Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only treatment with curative potential for chronic myelomonocytic leukemia (CMML).¹ However, the significant toxicity associated with the procedure necessitates rigorous patient selection.¹ Determining the optimal timing of allogeneic-HSCT continues to be a critical challenge, as existing prognostic models, limited in molecular integration, demonstrate suboptimal predictive performance in the transplant setting.¹ At the EHA Congress 2025, Dr. Matteo Giovanni Della Porta of IRCCS Humanitas Research Hospital, Italy, presented the International CMML Prognostic Scoring System (iCPSS).¹ This novel prognostic model integrates multiple clinical and cytogenetic parameters, providing superior risk stratification and more accurate survival predictions, including post-HSCT overall survival (OS) and relapse-free survival (RFS), compared to the conventional CPSS-Molecular Model (CPSS-Mol).¹

The iCPSS incorporates conventional hematological and cytogenetic features with mutational profiling of nine genes implicated in CMML pathophysiology, enabling stratification of patients into five distinct risk categories.¹ In its development phase, the model demonstrated strong predictive ability for OS and leukemic progression across two cohorts: a large international retrospective cohort (n=3,012) and a prospective validation cohort (n=516).¹ In both settings, iCPSS outperformed existing prognostic scores.¹

Building on these findings, a subsequent retrospective analysis was undertaken to develop and validate a decision support system (DSS) aimed at optimizing the timing of allogeneic HSCT in CMML.¹ This DSS integrates clinical and genomic data from the iCPSS to compare transplantation strategies based on iCPSS vs. the original CPSS-Mol, and to quantify the proportion of patients whose optimal HSCT timing would change with the incorporation of the new prognostic model into clinical decision-making.1 The analysis included data from 3,013 CMML patients treated at major international centers, of whom 829 (28%) underwent HSCT.¹ Comprehensive clinical and genomic information was obtained for all participants where available.¹

Findings from the study highlighted the ability of iCPSS-based stratification to guide transplant timing decisions.¹ Patients categorized as very low and low risk derived greater benefit from delayed HSCT, typically 24 to 36 months after diagnosis.¹ Conversely, patients in the intermediate-, high-, and very high-risk groups achieved longer life expectancy with early HSCT, defined as 3 to 6 months post-diagnosis.¹ Decision modeling indicated that iCPSS-based strategies resulted in changes to transplantation timing in 31% of patients compared with CPSS-Mol.1 Specifically, 36.6% of patients who would have been recommended for delayed HSCT under CPSS-Mol were identified by iCPSS as benefiting from earlier transplantation.¹ Overall, adoption of an iCPSS-guided strategy yielded a significant gain in life expectancy, with an average increase of 1.2 to 1.4 years (p<0.01).¹

A real-world analysis further underscored these findings.¹ When comparing transplantation strategies, an iCPSS-based approach was associated with a significant increase in restricted mean survival time (RMST) across all age groups (p<0.001).¹ Among the cohort, 41.3% of patients underwent HSCT within the defined optimal time window.¹ Patients transplanted during this window had an estimated 5-year OS of 56%, compared to 45% for those transplanted outside the optimal period.¹ The median survival gain associated with optimal timing was 26 months.¹ In a Cox proportional hazards model adjusted for age, disease status at HSCT, pre-transplant treatment response, and donor/conditioning type, transplantation within the optimal window remained significantly associated with prolonged survival.¹

In conclusion, the iCPSS represents a major advancement in prognostic modeling for CMML by incorporating a broader set of clinical and genomic parameters than its predecessors.¹ Routine mutational screening in CMML patients could inform HSCT decision-making, with iCPSS-based strategies supporting delayed transplantation for lower-risk patients and early transplantation for those at higher risk.¹