Contemporary CMML Risk Stratification and Management

Chronic myelomonocytic leukemia (CMML), a rare myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, poses diagnostic and therapeutic challenges due to its heterogeneity and rarity. This review highlights updates to CMML diagnostic criteria, examines risk stratification models and their clinical implications, and outlines both established and emerging therapies for this rare and likely underrecognized hematologic malignancy.

Updated diagnostic criteria from 2022 reduce the monocyte threshold to 0.5 × 10⁹/L for CMML diagnosis, which will reclassify many cases previously diagnosed as MDS. Risk stratification models continue to be refined allowing for improved prediction and may help select appropriate patients for allogeneic stem cell transplantation, the only curative therapeutic modality in CMML. Although trials in CMML were long relegated to subpopulation of MDS studies, there has recently been a flourishing of novel therapies being tested specifically in CMML. These include lenzilumab (anti-GM-CSF) and IO-202 (anti-LILRB4), which have demonstrated promising early efficacy signals but require further study. Established treatments, which include hypomethylating agents and hydroxyurea as well as the JAK1/2 inhibitor ruxolitinib, provide limited survival benefits in CMML, underscoring the urgent need for novel therapeutic development. Coordinated dedicated research efforts have started to evaluate new agents in CMML. Along with further diagnostic and prognostic refinement, these advances are welcomed for this rare and heterogenous disease.