• Dose of lestaurtinib [ Designated as safety issue: No ]
• Pharmacokinetic and pharmacodynamic profile of lestaurtinib [ Designated as safety issue: No ]
• Molecular mechanisms of resistance to lestaurtinib in leukemic blasts [ Designated as safety issue: No ]
• Levels of minimal residual disease [ Designated as safety issue: No ]
• Gene expression patterns [ Designated as safety issue: No ]
• Outcome of infants with MLL-germline ALL treated with a modified chemotherapy backbone that includes an extended continuation phase [ Designated as safety issue: No ]

• Dose of lestaurtinib
• Pharmacokinetic and pharmacodynamic profile of lestaurtinib
• Molecular mechanisms of resistance to lestaurtinib in leukemic blasts
• Levels of minimal residual disease
• Gene expression patterns
• Outcome of infants with MLL-germline ALL treated with a modified chemotherapy backbone that includes an extended continuation phase

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of stop cancer cells, either by killing the cells or by stopping them from dividing. Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) together with lestaurtinib may kill more cancer cells.

PURPOSE: This phase III trial is studying giving lestaurtinib together with combination chemotherapy to see how well it works compared to combination chemotherapy alone in treating infants with newly diagnosed acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• To compare the 3-year event-free survival of infants with mixed lineage leukemia rearranged (MLL-R) acute lymphoblastic leukemia (ALL) randomized to treatment with a modified P9407 chemotherapy backbone with or without the FLT3 inhibitor lestaurtinib.

Secondary

• To determine a safe, tolerable, and biologically active dose of lestaurtinib given in sequential combination with chemotherapy in MLL-R infants.
• To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants when given at the proposed dose in sequential combination with chemotherapy.
• To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts.
• To describe levels of minimal residual disease in infants with ALL within the context of the proposed therapy, and correlate with outcome.
• To identify gene expression patterns in diagnostic infant leukemia samples that correlate with outcome within the context of the proposed therapy.
• To describe the outcome of infants with MLL-germline ALL treated with a modified P9407 chemotherapy backbone that includes an extended continuation phase.

OUTLINE: 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.

• Drug: asparaginase
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: dexamethasone
• Drug: etoposide
• Drug: lestaurtinib
• Drug: leucovorin calcium
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: methylprednisolone
• Drug: pegaspargase
• Drug: prednisone
• Drug: therapeutic hydrocortisone
• Drug: vincristine sulfate

• Other: Patients receive combination chemotherapy for up to 104 weeks.
• Active Comparator: Patients receive a different combination chemotherapy regimen than in post-induction therapy A for up to 104 weeks.
• Experimental: Patients receive lestaurtinib and a different combination chemotherapy regimen than in either post-induction therapy A or post-induction therapy B for up to 104 weeks.

DISEASE CHARACTERISTICS:

• Newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia

  • T-cell ALL allowed
  • Bilineage or biphenotypic acute leukemia allowed provided the morphology and immunophenotype are predominately lymphoid
• Must be < 366 days of age at diagnosis; neonates in the first month of life must be > 36 weeks gestational age at diagnosis
• Must be enrolled on protocol COG-AALL03B1 prior to enrollment on this protocol

• Previously untreated except for the following:

  • Steroid treatment within the past 48 hours allowed, provided that a physical examination and CBC with differential were performed immediately prior to beginning steroids
  • Intrathecal (IT) chemotherapy (per protocol) is allowed for patient convenience at the time of the diagnostic bone marrow or venous line placement to avoid second lumbar puncture
• No B-cell ALL or acute myelogenous leukemia

PATIENT CHARACTERISTICS:

• No Down syndrome

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concurrent chronic steroid treatment for another disease
• No other concurrent non-protocol chemotherapy or investigational therapy