Cancer Management and Research (Oct 2019)
Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection
Abstract
Hussein A Abbas,* Mansour Alfayez,* Tapan Kadia, Farhad Ravandi-Kashani, Naval Daver Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this workCorrespondence: Naval DaverDepartment of Leukemia, University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Boulevard, Unit FC 4.2012, Houston, TX 77030, USATel +1713-794-4392Email [email protected]: Fms-related-tyrosine kinase 3 (FLT3) mutations occur in approximately a third of acute myeloid leukemia (AML) patients and confer an adverse prognosis. Numerous studies have evaluated FLT3 targeting as single agent and in combination approaches in frontline and relapsed AML. At this time, midostaurin, a multikinase inhibitor, is the only FLT3-inhibitor that is US FDA approved to be used in combination with induction therapy in the frontline FLT3-mutated AML setting based on improved overall survival noted in the RATIFY Phase III trial. The utility of midostaurin in maintenance post stem cell transplantation has shown promising results and further studies are still ongoing. In this review, we discuss the studies that led to the inception of midostaurin as a targeted kinase inhibitor, its evaluation in AML, the early clinical trials and the large Phase III clinical trial that led to its eventual US FDA-approval in FLT3-mutated AML. Our review also discusses data on midostaurin adverse effects, mechanisms of resistance and limitations of its utility. We further discuss emerging second-generation FLT3 inhibitors, with a focus on quizartinib and gilteritinib and future directions to enhance FLT3-inhibitor efficacy and overcome mechanisms of resistance.Keywords: acute myeloid leukemia, FLT3, midostaurin
