FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia

Abstract

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.