Disease Overview

The World Health Organization (WHO) classifies chronic myelomonocytic leukemia (CMML) as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).[1] The WHO recognizes a dysplastic subtype and a proliferative subtype, with prognostic groups differentiated by the circulating white blood cell (WBC) count or the percentage of blasts in the bone marrow (higher percentage with worse prognosis).[2]

CMML is a clonal disorder of a bone marrow stem cell. Monocytosis is a major defining feature. CMML exhibits heterogenous clinical, hematological, and morphological features, varying from predominantly myelodysplastic to predominantly myeloproliferative. Evolution to acute myeloid leukemia (AML) portends a particularly poor prognosis.[3]

CMML is characterized pathologically by:[4,5]

Clinical features of CMML include:[4,5]

The median age at diagnosis of CMML is 65 to 75 years with a male predominance of 1.5 to 3.1.[4,5] Because CMML is grouped with chronic myeloid leukemia in some epidemiologic surveys and with MDS in others, no reliable incidence data are available for CMML.[6] Although the specific etiology of CMML is unknown, exposure to occupational and environmental carcinogens, ionizing radiation, and cytotoxic agents has been associated in some cases.[6]

Morphologically, the disease is characterized by a persistent peripheral blood monocytosis (always >1 × 109/L) that may exceed 80 × 109/L with monocytes typically accounting for more than 10% of the WBCs.[4,5] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[7] Fewer than 20% blasts are seen in the blood or bone marrow. Neutrophilia occurs in nearly 50% of patients with neutrophil precursors (e.g., promyelocytes and myelocytes) accounting for more than 10% of the WBCs.[8] Mild normocytic anemia is common. Moderate thrombocytopenia is often present. Bone marrow findings include:[4,5,9,10]

Hepatosplenomegaly may be present.[4,5] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[11] Care should be taken to identify cases of CMML with eosinophilia, a subtype of CMML, because of its association with severe tissue damage secondary to eosinophil degranulation. In CMML with eosinophilia, all criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 × 109/L.[6]

Recurrent somatic pathogenic variants have been identified in most patients with CMML, resulting in altered signaling molecules (especially NRAS, KRAS, JAK2, and SETBP1), epigenetic regulators (especially TET2 and ASXL1), splicing factors (especially SRSF2), and transcription factors (especially RUNX1).[12-15] A CMML-specific prognostic scoring system can distinguish four risk groups based on the following factors:[16]

The best prognostic group has a median survival of more than 10 years with no leukemic evolution in the first decade of follow-up. The worst prognostic group has a median survival of 20 months with a 50% evolution to AML by 2 years.[16]

Prognostic factors associated with shorter survival include:[17,18]

Progression to acute leukemia occurs in approximately 15% to 20% of cases.[17,18]

CPSS-Mol is a CMML-specific prognostic scoring system that incorporates molecular genetic data, especially pathogenic variants in RUNX1, NRAS, SETBP1, and ASXL1. This system distinguishes low-risk disease with median survivals longer than 10 years from high-risk disease with median survivals of 2 to 4 years.[16]