Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia

摘要: FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and associated with poor clinical outcomes. Although initial responses to tyrosine inhibitors (TKIs) observed FLT3-ITD−positive patients, subsequent relapse often occurs upon acquisition of secondary domain (KD) mutations, primarily at residues D835 F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties is active against containing ITD and/or D835- or F691-activating mutations. Potent activity was AML cell lines. Crenolanib delayed the outgrowth MV4-11 cells xenograft mouse model, whereas combination II TKI sorafenib, significant decrease leukemic burden (P < .001) prolonged survival .01) compared either alone. Ba/F3 harboring FLT3-ITD KD sorafenib-resistant MOLM-13 FLT3-ITD/D835Y both vitro vivo. In addition, crenolanib inhibited drug-resistant primary blasts D835H/Y These preclinical data demonstrate effective suggesting may be useful therapeutic agent for TKI-naive AML.