Co-mutation signatures are age-dependent and impact the prognosis in NPM1-mutated acute myeloid leukemia: a PETHEMA...

NPM1-mutated acute myeloid leukemia is genetically heterogeneous, and risk assessment remains focused exclusively on FLT3-ITD despite the potential role of other co-mutations. We retrospectively analyzed 1,360 adults from a multicenter cohort to map age-resolved co-mutation architecture and prognostic impact. Co-mutations were present in 97% of patients (median = 3 mutations) with DNMT3A (45%), FLT3-ITD (42%), TET2 (27%), and IDH2 (20%) predominating. RTK/RAS partners were enriched in younger adults, whereas myelodysplasia-related genes (MR-genes), epigenetic lesions and higher mutation burden accumulated in the elderly. Pairwise co-mutations mapped to distinct clinical phenotypes with NPM1+FLT3-ITD showing a hyperproliferative profile, and NPM1+SRSF2/TET2 associated to older patients with cytopenic disease. In the 688 patients receiving upfront intensive therapy, NPM1 type Non-ABD exhibited a tendency toward poorer OS compared with type A. In competing-risk models, SRSF2 and DNMT3A were associated with a higher cumulative incidence of relapse (CIR). Consistently, multivariable analyses showed that increasing age and SRSF2 independently conferred adverse risk across OS, RFS, and EFS; KRAS adversely impacted OS, whereas FLT3-OTHER was associated with improved OS; and DNMT3A with inferior RFS and EFS but not OS. These findings show that co-mutation signatures in NPM1-mutated AML are age-structured and clinically meaningful, refining risk beyond FLT3-ITD.