Signaling Mutations Negate the Favorable Impact of NPM1 Mutations in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Treated With VEN / HMA

ABSTRACT Frameshift mutations in exon 12 of nucleophosmin 1 ( NPM1 mut ) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable‐risk in the absence of FLT3 ‐ITD. In the European LeukemiaNet (ELN) 2024 risk‐classification for patients treated with hypomethylating agents plus venetoclax (HMA + VEN), NPM1 mut is not considered favorable when co‐occurring with signaling gene (SG) mutations (i.e., FLT3 ‐ITD, NRAS , KRAS ). However, due to limited numbers in the original analysis, the prognostic impact of SG mutations in NPM1 ‐mutant AML remains unclear. We evaluated the prognostic significance of NPM1 mut with and without SG mutations in two independent cohorts of patients ≥ 60 years with ELN 2024 favorable‐ or intermediate‐risk AML treated with HMA + VEN. Cohort 1 included 322 patients treated in the academic setting. NPM1 mut ( n = 61) was associated with a nonsignificantly longer overall survival (OS) compared to NPM1 wild‐type ( NPM1 wt ) (median, 53.05 vs. 17.03 months, p = 0.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the NPM1 mut subgroup. Cohort 2 included 816 patients from a real‐world community‐treated cohort. NPM1 mut ( n = 124) had a longer OS compared with NPM1 wt (median, 15.3 vs. 14.4 months, p = 0.03). In MVA, NRAS, KRAS , and FLT3 ‐ITD were independent unfavorable prognostic factors; NPM1 mut with, compared to without, SG co‐mutation had a shorter OS (median, 9.4 vs. 31.6 months, p = 0.001). These findings suggest SG mutations negate the favorable impact of NPM1 mut in older patients treated with HMA + VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high‐risk subgroup.