Background: AML has high molecular complexity and certain markers are predictors of overall survival. Mutations in FLT3-ITD, for example, lead to a poor prognosis with outcomes further worsened by co-occurring mutations in DNMT3A. Small molecule inhibitors have been developed to target a select number of these mutations such as Midostaurin on FLT3-ITD and FLT3-D835. However, the impact of the specific FLT3 mutation or the effect of co-occurring mutations in DNMT3A and NPM1 on drug sensitivity is not fully known. Methods: We identified 503 primary AML samples tested with an ex-vivo drug sensitivity screen that includes 130 small-molecule inhibitors and over 10 FLT3 inhibitors. Mononuclear cells were screened, metabolic viability assessed, and drug response summarized by area under the curve (AUC). Results: FLT3-ITD was the strongest indicator for response to FLT3 inhibitors (Table 1). Sensitivities were similar with DNMT3A and/or NPM1 co-mutations. Further, FLT3-D835 mutant samples showed no increased sensitivity to FLT3 inhibitors compared to non-FLT3 mutated samples. Conclusions: The similar ex-vivo drug sensitivity profiles inFLT3-ITD AML with or without DNMT3A and/or NPM1 mutations suggest co-treatment with FLT3 inhibitors will allow for improved overall survival in these cohorts. Additional clinical testing may further characterize the effect of FLT3-D835 mutations on targeted therapies and the impact of co-mutations. Some FLT3-ITD inhibitors showed increased potency compared to Midostaurin suggesting alternative treatment choices for select AML patients.

*Drug AUC differs from Midostaurin (p < 0.001). Sample classification differs from FLT3 Negative cohort (p < 0.001).