A Comparative Assessment of Molecular-Based Prognostic Models in CMML Open Access

• IPSS-M can be used reliably in CMML to inform treatment decisions, and has comparable accuracy to the CPSS-Mol in predicting OS and LFS

• CPSS-Mol shows superior performance in risk assessment for CMML, supporting its universal adoption in clinical trial design and enrollment

Several prognostic systems integrating clinical, cytogenetic, and molecular parameters have been developed to estimate risk and inform treatment in chronic myelomonocytic leukemia (CMML). Recently, the molecular IPSS (IPSS-M) was introduced for risk stratification in myelodysplastic syndromes (MDS), demonstrating improved prognostic accuracy over the mutation-agnostic IPSS-R and potentially offering a novel tool for risk assessment in this population. We aimed to assess whether the applicability of the IPSS-M extends to CMML while providing a comprehensive comparison of all major molecular-based integrated models. Baseline clinical and molecular data were collected from 340 CMML patients. The most frequent mutations were TET2, SRSF2, ASXL1, RUNX1, and NRAS. The IPSS-M stratified patients into six risk categories, with median overall survival (mOS) of 18.5, 5.1, 3.9, 2.65, 1.7, and 1.1 years, corresponding to very low (VL) to very high (VH) risk disease (p<0.001). Additionally, the 4-year cumulative incidence of AML evolution was 4.2%, 12.1%, 19.4%, 25.9%, 32.8%, and 26.7%, respectively (p = 0.008). Both CPSS-Mol and IPSS-M improved OS discrimination compared to the MMM and GFM models. CPSS-Mol outperformed CPSS, and IPSS-M was superior to IPSS-R. CPSS-Mol demonstrated the highest prognostic accuracy for predicting leukemic evolution, establishing it as the superior overall model. Importantly, IPSS-M was reliably applicable in CMML and displayed prognostic accuracy comparable to CPSS-Mol. Furthermore, all models retained predictive validity in patients receiving frontline hypomethylating agent therapy, suggesting that using the IPSS-M is unlikely to adversely impact outcomes when guiding treatment decisions, particularly in community settings where CMML is often grouped with MDS.