AbstractAlthough the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults aged ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% were classified as having favorable-risk, 11% intermediate-risk, and 78% adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable-risk from intermediate-risk groups (P = .71). Within the adverse-risk AML group, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML favorable- (22%), Beat-AML intermediate- (41%), and Beat-AML adverse-risk (37%) groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001; C-index, 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making.