Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801

Guido Marcucci, Susan Geyer, Kristina Laumann, Weiqiang Zhao, Donna Bucci, Geoffrey L Uy, William Blum, Ann-Kathrin Eisfeld, Timothy S Pardee, Eunice S Wang, Wendy Stock, Jonathan E Kolitz, Jessica Kohlschmidt, Krzysztof Mrózek, Clara D Bloomfield, Richard M Stone, Richard A Larson, Guido Marcucci, Susan Geyer, Kristina Laumann, Weiqiang Zhao, Donna Bucci, Geoffrey L Uy, William Blum, Ann-Kathrin Eisfeld, Timothy S Pardee, Eunice S Wang, Wendy Stock, Jonathan E Kolitz, Jessica Kohlschmidt, Krzysztof Mrózek, Clara D Bloomfield, Richard M Stone, Richard A Larson

Abstract

Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11-positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged <60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions. CALGB 10801 was registered at www.clinicaltrials.gov as #NCT01238211.