 26, and 29; vincristine IV once on days 8, 15, 22, and 29; daunorubicin hydrochloride IV over 1 hour on days 8 and 15; and methotrexate intrathecally (IT) once on days 1, 15, and 33.
• Early intensification (EI) therapy: Patients receive cyclophosphamide IV over 1 hour on day 36, cytarabine IV continuously on days 38-41 and 45-48, oral mercaptopurine once daily on days 36-50, and methotrexate IT on days 38 and 45.
• Consolidation therapy: Two weeks after completing EI therapy, patients receive oral mercaptopurine once daily on days 1-56 and methotrexate IV over 24 hours and IT on days 8, 22, 36, and 50.
• Delayed intensification (DI) therapy:

• DI/a: Patients receive dexamethasone orally or IV three times daily on days 1-7 and 15-21, doxorubicin hydrochloride IV over 1 hour on days 1, 8, and 15; vincristine IV on days 1, 8, and 15; and asparaginase subcutaneously (SC) or IV over 1 hour on days 1, 4, 8, and 11.
• DI/b: Patients receive cyclophosphamide IV over 1 hour on day 29, cytarabine IV continuously on days 31-34 and 38-41, oral thioguanine once daily on days 29-42, and methotrexate IT on days 31 and 38.
• Maintenance therapy: Patients are randomized to one of two treatment arms. Patients who do not consent for randomization receive conventional therapy (arm I).

• Arm I (conventional): Patients receive oral mercaptopurine and oral methotrexate on days 1-56, dexamethasone IV on days 1-5 and 29-33, vincristine IV on days 1 and 29, and methotrexate IT on day 50. Treatment repeats every 8 weeks for up to 8 courses for girls or 11 courses for boys.
• Arm II (intervention): Patients receive oral mercaptopurine once daily on days 8-28 and 36-56; oral methotrexate once on days 8,15, 22, 36, 43, and 50; dexamethasone IV on days 1-5 and 29-33; and vincristine IV on days 1 and 29. Patients also receive methotrexate IT on day 1, every 8 weeks, for 8 courses.
• Patients with intermediate-risk disease:

• Induction therapy: Patients receive prednisolone, dexamethasone, and asparaginase as in standard-risk induction therapy. Patients also receive vincristine IV and daunorubicin hydrochloride IV over 1 hour on days 8, 15, 22, and 29; methotrexate IT on day 1; and triple intrathecal therapy (TIT; high-dose methotrexate, cytarabine, hydrocortisone sodium succinate) on days 15 and 33.
• First EI therapy: Patients receive cyclophosphamide, cytarabine, and mercaptopurine as in standard-risk EI. Patients also receive TIT on day 38.
• Second EI therapy: Beginning 2 weeks after completing first EI, patients receive cyclophosphamide over 1 hour on day 1, oral mercaptopurine on days 1-14, cytarabine IV on days 3-6 and 10-13, and TIT on day 3.
• Consolidation therapy: Beginning 2 weeks after completing second EI, patients receive mercaptopurine as in standard-risk consolidation therapy. Patients also receive methotrexate IV over 24 hours and TIT on days 8, 22, 36, and 50.
• First DI therapy: Patients receive treatment as in standard-risk DI.
• Interim maintenance therapy: Patients receive oral mercaptopurine and oral methotrexate on days 1-56.
• Second DI therapy: Patients receive DI/a and D1/b (without methotrexate) as in standard-risk DI. Patients also receive TIT on days 31 and 38.
• Maintenance therapy: Patients are randomized to 1 of 2 treatment arms:

• Arm I (conventional): Patients receive mercaptopurine, methotrexate, dexamethasone, and vincristine as in standard-risk maintenance therapy arm I. Patients also receive TIT on day 50. Treatment repeats every 8 weeks for up to 8 courses for girls or 11 courses for boys.
• Arm II (intervention): Patients receive treatment as in standard-risk maintenance therapy arm II.
• Patients with high-risk disease:

