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Chronic myelomonocytic leukemia

Authors
David P Steensma, MD
Eric Padron, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

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 (table 1).

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.

The epidemiology, diagnosis, and management of CMML will be reviewed here. Other myeloproliferative neoplasms and myelodysplastic syndromes are presented separately. (See "Overview of the myeloproliferative neoplasms" and "Overview of the treatment of myelodysplastic syndromes" and "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)

PATHOGENESIS

The pathogenesis of CMML is poorly understood. CMML is thought to arise via the serial acquisition of somatic genetic events that aggregate by Darwinian principles into distinct neoplastic cell clones [1]. Most cases of CMML appear to comprise more than one clone and are genetically dynamic. Many of the genetic mutations identified in patients with CMML induce a CMML phenotype in murine models [2-5]. Although CMML does have a distinct "genetic fingerprint" (ie, a unique frequency and pattern of mutated genes), there is no single disease-defining mutation or chromosomal abnormality.

The most common cytogenetic abnormalities observed in CMML are rearrangements or deletions of chromosome 7, and trisomy 8 [6]. Marrow and blood cells from most patients with CMML have acquired mutations in genes that encode epigenetic modifiers (eg, TET2, ASXL1, EZH2), regulators of alternative mRNA splicing (eg, SRSF2, SF3B1, ZRSF2), transcription factors (eg, RUNX1), and cytokine signaling (eg, NRAS, CBL, KRAS, JAK2) [7-10]. Similar to the closely related pediatric disease juvenile myelomonocytic leukemia (JMML), a large fraction of CMML cases display hypersensitivity to granulocyte macrophage colony-stimulating factor (GM-CSF) in vitro, which likely contributes to the monocytosis characteristic of the disease [11-13]. These data suggest that the genetic pathogenesis of CMML is complex but converges on a phenotype that is skewed towards monocytic hematopoiesis and GM-CSF hypersensitivity.

                                   

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Literature review current through: Nov 2016. | This topic last updated: Wed Oct 05 00:00:00 GMT 2016.
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