Prognostic impact of age and MDS-associated mutations in NPM1-mutated AML

Nucleophosmin-1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML) and is generally associated with favorable prognosis. However, the impact of myelodysplastic syndrome-associated mutations (MDS^m+) on patient outcomes within this subgroup remains uncertain. We retrospectively analyzed 271 patients with NPM1-mutated AML from 3 independent cohorts (SWOG, Fred Hutch, and Beat AML) to assess the prognostic significance of MDS^m+ and its interaction with age. MDS^m+ occurred in 17% of patients, most commonly involving SRSF2 and SF3B1. Although MDS^m+ was associated with inferior overall survival (OS) compared with MDS^m- in European LeukemiaNet (ELN) 2022 favorable-risk patients (hazard ratio [HR], 2.0; P = .008), this effect was largely driven by worse outcomes in older patients (≥65 years) as older ELN2022 favorable-risk patients had poor OS regardless of the presence of MDS^m+ compared with younger patients. After stratification of patients by age, there was not a significant difference between MDS^m+ and MDS^m- in either younger patients (HR, 0.99; P = .98) or older patients (HR, 1.42; P = .33). These findings indicate that MDS^m+ in NPM1 ⁺ AML is not independently associated with adverse risk after adjusting for age, and highlight the need for age-adjusted AML risk models.