Chronic myelomonocytic leukemia beyond the marrow: biology, patterns, and management of extramedullary disease.

Chronic myelomonocytic leukemia (CMML) is an MDS/MPN overlap neoplasm defined by monocytosis, clonal hematopoiesis, and marrow dysplasia, with outcomes ranging from indolent cytopenic disease to aggressive proliferative phenotypes with early AML transformation. Extramedullary disease (EMD) refers to clonal myelomonocytic infiltration outside the bone marrow and is an underrecognized, consequential manifestation that can dominate presentation, drive morbidity, and identify adverse disease biology. While hepatosplenic involvement, often reflecting extramedullary hematopoiesis, is common, biopsy proven non-hepatosplenic EMD occurs in a subset of patients, 10-15 percent, and most frequently involves skin, lymph nodes, serosal fluids, and soft tissue, with visceral sites including lung, kidney, and central nervous system. Importantly, EMD is enriched in proliferative and higher grade CMML and is associated with inferior outcomes, including shorter overall survival and increased AML transformation, with poor prognosis after EMD onset. Biologically, EMD appears linked to mutation-driven proliferative signaling, enrichment of RAS MAPK pathway alterations, co-occurring with adverse epigenetic lesions such as ASXL1, together with cytokine-mediated inflammation and dysregulated trafficking and retention programs that facilitate tissue homing and persistence. Because EMD frequently mimics infection, autoimmune and inflammatory syndromes common in CMML, or second malignancy, diagnosis requires an integrated strategy incorporating cross sectional imaging, PET-CT to localize and prioritize biopsy targets, and tissue confirmation with immunophenotyping including CD68, CD163, and lysozyme and selective molecular profiling to establish clonality. Management is primarily systemic, with hypomethylating agents as the backbone, cytoreduction for proliferative disease, local radiotherapy for symptomatic lesions, and early consideration of allogeneic transplantation in eligible high risk or refractory cases. This review synthesizes current evidence on the epidemiology, biology, diagnostic approach, prognostic implications, and treatment of EMD in CMML and highlights the need for standardized definitions and prospective, genomics-informed studies to improve detection and outcomes.