A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia |
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| Affiliation: | 1. Children''s Hospital, University of Helsinki and Helsinki University Hospital, Finland;2. Department of Children''s Clinical Neurophysiology, HUS Medical Imaging Center and Children''s Hospital, Helsinki University Hospital and University of Helsinki, Finland;3. Clinical Neurosciences, Neurology, University of Helsinki and Hyvinkää Hospital, Helsinki and Uusimaa Hospital District, Finland;4. Clinical Neurosciences, Head and Neck Center, Neuropsychology, University of Helsinki and Helsinki University Hospital, Finland;5. Infant Cognition Laboratory, Center for Child Health Research, School of Medicine, University of Tampere, Finland;1. Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran;2. Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran;3. Universal Council of Epidemiology (UCE) Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran;4. University of Toronto, St. Michael''s Hospital Multiple Sclerosis clinic, Toronto, ON, Canada |
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| Abstract: | BackgroundMidostaurin, 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 patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.Patients and MethodsPrimary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m2 on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.ResultsTwenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.ConclusionMultiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML. |
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| Keywords: | Acute myeloid leukemia Efficacy and toxicity of low intensity treatment FLT3 phosphorylation Front line therapy Sequential azacitidine and midostaurin |
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