Molecular characterization and improved risk stratification of myelodysplastic syndromes with bone marrow fibrosis through integration of TP53 and MPL mutations

Myelodysplastic syndromes with moderate-to-severe bone marrow fibrosis (MDS-F) represent a distinct entity with poor prognosis, yet their molecular landscape and precise risk stratification remain poorly defined. This study aimed to characterize the genetic landscape of MDS-F and develop an integrated prognostic model. In this study, clinical and genetic data from 102 treatment-naïve MDS patients with moderate to severe marrow fibrosis (MF-2 and MF-3) were analyzed retrospectively. The cohort comprised 63 MF-2 and 39 MF-3 cases showing comparable clinical characteristics and survival outcomes. Targeted next-generation sequencing of 29 myeloid-associated genes demonstrated distinct mutational patterns: 19.6% harbored TP53 mutations, while 19.6% exhibited JAK-STAT pathway mutations (JAK2: 9.8%, MPL:7.8%, CALR: 2%). Notably, patients with JAK-STAT mutations displayed superior clinical outcomes compared to wild-type counterparts, with the favorable prognostic impact appearing to be primarily driven by MPL mutations (median OS: not reached vs. 24 months, p = 0.004). In the univariate analysis, age, IPSS-R score, as well as TP53, IDH1/2 and MPL mutations were evidently linked with overall survival (OS) and leukemia-free survival (LFS). Of these factors, only IPSS-R score, TP53 mutations and MPL mutations retained independent prognostic significance in the multivariate analysis (p < 0.05). By incorporating IPSS-R and genetic mutations, we generated a novel prognostic model that improved risk stratification, delineating four distinct survival trajectories (median OS: not reached vs. 40 vs. 26 vs. 11 months, log-rank test p < 0.001). In conclusion, MDS patients with MF had specific genetic lesions. The integration of mutational profiling, including the potentially favorable impact of MPL mutations, with conventional scoring systems enables refined prognostic assessment and warrants further validation to guide risk-adapted therapeutic strategies.