Chronic Myelomonocytic Leukemia (CMML)
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 but does not make dysplasia a separate obligatory criterion in a clonal case.
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
CMML: proliferative vs dysplastic
| Subtype | Criterion | Features |
|---|---|---|
| Proliferative CMML (MP-CMML) | WBC ≥13 × 109/L | More myeloproliferative behavior (leukocytosis, hepatosplenomegaly); enriched for RAS-pathway mutations. |
| Dysplastic CMML (MD-CMML) | WBC <13 × 109/L | More MDS-like (cytopenias, dysplasia). |
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)
CMML blast-based groups and managementWHO 2016
| Group | Peripheral blood blasts | Bone marrow blasts | Typical approach |
|---|---|---|---|
| CMML-0 | <2% | <5% | Observation |
| CMML-1 | 2 to 4% | 5 to 9% | Observe if lower risk and asymptomatic; hypomethylating agent (HMA) if higher risk or symptomatic |
| CMML-2 | 5 to 19% | 10 to 19% (or Auer rods present) | HMA; consider alloSCT if fit |
- 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). 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.
Veli Bakalov MD, Board Review Notes 2026