Cladribine, Cytarabine, and Imatinib Mesylate in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Blastic Phase Chronic Myelogenous Leukemia

OBJECTIVES:

• Determine the safety and feasibility of cladribine, cytarabine, and imatinib mesylate in patients with refractory or relapsed acute myeloid leukemia or blastic phase chronic myelogenous leukemia.
• Determine the maximum tolerated dose of imatinib mesylate in patients treated with this regimen.
• Correlate the expression of c-kit and the presence of c-kit mutations with clinical response in patients treated with this regimen.
• Correlate the in vitro inhibitory effects of imatinib mesylate and cytarabine on the proliferation and survival of leukemic cells with clinical response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of imatinib mesylate.

Patients receive oral imatinib mesylate once daily on days 1-15 and cladribine IV over 2 hours and cytarabine IV over 4 hours on days 3-7. Patients also receive filgrastim (G-CSF) subcutaneously on days 2-7. Treatment repeats every 15 days for 2 courses in the absence of disease progression or unacceptable toxicity.

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

After completion of study treatment, patients are followed periodically for up to 1 year.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia (AML) or blastic phase chronic myelogenous leukemia (CML)

• Refractory AML defined as any of the following:

• Failure to achieve complete response (CR) after 2 courses of induction chemotherapy
• Persistent bone marrow blasts > 40% after 1 course of induction chemotherapy
• Relapse of disease within 3 months since CR
• Relapsed AML defined as the following:

• Any evidence of disease recurrence after CR (early relapse occurs within 3-12 months and late relapse occurs > 12 months later)
• No acute promyelocytic leukemia (AML-M3 FAB subgroup)

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin ≤ 2.0 mg/dL
• AST ≤ 2.5 times upper limit of normal
• No known chronic liver disease (e.g., chronic active hepatitis or cirrhosis)

Renal

• Creatinine < 2.5 mg/dL (if 2.0-2.5 mg/dL, glomerular filtration rate must be measured and dose of cytarabine adjusted if necessary)

Cardiovascular

• No New York Heart Association grade III-IV heart disease
• No congestive heart failure
• No myocardial infarction within the past 6 months
• Ejection fraction ≥ 30%

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 3 months after completion of study treatment
• No uncontrolled systemic active infection
• No known HIV infection
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
• No history of other curatively treated malignancy except nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No other concurrent biologic agents

Chemotherapy

• See Disease Characteristics
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent birth control pills

Other

• More than 1 week since any prior investigational agent
• No other concurrent investigational agents or therapies
• No other concurrent anticancer agents
• No concurrent therapeutic anticoagulation with warfarin

• Low molecular weight heparin or heparin allowed for therapeutic anticoagulation
• Mini-dose warfarin (e.g., 1 mg per day) allowed for prophylaxis of central venous catheter thrombosis