CHRONIC MYELOMONOCYTIC LEUKEMIA

Chronic myelomonocytic leukemia (CMML) is a clonal hematologic malignancy at the interface between myelodysplastic syndromes and myeloproliferative neoplasms. It is characterized by considerable biological and clinical heterogeneity, leading to outcomes that range from indolent courses to aggressive proliferative disease with early leukemic transformation1. This heterogeneity translates into persistent prognostic uncertainty, making therapeutic decision-making particularly challenging. Several prognostic systems have been developed to refine risk assessment2. The CPSS3 remains widely used, and has been further improved by the CPSS-mol4, which incorporates cytogenetic risk and recurrent mutations such as ASXL1, RUNX1, NRAS, and SETBP1. Very recently, in 2025, the Mayo “BLAST” model and its molecular extension (BLAST-mol) have been published, integrating clinical and mutational features to predict overall and leukemia-free survival and provided an easy-to-implement, globally applicable, molecularly adaptive risk model for CMML5. Most recently, the international CPSS (iCPSS)6, developed from large international cohorts, has shown improved accuracy in defining five risk categories, although it is still awaiting publication in extenso. Together, these tools allow a more precise identification of high-risk patients, particularly those who should be considered for curative strategies. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in CMML7. However, its application is limited by advanced patient age and treatment-related morbidity and mortality8. In fit patients of transplant age, high-risk disease according to validated models should prompt early referral for transplant evaluation. The recent recommendations from the EBMT PH&G Committee9 (Blood 2024) emphasize that, whenever feasible, upfront allo-HCT should be preferred, rather than deferring treatment or using unnecessary bridging approaches, which may increase toxicity and compromise eligibility. Reduced-intensity or reduced-toxicity conditioning regimens are generally favoured, together with structured post-transplant monitoring and early relapse management. In summary, integration of molecularly informed prognostic scores with evidence-based transplant recommendations highlights the importance of timely, individualized decision-making. Identification and referral of high-risk, fit patients remain essential to improving outcomes in this rare and heterogeneous disease. References 1. Patnaik MM, Tefferi A.Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management. Am J Hematol. 2024;99(6):1142-1165. 2. Onida F Models of Prognostication in Chronic Myelomonocytic Leukemia. Curr Hematol Malig Rep. 2017;12(6):513-521. 3. Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121(15):3005-15. 4. Elena C, Gallì A, Such E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408-17. 5. Tefferi A, Fathima S, Abdelmagid M, et al. BLAST: a globally applicable and molecularly versatile survival model for chronic myelomonocytic leukemia. Blood. 2025;146(7):874-886. 6. Lanino L, Hunter AM, Gagelmann N, et al. A Molecular-Based Ecosystem to Improve Personalized Medicine in Patients with Chronic Myelomonocytic Leukemia (CMML). Blood (2024) 144 (Supplement 1): 1003. 7. Onida F, Chalandon Y.Myelodysplastic/Myeloproliferative Neoplasms. 2024. In: Sureda A, Corbacioglu S, Greco R, Kröger N, Carreras E, editors. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies [Internet]. 8th edition. Cham (CH): Springer; 2024. Chapter 76. 8. Rovó A, Gras L, Piepenbroek B, et al. Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT. Am J Hematol. 2024;99(2):203-215. 9. Onida F, Gagelmann N, Chalandon Y, et al. Management of adult patients with CMML undergoing allo-HCT: recommendations from the EBMT PH&G Committee. Blood. 2024;143(22):2227-2244.