Impact of and mutations on outcomes in acute myeloid leukemia.

The prognostic significance of mutations in AML is poorly understood. In this ambispective cohort study of 239 newly-diagnosed AML patients at the University of Maryland, we assessed the median overall survival (mOS) and median event-free survival (mEFS) in wild-type (WT) AML ( = 196), -mutated AML ( = 11), -mutated AML ( = 25), and /-mutated AML ( = 7). We used propensity score to adjust outcomes. mutated AML had a similar response rate to first-line treatment and mOS compared to -WT AML (57 vs. 54%,  = 0.8, 22.7 vs. 14.6 months,  = 0.7). The mOS of mutated AML was shorter compared to -WT AML ( = 0.049) and -mutated AML ( = 0.02). mutated AML treated with anthracycline-based first-line regimens had a lower relative mortality compared to treatment with hypomethylating agents with venetoclax (HR <0.01,  = 0.04) and without venetoclax (HR <0.01,  = 0.04). This study demonstrates that but not NRAS mutations are associated with worse outcomes in AML.NOVELTY STATEMENT The clinical significance of mutations remains poorly defined and prior studies have yielded conflicting results. We used causal inferential methods, propensity score modeling, to determine the impact of and mutation on survival in newly diagnosed AML patients, independent of other risk factors. Moreover, we analyzed the outcomes of and -mutated AML patients receiving first-line therapy with hypomethylating agents and other non-anthracycline-based regimens. We provided a detailed description of -mutated AML, including co-occurring mutations and cytogenetic abnormalities. mutations but not mutations in AML are directly linked to worse outcomes even after controlling for differences in AML type, co-occurring cytogenetic changes, treatment regimens, and comorbidities. mutated AML has a higher relative mortality when treated with a hypomethylating agent-based first-line induction regimen compared to treatment with an anthracycline-based regimen. Our findings can help refine our genetic profiles of AML, improve prognostic models, and better stratify treatment regimens.