Chronic Myelomonocytic Leukemia (CMML)

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder classified under myelodysplastic-myeloproliferative neoplasms (MDS/MPN) in the WHO 2017/2022 classification, distinct from MDS, MPN, and chronic myeloid leukemia. Diagnostic criteria require: (1) persistent peripheral blood monocytosis ≥1,000/uL absolute count and ≥10% of white blood cell differential count, lasting at least 3 months; (2) absence of BCR-ABL1 fusion gene; (3) absence of PDGFRA, PDGFRB, FGFR1 rearrangements or PCM1-JAK2 fusion (exclusion of myeloid/lymphoid neoplasms with eosinophilia); (4) less than 20% blasts (including monoblasts and promonocytes) in blood and bone marrow; (5) dysplasia in one or more myeloid lineages, OR if dysplasia minimal/absent: clonal cytogenetic or molecular abnormality, or persistent monocytosis ≥3 months with exclusion of other causes of monocytosis (infection, autoimmune disease, lymphoma).

Subclassification (WHO 2022): based on blast count — CMML-0 (<2% blasts in blood, <5% in marrow), CMML-1 (2-4% blood blasts, 5-9% marrow blasts), CMML-2 (5-19% blood blasts or 10-19% marrow blasts, or any Auer rods). Clinical phenotypes: dysplastic CMML (MD-CMML, WBC <13,000/uL, more dysplastic features) and proliferative CMML (MP-CMML, WBC ≥13,000/uL, more proliferative features with hepatosplenomegaly). Molecular landscape (>90% have somatic mutations): TET2 (50-60%, often early founder), SRSF2 (40-50%), ASXL1 (40%, adverse prognosis), KRAS/NRAS (15-30%), CBL (15%), JAK2 V617F (5-10%, more in MP-CMML), DNMT3A, IDH1/2, RUNX1, U2AF1, EZH2, NF1, SETBP1. Cytogenetic abnormalities in 30%: trisomy 8, monosomy 7/del(7q), complex karyotype (adverse). Prognostic scoring systems: CPSS-Mol, GFM Score, Mayo Molecular score — incorporate clinical (cytopenias, blast count) and molecular (ASXL1, NRAS, RUNX1, SETBP1) features.

Clinical presentation: bimodal — dysplastic phenotype with cytopenias (fatigue, infections, bleeding) similar to MDS, or proliferative phenotype with leukocytosis and organomegaly similar to MPN; B-symptoms (fever, night sweats, weight loss), splenomegaly (40-60%), hepatomegaly (20-30%), skin involvement (leukemia cutis 5-20% — characteristic of CMML), serous effusions, autoimmune phenomena. Diagnosis: CBC with differential (monocytosis), peripheral blood smear (dysplastic neutrophils, monocytes, sometimes promonocytes), bone marrow biopsy and aspirate (dysplasia, hypercellularity, monocyte proliferation, blast percentage), flow cytometry, comprehensive cytogenetics, molecular testing (NGS panel for TET2, SRSF2, ASXL1, RAS pathway, JAK2, etc.), exclusion of reactive monocytosis (infection, autoimmune, malignancy). Treatment depends on risk and phenotype: low-risk asymptomatic disease — observation; cytopenia-driven symptoms — supportive care (transfusions, growth factors), hypomethylating agents (azacitidine, decitabine — modest response 20-40%, may improve survival), allogeneic stem cell transplantation (only curative therapy for fit patients, especially high-risk); proliferative phenotype — hydroxyurea for cytoreduction, hypomethylating agents; targeted therapies emerging (tagraxofusp for CD123+ disease, MEK inhibitors for RAS-mutated, IDH inhibitors for IDH-mutated). Transformation to AML occurs in 15-30% with poor prognosis, treated as therapy-related AML. Median overall survival varies by risk: low-risk 5+ years, intermediate-risk 2-3 years, high-risk <1 year. Active areas of research: combination therapies (HMA + venetoclax), oral hypomethylating agents (oral azacitidine), JAK inhibitors for proliferative CMML, targeted therapies based on molecular profile.