Chronic myelomonocytic leukemia (CMML) is a malignant hematopoietic stem cell disorder with clinical and pathological features of both a myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). CMML is characterized by a peripheral blood monocytosis accompanied by bone marrow dysplasia; cytopenias and hepatosplenomegaly are common. There is a propensity for progression to acute myeloid leukemia (AML), which is defined by ≥20 percent marrow blast cells. Although historically considered a subtype of MDS, CMML is a clinically and genetically distinct entity with a unique clinical presentation and natural history. CMML is among the most aggressive chronic leukemias, and there are fewer effective therapies than for most other hematologic malignancies. However, murine models and genomic data have laid a scientific foundation for the generation of novel therapeutics that is anticipated to broaden treatment options for CMML patients.
Diagnostic Tests:
The diagnosis of CMML should be considered in all patients with persistent, unexplained peripheral monocytosis. The diagnosis is usually made based upon findings in the peripheral blood and bone marrow as interpreted within the clinical context.
Pathologic features:
All patients will demonstrate involvement of the peripheral blood and bone marrow at the time of presentation. Extramedullary infiltration of the spleen, liver, skin, and lymph nodes are less common.
Peripheral blood:
Cases of CMML have a persistent peripheral blood monocyte count >1000/microL that makes up >10 percent of the entire leukocyte differential. Patients with extreme leukocytosis due to other causes, such as severe infection or therapy with hematopoietic growth factors, should not be confused with CMML, as while they may have an absolute monocyte count >1000/microL, monocytes make up only a small fraction of the total white blood cell count. Despite a relative increase in monocytes, the total white blood cell count is not increased in many CMML cases. Myeloid dysplasia may be seen in all myeloid subsets, and unique abnormal mononuclear cells exhibiting features intermediate between myelocytes and monocytes, termed “paramyeloid cells,” are often apparent. By definition, the peripheral blood blast percentage must be lower than 20 percent. Cytopenias and other common features of myelodysplastic syndrome (MDS), such as neutrophil hypolobation, may be seen in the peripheral blood
Bone marrow biopsy and aspirate
The bone marrow in CMML is uniformly hypercellular, with increased mononuclear cells and their progenitors, as well as abnormal mononuclear cells exhibiting features intermediate between myelocytes and monocytes. Cells of the monocytic line can be distinguished from granulocytic myeloid precursors using a combined esterase stain.
Clinical genetic evaluation:
Cytogenetic abnormalities are identified in 30 percent of CMML cases. Given that dysplasia is often subtle in CMML and clonal karyotypic markers are absent in 70 percent of cases, clinicians are often faced with the diagnostic challenge of a patient who has persistent monocytosis in whom benign causes of monocytosis cannot be excluded. It is within this clinical scenario that mutational analysis can be beneficial. Genetic profiling can be done using cells from the bone marrow or peripheral blood. In one analysis, sequencing nine genes (ie, SRSF2, ASXL1, CBL, EZH2, JAK2, KRAS, NRAS, RUNX1, and TET2) could identify a clonal event in >90 percent of suspected CMML cases [8]. Detection of a somatic mutation provides definitive evidence of clonality, which along with persistent monocytosis supports a diagnosis of CMML. Further, mutational profiling is integrated in several prognostic scores that accurately risk stratify cases of CMML.
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