Chronic Myelomonocytic Leukemia: History, Pathobiology, Diagnostic Controversies, and Evolving Classification

Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic/myeloproliferative neoplasm characterized by sustained monocytosis, recurrent gene mutations, and a risk of transformation to acute myeloid leukemia (AML). This review examines the historical evolution of CMML as a diagnostic entity, its genetic landscape, fundamental controversies in definition, including the contentious boundaries of oligomonocytic CMML (OM-CMML), and the spectrum of associated phenomena, such as plasmacytoid dendritic cell proliferations, systemic mastocytosis, extramedullary disease, and autoimmune manifestations.

Since the publication of the most recent myeloid classification systems, genomic studies in large CMML cohorts have clarified that cases with borderline monocyte counts are biologically heterogeneous: a subset with bi-allelic TET2 inactivation or TET2 + SRSF2 co-mutation bears the greatest similarity to true CMML, while cases harboring SF3B1, bi-allelic TP53 inactivation (biTP53), or del(5q) may be better classified as myelodysplastic syndrome/neoplasm (MDS), irrespective of the presence of borderline monocytosis. Molecular evolution from clonal hematopoiesis through OM-CMML to overt CMML, and ultimately to acute myeloid leukemia (AML), follows a defined clonal trajectory characterized by the stepwise acquisition of spliceosome, epigenetic, and signaling mutations. Plasmacytoid dendritic cell proliferations, particularly blastic forms, arising in association with or following CMML, share clonal origin and represent a distinct spectrum of monocyte/plasmacytoid dendritic cell lineage dysregulation. In future classification systems, better biologic homogeneity of CMML may be achieved by incorporating specific molecular signatures in the diagnostic criteria and by excluding cases with biTP53 or AML-defining alterations. CMML is defined by its combination of proliferative (monocytic) and dysplastic features, but exhibits considerable genetic heterogeneity. Optimal diagnosis and distinction from related entities require integration of morphology, immunophenotype, and comprehensive genomic profiling.