Imatinib Mesylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia Who Have Received Chemotherapy

A Phase 2 Study of Imatinib Mesylate (Gleevec) as Maintenance Therapy After Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed C-kit Positive Acute Myeloid Leukemia

RATIONALE: Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well imatinib mesylate works in treating patients with newly diagnosed acute myeloid leukemia who have received chemotherapy.

OBJECTIVES:

Primary

• To determine whether adding imatinib mesylate as maintenance therapy improves progression-free survival in patients with c-kit positive acute myeloid leukemia (AML) compared with historical controls.

Secondary

• To assess the feasibility of administering imatinib mesylate as maintenance therapy after the completion of induction and consolidation therapy in these patients.
• To evaluate potential mechanisms of relapse/resistance in c-kit positive AML by examining multidrug resistance gene expression and AF1q gene expression and to determine whether these levels correlate with c-kit expression.

OUTLINE: This is a multicenter study.

Patients receive oral imatinib mesylate once daily for up to 12 months.

Bone marrow and peripheral blood are collected at baseline. Laboratory endpoints are evaluated by flow cytometry; mutation and gene analysis by PCR.

INCLUSION CRITERIA

• Diagnostic bone marrow aspirate/ biopsy or peripheral blood confirming AML.
• At the time of diagnosis, patients must have c-kit (also known as CD117) positive AML (20% or more of the blasts express c-kit[CD117]).
• A flow scattergram (from the diagnostic AML specimen) must be available to calculate a c-kit MFI.
• Patients must have received standard induction chemotherapy with ADE (cytarabine, daunorubicin, and etoposide) or with 7+3 (7 days of cytarabine continuous infusion and 3 days of an anthracycline (idarubicin, daunorubicin, or mitoxantrone). Patients with persistent leukemia on a Day 10-28 marrow may have received a second course of chemotherapy.
• After the completion of induction therapy, patients must have attained a complete remission based on blood count recovery (neutrophil count ≥ 1,000/µL, platelet count ≥ 100,000/µL), and bone marrow aspirate and biopsy (< 5% myeloblasts).
• For patients < 60 years of age, patients must have received at least 2 courses of post-remission therapy with at least intermediate dose (400 mg/m2/day). *Patients with t(8;21) or inversion 16 at the time of diagnosis must have received at least 2 courses of high dose cytarabine. For patients > or = 60 years of age, patients must have received 1 course of post-remission therapy (the type of chemotherapy will not be specified).
• Patients must be registered on this study (maintenance Imatinib mesylate) within 60 days of the last dose of post-remission therapy.
• A bone marrow aspirate and/or biopsy must be done within 3 weeks of registration documenting CR.
• Women of childbearing potential and sexually active males must use an effective method of contraception.
• Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
• ECOG Performance Status 0-2.
• Creatinine must be ≤ 1.5 x upper limit of normal.
• Total bilirubin must be ≤ 2 mg/dl and AST and ALT must be ≤ 2 times the upper limit of normal.
• Previous treatment-related toxicities must have resolved to ≤ Grade 1 excluding alopecia.
• Written, voluntary informed consent.

EXCLUSION CRITERIA

• Acute promyelocytic leukemia.
• Patients with an autologous or allogeneic bone marrow transplant.
• History of HIV.
• Pregnant or breast-feeding.
• Serious or poorly controlled medical conditions that would interfere with the protocol.
• At the time of study entry, any medications which could significantly interact with imatinib mesylate must be discontinued.
• Patients with active extramedullary disease are not eligible.
• Patient has received any other investigational agents within 28 days of first day of study drug dosing.
• Patient is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
• Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
• Patient previously received radiotherapy to ≥ 25 % of the bone marrow
• Patient had a major surgery within 2 weeks prior to study entry.
• Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.