Chronic Myelomonocytic Leukemia

MDS/MPN overlap — persistent monocytosis, TET2/SRSF2/ASXL1 mutations, hypomethylating agent therapy, and allogeneic transplantation as the only curative option

Key Points

• CMML is a clonal hematopoietic malignancy classified as an MDS/MPN overlap syndrome, defined by persistent peripheral blood monocytosis (≥500/μL with monocytes ≥10% of WBC differential) for ≥3 months.
• CMML is further divided into myelodysplastic (WBC <13,000/μL) and myeloproliferative (WBC ≥13,000/μL) subtypes, with the myeloproliferative subtype having inferior outcomes.
• WHO 2022 revised the diagnostic monocyte threshold to ≥500/μL (down from ≥1,000/μL) and divides CMML into CMML-1 (<5% PB blasts, <10% BM blasts) and CMML-2 (5–19% PB or 10–19% BM blasts).
• The most frequently mutated genes are TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and RAS pathway genes (NRAS, KRAS, CBL — ~30%); ASXL1 and RAS mutations are independently associated with inferior outcomes.
• Azacitidine and decitabine are the only FDA-approved agents for CMML; they improve cytopenias and reduce transfusion dependence but rarely achieve durable CR and do not improve OS vs. hydroxyurea.
• Allogeneic stem cell transplantation (alloSCT) is the only potentially curative approach and is recommended for eligible patients with CMML-2, high-risk CMML-1, or rapidly progressing disease.
• Median overall survival ranges from ~12–18 months (CMML-2, high-risk) to ~48–60 months (low-risk CMML-1); ~15–20% of CMML cases transform to AML, which carries a very poor prognosis.

Epidemiology & Classification

Chronic myelomonocytic leukemia is a rare hematologic malignancy with an estimated incidence of 3–4 cases per 100,000 person-years in the United States, equating to approximately 1,100–1,300 new cases annually. The disease predominantly affects older adults, with a median age at diagnosis of 73 years, and is nearly twice as common in men as in women. CMML is exceedingly rare before age 50. CMML occupies a unique nosologic position: it is classified as an MDS/MPN overlap syndrome by both the 2022 WHO Classification and the 2022 ICC (International Consensus Classification), reflecting its…

Molecular Landscape

CMML has a characteristic molecular signature. Nearly all patients harbor somatic mutations detectable by NGS panels, often in combinations reflecting clonal hierarchy: DNA methylation and chromatin modifiers (most common): • TET2 (~60%): Loss-of-function mutations in the TET2 dioxygenase gene, which normally promotes DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine; founding clonal events in many cases. Biallelic TET2 mutations are particularly common in CMML. TET2 loss alone is insufficient for CMML — secondary cooperating mutations are required. • ASXL1 (~40%):…

Clinical Presentation

CMML has a broad clinical spectrum, shaped by the balance of myelodysplastic and myeloproliferative features: Myelodysplastic-dominant presentation (dCMML, WBC <13,000/μL): • Symptoms predominantly from cytopenias: Fatigue and dyspnea from anemia (most common presenting symptom); recurrent bacterial infections from neutropenia; easy bruising and mucosal bleeding from thrombocytopenia. • May resemble MDS clinically — indolent course, primarily transfusion-dependent. Myeloproliferative-dominant presentation (pCMML, WBC ≥13,000/μL): • Organomegaly: Splenomegaly (present in ~40–50%) — often…

Diagnosis & Workup

CMML diagnosis requires meticulous exclusion of reactive monocytosis and other clonal conditions. Diagnostic criteria (WHO 2022 — all required): 1. Persistent peripheral blood monocytosis ≥500/μL with monocytes ≥10% of WBC differential for ≥3 months 2. No BCR-ABL1 fusion (Philadelphia chromosome negative) 3. No rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 (these define separate entities, some TKI-sensitive) 4. <20% blasts + blast equivalents (promonocytes) in PB and BM (≥20% = AML) 5. Dysplasia in ≥1 myeloid lineage OR a clonal cytogenetic/molecular abnormality in the absence of…

Treatment

CMML management is risk-stratified. There is no curative medical therapy; alloSCT is the only potential cure. Watch-and-wait: Appropriate for low-risk, asymptomatic CMML-1 with stable counts and no significant cytopenias. Regular monitoring every 3 months; treatment initiated when symptomatic or criteria met. Hypomethylating agents (HMAs) — the primary medical treatment: • Azacitidine (75 mg/m² SC/IV days 1–7 every 28 days): FDA approved for MDS/CMML; hematologic improvement in ~40–50%; CR rate ~15–20%; transfusion independence in ~25–35%; median time to response ~3 cycles (up to 6 cycles…