Imatinib Mesylate, Daunorubicin, and Cytarabine in Treating Patients With Relapsed Acute Myeloid Leukemia

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) and recommended phase II dose of imatinib mesylate in combination with daunorubicin hydrochloride and cytarabine in patients with relapsed acute myeloid leukemia.

Secondary

• Assess the non-dose-limiting toxicities associated with this regimen in these patients.
• Determine any preliminary evidence of clinical activity of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of imatinib mesylate.

Patients receive daunorubicin IV on days 1-3 and cytarabine IV continuously on days 1-7. Patients also receive oral imatinib mesylate once daily beginning on day 1 and continuing until disease progression or unacceptable toxicity. Patients with persistent leukemia on day 14 bone marrow biopsy but ≥ 50% reduction in bone marrow blasts receive 5 more days of cytarabine and 2 more days of daunorubicin while continuing imatinib mesylate.

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 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Bone marrow biopsy confirming acute myeloid leukemia (AML)

• No M3 AML
• Patient must have relapsed to standard chemotherapy

• Patients who relapse within six months of response to treatment or those who never responded to an anthracycline/cytarabine combination will be excluded
• At least 20% of peripheral blood or bone marrow blasts positive for c-kit
• No evidence of leptomeningeal involvement

PATIENT CHARACTERISTICS:

• ECOG Performance Status 0-2
• Liver enzymes (AST and ALT) and total bilirubin ≤ 2 times upper limit of normal
• Serum creatinine ≤ 2 times upper limit of normal
• No New York Heart Association grade III or IV cardiac problems

• Defined as congestive heart failure or myocardial infraction within the past 6 months
• No known chronic liver disease (i.e., chronic active hepatitis and cirrhosis)
• No serious or poorly controlled medical conditions that could be exacerbated by the treatment or would seriously complicate compliance with this study
• No other active primary malignancy unless it is not currently clinically significant and does not require active intervention
• No history of HIV infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No significant history of noncompliance to medical regimens or inability to grant reliable informed consent

PRIOR CONCURRENT THERAPY:

• Previous treatment-related toxicities should be resolved
• No other investigational agents within the past 28 days
• No chemotherapy within the past 4 weeks

• 6 weeks for nitrosourea or mitomycin C
• No major surgery within the past 4 weeks
• No concurrent use of the following drugs is allowed: ketoconazole, dilantin, itraconazole, erythromycin, clarithromycin, dexamethasone, rifampin, tegretol, phenobarbital, Hypericum perforatum (St. John's wort), cyclosporine, pimozide, warfarin, certain HMG-CoA reductase inhibitors, traizolo-benzodiazepines, or dihydropyridine calcium channel blockers
• No other concurrent anticancer agents, including chemotherapy and biologic agents
• No other concurrent investigational drugs
• Concurrent medications known to be metabolized by cytochrome p450 enzymes are allowed
• No therapeutic anticoagulation with warfarin will be permitted in patients participating in this study

• Therapeutic anticoagulation may be accomplished using low-molecular weight heparin
• Mini-dose warfarin for prophylaxis of central venous catheter thrombosis allowed
• No concurrent routine use of systemic corticosteroid therapy