OBJECTIVES:
Primary
- Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia.
Secondary
- Compare the 3-year event-free survival and frequency and severity of adverse effects in patients treated with high-dose (closed to accrual as of 9/2010) vs low-dose vincristine.
- Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors).
OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment arms (randomization closed as of 09/2010).
- Induction therapy 1 (weeks 1-5):
- Arm I: Patients receive low-dose vincristine IV on days 1, 8, 15, and 22; oral prednisone 3 times daily on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29.
- Arm II (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate* as in arm I.
NOTE: *CNS-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36.
Patients in both arms then proceed to induction therapy 2**.
NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2.
NOTE: *** Patients already enrolled on arm II are crossover to arm I.
- Induction therapy 2 (weeks 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.
NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22.
Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily, 5 days a week, for 12 days during induction therapy 2**.
NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy.
All patients then proceed to induction therapy 3.
- Induction therapy 3 (weeks 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover.
Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized arm in induction therapy 1).
- Intensification therapy 1 (weeks 16-27 or 17-28):
- Arm I: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses).
- Arm II(closed to accrual as of 09/2010)**: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in arm I.
NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses.
NOTE: ** Patients already enrolled on arm II are crossover to arm I.
Patients in both arms then proceed to reinduction therapy (as per their randomized arm in induction therapy 1).
- Reinduction therapy (weeks 28-32 or 29-33):
- Arm I: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28.
- Arm II (closed to accrual as of 09/2010)**: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in arm I.
NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28.
NOTE: ** Patients already enrolled on arm II are crossover to arm I.
Patients in both arms then proceed to intensification therapy 2 (as per their randomized arm in induction therapy 1).
- Intensification therapy 2 (weeks 33-56 or 34-57):
- Arm I: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses).
- Arm II: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in arm I. Patients also receive high-dose vincristine IV on days 22 and 29.
NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses.
Patients in both arms then proceed to maintenance therapy (as per their randomized arm in induction therapy 1).
- Maintenance therapy (week 57-106 or 58-107):
- Arm I: Patients receive methotrexate IT on day 1* and then orally on days 8, 15, 22, 29, and 36; oral mercaptopurine once daily on days 1-42; oral dexamethasone twice daily on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses.
- Arm II: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in arm I. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64.
NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate.
Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy once daily, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy.
After completion of study therapy, patients are followed periodically for 5 years.
PROJECTED ACCRUAL: A total of 418 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
- Diagnosis of acute lymphoblastic leukemia (ALL)
- Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow)
- Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are not eligible (considered Burkitt's or mature B-cell leukemia)
- Intermediate-risk relapsed disease, meeting 1 of the following criteria:
- Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow after previous remission from ALL)
- Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36 months after initial diagnosis
- Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after initial diagnosis NOTE: *CNS relapse is defined as WBC ≥ 5/mm³ in cerebral spinal fluid (CSF) with blasts present on cytospin OR any number of WBC in CSF with immunophenotypic proof of leukemic relapse (defined as identifiable blasts plus [for B-lineage] TdT or CD-10 positivity on 2 consecutive CSF samples obtained 4 weeks apart)
NOTE: **Testicular relapse is defined as unilateral or bilateral testiculomegaly with biopsy-proven testicular involvement OR unilateral or bilateral testiculomegaly with concurrent relapse in the bone marrow and/or CNS
- The following subtypes are not allowed:
- T-lineage ALL
- Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of c-myc translocation)
- Philadelphia-chromosome positive disease
- No Down syndrome (trisomy 21)
PATIENT CHARACTERISTICS:
- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
- Bilirubin < 3.0 mg/dL
- Not pregnant
- Fertile patients must use effective contraception
- No history of peripheral neuropathy ≥ grade 3 within the past month
- No toxicity (i.e. peripheral neuropathy) ≥ grade 3 attributable to vincristine within the past month
PRIOR CONCURRENT THERAPY:
- At least 5 days since prior intrathecal chemotherapy
- No prior hematopoietic stem cell or marrow transplantation
- No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse)
- No concurrent stem cell transplant
- No concurrent alternative therapy
- No concurrent itraconazole in patients receiving vincristine
- No concurrent intensity-modulated radiotherapy
Last updated: 05/15/2013
NCT ID: NCT00381680
IRB Number:07-006053
Find Mayo Clinic on