A Phase II Study of Midostaurin and 5-Azacitidine for Untreated FLT3 Wild Type Elderly and Unfit Acute Myelogenous Leukemia Patients

Abstract: Background Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3 mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients AML. Methods Primary objectives were to further describe the toxicity profile and determine the response rate in untreated AML. Patients received midostaurin 75mg orally twice daily days 8-21 in combination with intravenous azacitidine at 75mg/m2 on days 1-7. Plasma inhibitory activity (PIA) assay for FLT3 was performed pretreatment, days 8, and day 15 of each cycle. Results Twenty-six patients median age 74 (59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range 1-10). Seven of 24 evaluable patients (29%) achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). Median overall survival was 244 (95% CI 203-467) days. Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3-wild type phosphorylation (phospho-FLT3wt) declined to 8-55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles ( Discussion Multiple cycles of azacitidine and midostaurin were not well tolerated, but persistent inhibition of phospho-FLT3wt suggest intermittent dosing of midostaurin should be considered in future low intensity regimens for FLT3 mutant AML.