Chronic Myelomonocytic Leukemia (CMML)

Definition and classification

• MDS/MPN overlap neoplasm: CMML sits in the MDS/myeloproliferative neoplasm (MDS/MPN) overlap category, sharing both dysplastic (ineffective hematopoiesis) and proliferative features (leukocytosis, thrombocytosis). It combines myeloid cell proliferation, driven in part by myeloid progenitor hypersensitivity to GM-CSF, with myeloid dysplasia and ineffective hematopoiesis. The other classic MDS/MPN entities include MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T, which requires platelets ≥450 × 10⁹/L).
• Defining monocytosis: sustained peripheral blood monocytosis with an absolute monocyte count ≥1 × 10⁹/L (>1,000/µL) AND monocytes constituting ≥10% of the white blood cell differential (WHO 2016). WHO 5th edition and ICC 2022 lowered the threshold to ≥0.5 × 10⁹/L (still ≥10%); for an absolute monocyte count 0.5 to <1 × 10⁹/L: WHO 5th edition requires both marrow dysplasia and an acquired clonal abnormality; ICC 2022 requires clonality (a myeloid neoplasm-associated mutation at VAF ≥10% or a clonal cytogenetic abnormality) plus bone marrow findings consistent with CMML (hypercellular myeloid proliferation, often with increased monocytes), but dysplasia is not obligatory (sustained clonal monocytosis without CMML marrow findings is CMUS, or CCMUS with cytopenia); ICC 2022 also requires at least one cytopenia for any CMML diagnosis.

Diagnosis and distinction from CML

• CMML is distinct from CML: CMML is NEGATIVE for BCR-ABL1. It must also lack the tyrosine-kinase rearrangements that define the myeloid/lymphoid neoplasms with eosinophilia: PDGFRA, PDGFRB, FGFR1, JAK2 (PCM1::JAK2 and other JAK2 fusions), plus FLT3 and ETV6::ABL1 rearrangements (these need not show eosinophilia). (Recall that ETV6-PDGFRB, t(5;12), can mimic CMML with eosinophilia and responds to imatinib, so it must be excluded.)
• Marrow: dysplasia in one or more lineages; blasts (plus promonocytes) must be <20% in blood and marrow (20% or more defines acute leukemia).

Proliferative vs dysplastic subtypes

Blast-based groups (prognostic)

• Treatment is guided by risk (CPSS/CPSS-Mol), cytopenias, symptoms, proliferative burden, and transplant eligibility, not by blast group alone (ruxolitinib is investigational/symptom-directed, not a standard CMML-2 HMA add-on).

• The percentage of blasts plus promonocytes in blood and marrow carries prognostic significance. WHO 5th edition and ICC 2022 eliminated CMML-0: CMML-1 is PB blasts <5% and BM <10%; CMML-2 is PB 5 to 19%, BM 10 to 19%, or Auer rods. For blast counting in CMML, promonocytes are counted as blast equivalents.

Common mutations

• Frequent mutations: TET2, SRSF2, ASXL1, RUNX1, NRAS (RAS pathway), and CBL.
  • ASXL1 mutation is the strongest adverse molecular prognostic factor and is incorporated into molecular scoring.
  • RAS-pathway lesions (NRAS/KRAS/CBL) associate with the proliferative phenotype.

Risk stratification: CPSS and CPSS-Mol

• CPSS (CMML-specific Prognostic Scoring System): a disease-specific score built from the WHO subtype (CMML-1 vs CMML-2), the FAB subtype (myeloproliferative vs myelodysplastic), red cell transfusion dependency, and CMML-specific cytogenetic risk. It stratifies patients into low, intermediate-1, intermediate-2, and high-risk groups predicting overall survival and risk of AML transformation.
• CPSS-Mol (molecular CPSS): refines the CPSS by adding gene mutation status (adverse markers include ASXL1, NRAS, RUNX1, and SETBP1) (the genetic score also incorporates CMML-specific cytogenetic risk) together with marrow blasts ≥5%, WBC ≥13 × 10⁹/L, and RBC transfusion dependency, improving prognostic discrimination over the clinical score alone.

Treatment

• Lower-risk / asymptomatic (e.g., CMML-0): observation. Patients with low-risk disease can delay transplant until progression.
• Higher-risk or symptomatic disease: hypomethylating agents (azacitidine or decitabine) are the mainstay of non-curative therapy; they can improve counts and quality of life but are not curative.
• Proliferative features: consider ruxolitinib (investigational, symptom-directed) for symptomatic splenomegaly/constitutional symptoms in proliferative disease; hydroxyurea can be used for cytoreduction of leukocytosis.
• Allogeneic stem cell transplant (AlloSCT): the only curative option, but appropriate for only a small proportion of patients. Reserve for fit, higher-risk patients; low-risk patients may defer transplant until progression.

High yield (CMML)

• MDS/MPN overlap: monocytosis ≥0.5 × 10⁹/L (WHO 5th/ICC 2022; formerly ≥1) AND ≥10% of the differential, with blasts <20%; if monocytes ≥1,000/µL, at least one supporting criterion (dysplasia, an acquired clonal cytogenetic/molecular abnormality, or abnormal monocyte partitioning); if 500 to <1,000/µL, WHO 5th requires both dysplasia and a clonal abnormality (ICC: clonality, plus at least one cytopenia in all cases). Dysplasia is not universally required.
• Always exclude BCR-ABL1 and PDGFRA/PDGFRB/FGFR1/PCM1-JAK2 rearrangements.
• Proliferative (WBC ≥13) vs dysplastic (WBC <13) subtypes.
• Core mutations: TET2, SRSF2, ASXL1, RUNX1, NRAS, CBL; ASXL1 is the key adverse marker.
• Risk stratify with CPSS / CPSS-Mol; treat with HMA and consider AlloSCT (only cure) in fit higher-risk patients.