Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia

Abstract

FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.

Keywords: FMS-like tyrosine kinase 3; acute myeloid leukemia; gilteritinib; midostaurin.

Figure 1

Proposed mechanisms of FLT3 inhibitor resistance and the established overcoming agents. Schematic of FLT3 inhibitor resistance mechanism including several types of FLT3 mutations were present. Several targeted agents such as venetoclax, proteasome inhibitors, multikinase inhibitors, novel dual agents, and novel FLT3 inhibits biologic agents, could overcome and thus lead to cancer cell growth, proliferation, and prolonged survival of the FLT3 mutations by several mechanisms.