Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Relapsed or Refractory Acute Leukemia

OBJECTIVES:

I. Determine the toxicities of escalating doses of flavopiridol administered by "hybrid" bolus-infusion schedule and given in timed sequence with cytarabine and mitoxantrone hydrochloride in patients with refractory or relapsed acute leukemia.

II. Determine the incidence of clinical response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of flavopiridol. Patients receive flavopiridol IV over 30 minutes on days 1, 2, and 3.

Patients receive cytarabine IV continuously over 72 hours beginning on day 6 and mitoxantrone hydrochloride IV over 60-120 minutes on day 9. Treatment repeats every 35-63 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Serum and bone marrow samples are collected at baseline, during, and after completion of treatment for future studies. Flavopiridol levels are measured at baseline and on days 1-3 for pharmacokinetics.

Inclusion criteria

• Pathologically confirmed acute myeloid leukemia or acute lymphoblastic leukemia:

• Relapsed >= 1 time OR refractory disease:

• Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy
• Relapsed >= 1 time OR refractory disease
• Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy
• No active CNS leukemia
• ECOG performance status 0-2
• AST and ALT =< 5 times upper limit normal (ULN)
• Alkaline phosphatase =< 5 times ULN
• Bilirubin =< 2.0 mg/dL
• Creatinine =< 2.0 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• LVEF >= 45% by MUGA or ECHO
• No active, uncontrolled infection
• No other life-threatening illness
• No mental deficits and/or psychiatric history that would preclude study compliance
• No active graft-vs-host disease
• Recovered from all prior therapies
• At least 24 hours since prior hydroxyurea, steroids, imatinib mesylate, arsenic trioxide, interferon, or leukapheresis for blast count control
• At least 4 weeks since prior stem cell transplantation (autologous or allogeneic)
• At least 4 days since prior growth factors
• At least 3 weeks since prior chemotherapy, except for non-aplasia producing treatments (e.g., low-dose cyclophosphamide, hydroxyurea, interferon, imatinib mesylate, mercaptopurine, thalidomide, azacitidine, or decitabine)
• No prior flavopiridol
• No other concurrent chemotherapy, radiotherapy, or immunotherapy
• No acute promyelocytic leukemia (M3)
• No hyperleukocytosis with > 50,000 blasts/mm^3