Clinical and Prognostic Significance of CEBPA Mutations in Myelodysplastic Syndromes

Background/Objectives: Myelodysplastic syndromes (MDS) carry a highly variable prognosis, stratified by the Revised International Prognostic Scoring System (IPSS-R) and the Molecular IPSS (IPSS-M). CEBPA mutations define a favorable-risk subgroup in acute myeloid leukemia (AML), yet their prognostic significance in MDS has not been characterized. Methods: We analyzed 2442 patients from the International Working Group (IWG) 2022 multi-center MDS registry after pre-specified exclusions. Overall survival (OS) and leukemia-free survival (LFS) were compared between CEBPA-mutated (n = 66; 2.7%) and wild-type patients using Kaplan–Meier estimation and Cox proportional hazards regression, adjusting for age, sex, and IPSS-R score; pre-specified subgroup, sensitivity, competing-risk, and mutation subtype analyses were performed. Results:CEBPA-mutated patients had markedly inferior OS (median 17.2 versus 42.2 months; HR 2.05, 95% CI 1.50–2.79; p < 0.001). After IPSS-R adjustment, the hazard ratio remained adverse (HR 1.39, 95% CI 1.00–1.94; p = 0.053), with uniform directionality across all 13 evaluable subgroups and no significant interaction. Co-mutation adjustment for ASXL1 and STAG2 further attenuated the hazard ratio to HR 1.11 (95% CI 0.79–1.57; p = 0.54), suggesting part of the observed signal reflects co-mutation burden rather than an independent CEBPA effect. Competing-risk analysis suggested that the excess mortality is mediated through AML transformation (CEBPA-mutated versus wild-type subdistribution hazard ratio of 1.89, 95% CI 1.20–2.99; p = 0.006) rather than non-transformative MDS mortality (cause-specific HR 0.97; p = 0.890). Truncating mutations drove the adverse signal (HR 2.21; p = 0.023), while basic leucine zipper (bZIP) domain mutations showed no significant effect (HR 1.25; p = 0.470). Conclusions:CEBPA mutations identify a rare MDS subgroup with markedly inferior survival, driven by truncating loss-of-function mutations and associated with leukemic transformation; the AML-derived bZIP-favorable paradigm does not translate to MDS, and CEBPA mutation status merits a prospective study to assess clinical utility for risk stratification.