• Induction therapy: Patients receive treatment as in intermediate-risk induction therapy.
• First EI therapy: Patients receive treatment as in intermediate-risk first EI.
• Second EI therapy: Patients receive treatment as in intermediate-risk second EI.
• Consolidation therapy (interval between blocks is 2 weeks):

• Block 1: Patients receive dexamethasone orally or IV three times daily on days 1-5, vincristine IV on days 1 and 6, high-dose methotrexate IV over 24 hours on day 1, cyclophosphamide IV over 1 hour twice daily on days 2-4, cytarabine IV over 3 hours twice on day 5, asparaginase IV over 2 hours on days 6 and 11, and TIT on day 1.
• Block 2: Patients receive dexamethasone, high-dose methotrexate, asparaginase, and TIT as in block 1. Patients also receive vindesine IV twice daily on days 1 and 6, ifosfamide IV over 1 hour twice daily on days 2-4, and daunorubicin hydrochloride IV over 24 hours on day 5.
• Block 3: Patients receive dexamethasone and asparaginase as in block 1. Patients also receive high-dose cytarabine IV over 3 hours twice daily on days 1 and 2, etoposide IV over 1 hour five times on days 3-5, and TIT on day 5.
• Blocks 1-3 are then repeated once. Patients then proceed to delayed intensification therapy.
• Delayed intensification therapy: Patients receive dexamethasone orally or IV three times daily on days 1-7 and 15-21; doxorubicin hydrochloride IV and vincristine IV on days 8, 15, 22, and 29; and asparaginase IV on days 8, 11, 15, and 18. Patients also receive cyclophosphamide IV on day 36, cytarabine IV on days 38-41 and 45-48, thioguanine IV on days 36-49, and TIT on days 38 and 45.
• Maintenance therapy: Patients receive oral mercaptopurine and oral methotrexate once daily on days 1-14, cyclophosphamide over 1 hour and cytarabine over 1 hour once between days 15-21, oral dexamethasone two or three times daily for 5 days between days 29-35, vincristine IV on day 29, and TIT on day 22. Treatment repeats every 4 weeks. After 10 courses, patients no longer receive TIT. After 12 courses, patients no longer receive cyclophosphamide and cytarabine. At this time patients continue mercaptopurine and methotrexate on days 1-21. After 20 courses, patients no longer receive dexamethasone or vincristine. At this time, patients continue mercaptopurine and methotrexate on days 1-28. Females receive up to 17 courses and males up to 23 courses.

Some patients may also undergo radiotherapy or stem cell transplantation.

DISEASE CHARACTERISTICS:

• Newly diagnosed acute lymphoblastic leukemia meeting 1 of the following risk definitions:

• Standard-risk disease:

• Age 1 to 9 years
• White blood cell (WBC) < 50/mm^3 OR t(12;21) or molecular fusion product -positive disease
• Good response to prior prednisone (day 8 peripheral blood blast < 1,000/mm^3)
• None of the following subtypes:

• T-cell
• t(9;22)
• t(4;11)
• t(1;19)
• Molecular
• Bone marrow (BM) M1 or M2 on day 15, BM remission (< 5% blast) on day 33
• Intermediate-risk disease:

• Good response to prior prednisone
• BM M1/M2 on day 15
• Meets 1 of the following criteria:

• At least 10 years old
• WBC > 50/mm^3
• Under 1 year old without Mixed Lineage Leukemia (MLL) gene rearrangement
• T-cell OR t(1;19) or molecular fusion product positive.
• Standard-risk patient with BM M3 on day 15
• If minimal residual disease (MRD) available, day 33 MRD < 10^-2
• High-risk disease, meeting 1 of the following criteria:

• Poor response to prior prednisone
• t(9;22) or molecular fusion product (BCR/ABL1), t(4;11) or molecular fusion product (MLL/AF4)
• Intermediate-risk patient with BM M3 on day 15
• BM M2/M3 on day 33
• If MRD available, flow cytometry/polymerase chain reaction (PCR) > 10% on days 15 OR MRD > 10^-2 on day 33 OR MRD (before mini-M phase or M phase) > 10^-3 on day 84

PATIENT CHARACTERISTICS:

• Not specified

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics