KRAS mutation status critically determines the clinical outcome of patients with KMT2A‐rearranged acute myeloid leukemia

Abstract Background KMT2A (11q23)‐rearranged acute myeloid leukemia ( KMT2A ‐r AML) represents a clinically aggressive subtype with heterogeneous outcomes. Current evidence remains inconclusive regarding the prognostic relevance of fusion partners in 11q23/ KMT2A ‐rearranged AML. The comprehensive mutational landscape and prognostic implications of co‐occurring driver mutations remain poorly characterized. Methods A comprehensive clinicogenomic analysis of 159 de novo KMT2A ‐r AML patients was conducted to assess the correlation between molecular profiles and clinical outcomes. Results Notably, the KMT2A::MLLT4 subgroup exhibited significantly higher KRAS mutation frequencies compared to other rearrangement groups ( p < .05). Survival analysis revealed that the KMT2A::MLLT4 cohort demonstrated trends toward inferior overall survival (OS) and increased cumulative incidence of relapse (CIR) relative to other rearrangement subgroups. Stratified by mutational status, patients with KRAS mutations exhibited significantly inferior 2‐year OS rates (24.6% vs. 50.5%; p = .001) and higher 2‐year CIR (56.3% vs. 34.6%; p = .018) compared to KRAS wild‐type counterparts. This adverse prognostic association remained in the transplanted cohort (OS: 32.3% vs. 73.5%; p < .001; CIR: 73.6% vs. 23.0%; p < .001). In contrast, mutations in NRAS , FLT3 did not demonstrate statistically significant associations with OS or CIR in either the overall cohort or transplant subgroup. Multivariable Cox regression confirmed KRAS mutation as an independent adverse prognostic factor for both 2‐year OS (hazard ratio [HR], 0.51; 95% CI, 0.31–0.84; p = .008) and CIR (HR, 1.80; 95% CI, 1.04–3.12; p = .037) in the overall cohort. This association persisted in the transplanted patients subgroup (OS: HR, 0.18; 95% CI, 0.06–0.52; p = .001; CIR: HR, 3.89; 95% CI, 1.05–14.37; p = .042). Conclusions These results demonstrate the independent prognostic value of KRAS mutations across treatment modalities, including both conventional chemotherapy and hematopoietic stem cell transplantation.