Laromustine, Daunorubicin, and Cytarabine in Treating Patients With Acute Myeloid Leukemia

OBJECTIVES:

Primary

• To determine the dose of laromustine that can be combined with daunorubicin hydrochloride and cytarabine in patients with previously untreated acute myeloid leukemia with unfavorable cytogenetics. (Phase I)
• To determine the complete remission rate of this regimen as induction therapy. (Phase II)

Secondary

• To determine the complete response rate.
• To determine the safety profile of this regimen.
• To determine the overall and relapse-free survival.
• To evaluate the prognostic value of the molecular markers FLT3, duplications of MLL, and Evi-1.

OUTLINE: This is a multicenter, phase I dose-escalation study of laromustine followed by a phase II study.

• Induction treatment: Patients receive laromustine IV on day 4, daunorubicin hydrochloride IV on days 1-3, and cytarabine IV continuously on days 1-7. Patients not attaining complete remission (CR) after first induction receive a second induction treatment comprising daunorubicin hydrochloride IV on days 1-3 and cytarabine IV twice daily on days 1-4. Patients in CR after 1 or 2 induction treatments proceed to consolidation treatment.
• Consolidation treatment: Patients receive mini-consolidation treatment comprising amsacrine on day 1 and cytarabine IV twice daily on days 1-5 followed by 2 courses of continuing consolidation treatment comprising mitoxantrone hydrochloride on days 1 and 2 and cytarabine IV over 12 hours on days 1-5.
• Allogeneic or autologous stem cell transplantation: Patients receive busulfan four times daily for 4 days and melphalan followed by allogeneic or autologous stem cell transplantation.

After completion of study treatment, patients are followed periodically for 5 years.

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia (AML)

• Untreated disease
• No promyelocytic AML
• Unfavorable prognosis, defined as at least one of the following:

• Cytogenetic abnormalities including -5/5q-, -7/7q-, 3q, 11q23, t(6;9), and complex abnormalities (≥ 3 clonal abnormalities), excluding t(9;11)
• Baseline hyperleukocytosis ≥ 100 g/L or progression of leukocytosis or extra-medullary localizations despite treatment with hydroxyurea
• No AML with favorable or intermediate prognosis
• No AML secondary to myelodysplastic syndrome diagnosed within the past 3 months or myeloproliferative syndrome

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Total bilirubin < 35 μmol/L
• Transaminases < 2.5 times upper limit of normal in the absence of leukemia-related abnormalities
• Creatinine < 170 μmol/L OR creatinine clearance ≥ 50 mL/min in the absence of leukemia-related abnormalities
• Not pregnant or nursing
• Normal cardiac function by LVEF (echographic ≥ 40% or isotopic ≥ 50%)
• Affiliated with a social security system
• No uncontrolled or severe cardiovascular disease, including any of the following:

• Myocardial infarction within the past 3 months
• Cardiac insufficiency
• Uncontrolled arrhythmia
• No other active cancer within the past year except for basal cell carcinoma of the skin or epithelioma in situ of the cervix
• No patients deprived of freedom or under guardianship (including temporary guardianship)
• No psychological, familial, geographical, or social situations that preclude follow-up
• No other contraindications to study treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior hydroxyurea allowed
• No concurrent disulfiram
• No concurrent participation in another study with an experimental drug