OBJECTIVES: Primary
- Compare event-free survival of pediatric patients with newly diagnosed, standard-risk (SR)-average, B-precursor acute lymphoblastic leukemia (ALL) treated with induction therapy followed by 1 of 4 intensified phases of post-induction therapy.
- Compare event-free survival of pediatric patients with SR-low ALL treated with consolidation and interim maintenance therapy with or without additional pegaspargase.
Secondary
- Correlate day 29 minimal residual disease (MRD) status with event-free survival and overall survival of patients treated with these regimens.
- Correlate early marrow response with day 29 MRD status in patients treated with these regimens.
- Determine whether outcome is improved for SR-high patients by identifying these patients by day 29 MRD status and subsequently treating these patients with a fully augmented Berlin Frankfurt Munster regimen.
- Correlate relative contributions of genetic factors and early treatment response with outcome in patients treated with these regimens.
OUTLINE: This is a 2-part, partially randomized, multicenter study. Patients are stratified according to early response to study induction therapy (rapid early response [standard risk (SR)-low or SR-average acute lymphoblastic leukemia (ALL)] vs slow early response [SR-high ALL]). After completion of induction therapy but before proceeding to part II therapy, patients are assigned to 1 of 3 groups based on stratification. Part I
- Induction therapy: All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally twice daily on days 1-28; pegaspargase intramuscularly (IM) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT .
Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD ≥ 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD ≥ 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.
- Extended induction therapy: Patients receive dexamethasone IV or orally twice daily on days 1-14; vincristine IV on days 1 and 8; pegaspargase IM on day 4, 5, or 6; and daunorubicin hydrochloride IV over 15 minutes to 2 hours on day 1.
Patients with M1 bone marrow and MRD < 1% after extended induction therapy proceed to therapy in part II. Patients with M2 or M3 bone marrow after extended induction therapy are removed from the study. Part II
- Group 1 (SR-low ALL): Patients are randomized to 1 of 2 treatment arms.
- Arm I:
- Standard consolidation therapy: Patients receive vincristine IV on day 1; oral mercaptopurine on days 1-28; and methotrexate IT on days 1, 8, and 15. Patients with Down syndrome (DS) receive oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.
- Standard interim maintenance therapy: Patients receive vincristine IV on days 1 and 29; dexamethasone IV or orally twice daily on days 1-5 and 29-33; oral mercaptopurine on days 1-50; oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50; and methotrexate IT on day 29. Patients with DS receive oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.
- Standard delayed intensification (DI) therapy: Patients receive vincristine IV on days 1, 8, and 15; dexamethasone IV or orally twice daily on days 1-21; doxorubicin hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1 and 29.
Patients with DS receive dexamethasone IV or orally twice daily on days 1-7 and 15-21 and oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.
- Arm II:
- Experimental consolidation therapy: Patients receive vincristine, mercaptopurine, methotrexate, and leucovorin calcium as in arm I and pegaspargase IM on days 1 and 22.
- Experimental interim maintenance therapy: Patients receive vincristine, dexamethasone, mercaptopurine, oral methotrexate, and methotrexate IT as in arm I and pegaspargase IM on days 15 and 36.
- Standard DI therapy: Patients receive standard DI therapy as in arm I.
- Group 2 (SR-average ALL): Patients are randomized to 1 of 4 treatment arms.
- Arm I: Patients receive standard consolidation therapy, standard interim maintenance therapy, and standard DI therapy as in group 1, arm I.
- Arm II:
- Standard consolidation therapy: Patients receive standard consolidation therapy as in group 1, arm I.
- Augmented interim maintenance therapy: Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IM on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS receive oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.
- Augmented DI therapy: Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily on days 1-21; doxorubicin hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6 AND day 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36. Patients with DS receive dexamethasone on days 1-7 and 15-21 and oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.
- Arm III:
- Intensified consolidation therapy: Patients receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; pegaspargase IM on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients with DS receive oral leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT*.
NOTE: *Patients with CNS3 disease at diagnosis do not receive methotrexate on days 15 and 22 or leucovorin calcium
- Standard interim maintenance therapy: Patients receive standard interim maintenance therapy as in group 1, arm I.
- Standard DI therapy: Patients receive standard DI therapy as in group 1, arm I.
- Intensified consolidation therapy: Patients receive intensified consolidation therapy as in group 2, arm III.
- Augmented interim maintenance therapy: Patients receive augmented interim maintenance therapy as in group 2, arm II.
- Augmented DI therapy: Patients receive augmented DI therapy as in group 2, arm II.
- Group 3 (SR-high ALL): Patients receive the following therapy:
- Intensified consolidation therapy: Patients receive intensified consolidation therapy as in group 2, arm III.
- Augmented interim maintenance therapy: Patients receive augmented interim maintenance therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses.
- Augmented DI therapy: Patients receive augmented DI therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses*.
NOTE: *Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days 29-33 and 36-40 during course 2 only; these patients do not receive methotrexate on day 36, thioguanine, or leucovorin calcium
- Maintenance therapy: All patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and methotrexate IT on day 1. Courses repeat every 84 days for a total of 2 years from the start of interim maintenance therapy for female patients and 3 years from the start of interim maintenance therapy for male patients. After the completion of study treatment, patients are followed every 1-2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.
PROJECTED ACCRUAL: A total of 3,381 patients (1,576 for group 1,278 for group 2, and 527 for group 3) will be accrued for this study within 4.25 years.
