Mitoxantrone-liposome Sensitizes FLT3-ITD Acute Myeloid Leukemia to Gilteritinib Treatment.

Abstract

FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML), and is associated with poor prognosis and a high relapse rate. Gilteritinib, a second-generation FLT3 inhibitor, is an important target drug for treating patients with FLT3-internal tandem duplication (ITD) AML, is approved for the treatment of relapsed/refractory FLT3-mutant acute myeloid leukemia, although challenges such as drug resistance and reduced potency remain. Herein, mitoxantrone-liposomes sensitized FLT3-ITD AML cells to gitretinib both in vivo and in vitro. RNA-sequencing revealed that combination treatment resulted in specific changes in gene expression as well as predicted the mechanism. Primary AML cells harvested from patients with FLT3-ITD AML showed a significant response to combination treatment in vitro. Our data suggests a novel and promising therapeutic strategy for patients with FLT3-ITD AML and relapsed/refractory FTL3-ITD AML.