Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes

Activating mutations in RAS have been reported in about 10–15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p =.01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7–192.7; p <.001) and OR 2.8 (95% CI: 1.1–6.9; p =.02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1–0.9; p =.04) and OR 0.22 (95% CI: 0.09–0.5; p =.001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9–12.2; p <.001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1–0.6; p =.002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2–0.6 p <.001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4–3.9; p =.001) and HR 1.7 (95% CI: 0.9–3.1; p =.06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.