PRIMARY OBJECTIVES:
I. To compare the immunologic complete response rate after one course of therapy in patients who receive cytarabine + daunorubicin + etoposide (ADE) with that in patients who receive clofarabine + cytarabine (Clo/AraC).
SECONDARY OBJECTIVES:
I. To estimate the event-free survival (EFS) of standard risk (SR) patients who receive chemotherapy alone and the EFS of SR patients who receive chemotherapy followed by natural killer (NK) cell transplantation.
EXPLORATORY OBJECTIVES:
I. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and after induction therapy, and to explore the associations of these features with treatment outcome.
II. To assess the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of induction I.
III. To validate new markers and methods for minimal residual disease (MRD) detection.
IV. To identify new prognostic factors by applying new technologies to study patient material
V. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.
VI. To describe the impact of antibiotic and antifungal prophylaxis on invasive bacterial and fungal infections, febrile neutropenia, hospitalization, and antibiotic resistance.
VII. To explore the feasibility and toxicity of administering vorinostat in combination with chemotherapy in selected high-risk patients.
OUTLINE: This is a randomized, phase III study of induction therapy and a phase II study of NK cell transplantation.
INDUCTION I: Patients are randomized to 1 of 2 treatment arms.
ARM I (high-dose [HD]-ADE): Patients receive cytarabine intravenously (IV) over 3 hours twice daily (BID) on days 1, 3, and 5; daunorubicin hydrochloride IV over 6 hours once daily (QD) on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 2-6.
ARM II (CLO/ARAC): Patients receive clofarabine IV over 2 hours QD on days 1-5 followed by cytarabine IV over 2 hours QD on days 1-5.
In both arms, treatment repeats every 21 days for up to 2 courses.
INDUCTION II (low-dose [LD]-ADE): Patients receive cytarabine IV over 30 minutes BID on days 1-8; daunorubicin hydrochloride IV over 6 hours QD on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 1-5. Patients with FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) also receive sorafenib tosylate orally (PO) BID beginning one day after completion of Induction II and continuing for 21 days. Other high-risk (HR) patients also receive vorinostat PO QD, BID, or thrice daily (TID) on days -2 to 0 and days 1-6.
CONSOLIDATION I: Patients not undergoing stem cell transplant (SCT) receive mitoxantrone hydrochloride IV over 1 hour QD on days 3-5 and cytarabine IV over 2 hours BID on days 1-4. Patients with low levels of MRD may proceed directly to SCT; patients with a killer immunoglobulin-like receptor (KIR)-mismatched family member may proceed to NK cell transplantation; and patients with higher levels of MRD may receive additional consolidation chemotherapy before SCT.
CONSOLIDATION II: Patients receive cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) or IV over 1 hour over 3 hours on days 2 and 9.
NK CELL TRANSPLANTATION: Patients receive cyclophosphamide IV over 1 hour on day -7; fludarabine phosphate IV over 30 minutes on days -6 to -2; aldesleukin subcutaneously (SC) on days -1, 1, 3, 5, 7, and 9. Patients undergo NK cell infusion on day 0. Patients then proceed to SCT.
CENTRAL NERVOUS SYSTEM (CNS) THERAPY: All patients undergo intrathecal (IT) chemotherapy comprising methotrexate, hydrocortisone, and cytarabine at the time of diagnosis.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically for 5 years.
