Combining Isocitrate Dehydrogenase Inhibitors With Existing Regimens in Acute Myeloid Leukemia

Abstract

Identification of recurrent mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) in patients with acute myeloid leukemia (AML) coupled with an understanding of the pathologic role these mutant IDH isoforms impart in leukemogenesis resulted in the development of IDH1 and IDH2 inhibitors comprising a novel, molecularly defined class of targeted therapies for the treatment of AML. This review herein describes the unique cellular pathophysiology and vulnerabilities in IDHmutated AML; the clinical development, efficacy, and known resistance mechanisms to first-generation IDH inhibitors; summarizes the literature surrounding combination therapies incorporating targeted or cytotoxic therapies with IDH inhibitors in patients with IDH-mutated AML; and identifies future challenges and areas of active ongoing investigation within this molecular subgroup.