Clinical Crenolanib Resistance in AML

FLT3 mutations are commonly detected in Acute Myeloid Leukemia (AML) patients and are associated with poor prognosis. Crenolanib, a potent type I pan-FLT3 (GeneID:2322) inhibitor, is effective against both internal tandem duplications (ITD) and resistance-conferring tyrosine kinase domain (TKD) mutations. While crenolanib monotherapy has demonstrated significant clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. To investigate the mechanisms of crenolanib resistance, we performed whole exome sequencing of AML patient samples before and after crenolanib treatment (122 samples from 59 patients). Unlike other FLT3 inhibitors, crenolanib did not induce FLT3 activation loop mutations, and mutations of the FLT3 "gatekeeper" residue were infrequent. Instead, mutations of NRAS (GeneID:4893) and IDH2 (GeneID:3418) arose, mostly as FLT3-independent subclones, while TET2 (GeneID:54790) and IDH1 (GeneID:3417) predominantly co-occurred with the FLT3-mutant clone and were enriched in crenolanib poor-responders. The remaining patients exhibited post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse non-FLT3 genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restored crenolanib sensitivity.]]> All patients 18 years or older with relapsed/refractory AML containing a FLT3-ITD or FLT3 tyrosine kinase domain point mutation were eligible for treatment with crenolanib on this study. Full list of inclusion/exclusion criteria are provided at ClinicalTrials.gov (NCT 01522469 and NCT 01657682). ]]> Samples were obtained according to the Declaration of Helsinki under IRB-approved protocols from patients who were enrolled on Phase II clinical trials of crenolanib (ClinicalTrials.gov NCT 01522469 and NCT 01657682) in relapsed or refractory AML at University of Texas Southwestern Medical Center and MD Anderson Cancer Center. ]]>