Blood Adv

Prognostication in chronic myelomonocytic leukemia (CMML) remains a challenge due to the biological complexity and variable clinical course of the disease. This study aimed to evaluate the prognostic utility of the International Prognostic Scoring System-Molecular (IPSS-M) in CMML and its applicability across the myelodysplastic and myeloproliferative subsets of the disease. We conducted a multicenter, retrospective study including 511 patients diagnosed with CMML. Clinical, cytogenetic, and molecular data were collected at diagnosis, including targeted NGS. Patients were stratified using IPSS-M, CPSS-Mol, and the recently developed iCPSS. IPSS-M effectively stratified patients into risk groups with significantly different overall survival (OS) and cumulative incidence of acute myeloid leukemia (AML) progression. Discrimination was maintained after merging overlapping intermediate risk categories, yielding a four-tier model with a c-index of 0.678 for OS and 0.628 for AML progression. This model retained its prognostic performance in both MD-CMML and MP-CMML subsets, with higher discrimination for OS in the MD-CMML group. When compared with CPSS-Mol and iCPSS, adapted IPSS-M showed comparable prognostic performance to iCPSS and improved discrimination compared with CPSS-Mol. These findings support the applicability of an adapted IPSS-M to CMML, extending its use beyond myelodysplastic syndromes and highlighting its potential utility in guiding clinical decision-making and therapeutic strategies. Moreover, this study also provides an external validation of the iCPSS in an independent and genetically well-characterized CMML cohort, reinforcing its clinical utility.