Prognostic implications of myelodysplasia-related gene mutations in NPM1-mutated acute myeloid leukemia: a systematic review and meta-analysis.

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) is generally classified as favorable-risk under the 2022 European LeukemiaNet (ELN-2022) guidelines, except in the presence of FLT3-internal tandem duplication or adverse-risk cytogenetics. However, the prognostic significance of co-occurring myelodysplasia-related gene (MRG) mutations remains unclear, with prior studies yielding inconsistent results. To clarify this issue, we conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, searching PubMed, Embase, and MEDLINE through March 2025. MRG mutations were defined as pathogenic variants in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and RUNX1, and the primary analysis incorporated studies regardless of RUNX1 inclusion. Data from ten cohorts across nine studies (1 of which included an independent validation cohort), encompassing a total of 4,363 patients, were analyzed. Of these, 655 patients (15.0%) harbored co-occurring MRG mutations. Among the patients with ELN-2022 intermediate risk (N=1,294), 108 (8.3%) had MRG mutations. The presence of MRG mutations was significantly associated with inferior overall survival (pooled hazard ratio [HR]=1.30; 95% confidence interval [CI]: 1.11-1.51; P<0.001; I²=39.2%), shorter event-free survival (HR=1.43; 95% CI: 1.11-1.85; P=0.006; I²=18.2%), and lower complete remission rates (risk ratio=0.94; 95% CI: 0.90-0.99; P=0.01; I²=0.0%). Subgroup analyses confirmed the adverse prognostic impact in patients receiving intensive therapy and those classified as ELN-2022 favorable risk. These findings suggest that MRG mutations confer an adverse prognostic effect in NPM1mut AML and support the integration of MRG status into future risk stratification frameworks for NPM1mut AML.