Patients are stratified according to risk group (standard risk [MLL-G: germline or non-rearranged] vs intermediate risk [MLL-R: rearranged, age ≥ 90 days at diagnosis] vs high risk [MLL-R, age < 90 days at diagnosis]).
All patients receive induction therapy (weeks 1-3) comprising vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase intramuscularly (IM) on day 4; oral prednisone or methylprednisolone IV three times daily on days 1-21; triple intrathecal (IT) chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on days 1, 8, and 15; and filgrastim IV or subcutaneously (SC) beginning on day 5 and continuing until blood counts recover.
Standard risk patients are nonrandomly assigned to receive a less intensive chemotherapy regimen without lestaurtinib (post-induction therapy A).
Post-induction therapy A (for standard-risk patients [MLL-G]):
Induction intensification (weeks 4-7): Patients receive high-dose methotrexate IV continuously over 24 hours on days 22 and 29; triple IT chemotherapy on days 22 and 29; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; cyclophosphamide IV over 30 minutes on days 36-40; etoposide IV over 2 hours on days 36-40; and filgrastim IV or SC beginning on day 41 and continuing until blood counts recover. Patients in morphologic remission proceed to re-induction therapy.
Re-induction (weeks 8-10):Patients receive vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase IM on day 4; dexamethasone IV or orally twice daily on days 1-7 and 15-21; triple IT chemotherapy on days 1 and 15; and filgrastim IV or SC beginning on day 5 and continuing until blood counts recover.
Consolidation (weeks 11-17): Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; triple IT chemotherapy on day 1; etoposide IV over 2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19; high-dose cytarabine IV over 3 hours every 12 hours on days 29 and 30; pegaspargase or asparaginase IM on day 30; and filgrastim IV or SC beginning on day 20 and day 31 and continuing until blood counts recover.
Continuation I (weeks 18-39):Patients receive vincristine IV on day 1 in weeks 18, 22, 29, and 33; dexamethasone IV or orally twice daily on days 1-5 in weeks 18, 22, 29, and 33; triple IT chemotherapy on day 1 in weeks 18, 22, 29, and 33; methotrexate IV on day 1 in weeks 19-21, 23-35, 30-32, and 34-36; etoposide IV over 2 hours on day 1-5 in weeks 26 and 37; cyclophosphamide IV over 30 minutes on days 1-5 in weeks 26 and 37; oral mercaptopurine on days 1-7 in weeks 19-21, 23-35, 30-32, and 34-36; and filgrastim SC or IV beginning on day 6 in weeks 26 and 37 and continuing until blood counts recover.
Continuation II (weeks 40-104):Patients receive vincristine IV on days 1, 29, and 57; dexamethasone IV or orally twice daily on days 1-5, 29-33, and 57-61; intrathecal methotrexate (IT MTX) on day 1; oral methotrexate on days 8, 15, 22, 36, 43, 50, 64, 71, and 78; and oral mercaptopurine on days 8-28, 36-56, and 64-84. Treatment repeats every 12 weeks for 2 years from diagnosis.
A safety/activity phase is conducted separately for the intermediate risk (IR) and high risk (HR) patients to identify a safe, tolerable, and biologically active dose of lestaurtinib combined with P9407-based chemotherapy backbone. Once a tolerable/active dose of lestaurtinib has been identified for IR patients, subsequent IR patients are eligible to proceed to an efficacy phase, where they are randomized to P9407- based chemotherapy backbone with or without lestaurtinib. HR patients separately proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR stratum. IR and HR patients are randomized to 1 of 2 post-induction therapy regimens (post-induction therapy B or C).
Post-induction therapy B (chemotherapy only for IR/HR patients classified as MLL-R; age ≥ 90 days at diagnosis):
Induction intensification (weeks 4-7):Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy A induction intensification. Patients in morphologic remission proceed to re-induction.
Re-induction (weeks 8-10):Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy A re-induction.
Consolidation (weeks 11-17): Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy A consolidation.
Continuation I (weeks 18-47) : Patients receive vincristine on day 1 in weeks 18, 22, 31, 35, and 44; dexamethasone orally or IV twice daily on days 1-5 in weeks 18, 22, 31, 35, and 44; triple IT chemotherapy on day 1 in weeks 18, 22, 31, 35, and 44; methotrexate IV on day 1 in weeks 19-21, 23, 24, 32-34, 36, 37, and 45-47; oral mercaptopurine on days 1-7 in weeks 19-21, 23, 24, 32-34, 36, 37, and 45-47; etoposide IV over 2 hours on days 1-5 in weeks 25 and 38, high-dose cytarabine IV over 3 hours every 12 hours on days 1 and 2 in weeks 28 and 41; pegaspargase or asparaginase IM on day 2 in weeks 28 and 41; and filgrastim SC or IV beginning on day 6 in weeks 25 and 38 and beginning on day 3 in weeks 28 and 41 and continuing until blood counts recover.
Continuation II (weeks 48-104): Patients receive vincristine, dexamethasone, IT methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction therapy A continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis.
Post-induction therapy C (chemotherapy and lestaurtinib for IR/HR patients classified as MLL-R; age < 90 days at diagnosis):
Induction intensification therapy (weeks 4-7): Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy B induction intensification. Patients also receive oral lestaurtinib twice daily on days 41-48. Patients in morphologic remission proceed to re-induction.
Re-induction (weeks 8-10): Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy B re-induction. Patients also receive oral lestaurtinib on days 5-20.
Consolidation (weeks 11-17): Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B consolidation. Patients also receive oral lestaurtinib on days 20-27 and 31-42.
Continuation I (weeks 18-47): Patients receive vincristine, dexamethasone, triple IT chemotherapy, methotrexate, mercaptopurine, etoposide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B continuation I. Patients also receive oral lestaurtinib on days 2-6 in weeks 18, 22, 31, 35, and 44; days 6 and 7 in weeks 25 and 38; days 1-7 in weeks 26 and 39; days 1-6 in weeks 27 and 40; days 3-7 in weeks 28 and 41; and days 1-7 in weeks 29 and 42.
Continuation II (weeks 48-104): Patients receive vincristine, dexamethasone, IT methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction therapy B continuation II. Patients also receive lestaurtinib on days 2-6, 30-34, and 58-62. Treatment repeats every 12 weeks for 2 years from diagnosis.
Blood samples are collected periodically for pharmacokinetic studies and plasma inhibitory activity assay.
After completion of study treatment, all patients are followed every 1-6 months for 4 years and then annually thereafter.
