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) (may give IV over 1 to 2 hours) 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.
- Arm IV:
- 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.
NOTE: *As of Amendment #7, all SR-High patients currently receiving AIM 1 therapy should complete this phase of therapy and proceed to ADI 1 therapy as originally planned including Capizzi methotrexate during AIM 1. Upon completion of ADI 1, patients should receive a second Interim Maintenance phase with high-dose methotrexate (IM HD) rather than Capizzi methotrexate. Patients should then proceed to ADI 2 and then Maintenance.
- Augmented DI* therapy: Patients receive augmented DI therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses**.
NOTE: *As of Amendment #7, all SR-High patients currently receiving ADI 1 therapy should complete this phase of therapy as originally planned. Upon completion of ADI 1, patients should receive a second Interim Maintenance phase with IM HD. Patients should then proceed to ADI 2 and then Maintenance.
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.
NOTE: *SR-High or CNS3 patients should receive up to a maximum of 23 intrathecal treatments for females and 26 intrathecal treatments for males.
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.
DISEASE CHARACTERISTICS:
- Newly diagnosed B-precursor acute lymphoblastic leukemia
- Standard-risk (SR) disease meeting 1 of the following criteria:
- SR-average by age and WBC
- No unfavorable features
- Rapid early responder (RER) by day 15
- CNS 1 or 2
- Minimal residual disease (MRD) negative on day 29
- Trisomies of 4, 10, and 17 or TEL-AML1 translocation and RER and CNS2 allowed
- SR-low by age and WBC
- No unfavorable features
- RER by day 15
- MRD negative on day 29
- CNS1
- Favorable cytogenetics-trisomies of 4, 10, and 17 or TEL-AML translocation
- SR-high
- Unfavorable features meeting ≥ 1 of the following criteria:
- MLL rearrangements and RER
- Steroid pretreatment
- CNS3
- Slow early responder by morphology or MRD
- Patients with Down syndrome are allowed
- Concurrently enrolled on COG-AALL03B1
PATIENT CHARACTERISTICS:
Age
- 1 to under 10
Performance status
- Not specified
Life expectancy
- Not specified
Hematopoietic
- Initial WBC < 50,000/mm^3
Hepatic
- Not specified
Renal
- Not specified
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Not specified
Chemotherapy
- No prior cytotoxic chemotherapy except intrathecal cytarabine
Endocrine therapy
- Prior steroid therapy allowed at the discretion of the investigator
- No contraindication to additional asparaginase therapy after induction for the standard risk-low study
Radiotherapy
- No concurrent intensity-modulated radiotherapy
Surgery
- Not specified
Last updated: 07/18/2012
NCT ID: NCT00103285
IRB Number:2127-05
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