Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis

INTRODUCTION — Chronic myelomonocytic leukemia (CMML) is a hybrid hematologic malignancy with clinical and pathological features of both myeloproliferative neoplasms (MPN) and myelodysplastic neoplasms/syndromes (MDS). CMML is characterized by peripheral blood monocytosis and bone marrow dysplasia, often accompanied by splenomegaly, constitutional symptoms, and/or cytopenias. CMML is a clinically and genetically distinct entity. The clinical features of CMML are heterogeneous, but it can be among the most aggressive of the chronic leukemias, with a propensity for progression to acute myeloid leukemia (AML).

The epidemiology, evaluation, and diagnosis of CMML are reviewed here.

Management and prognosis of CMML are discussed separately. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

PATHOGENESIS — The pathogenesis of CMML is not well understood. There is no single disease-defining chromosomal abnormality or mutation, but some genetic abnormalities may enhance hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocytopoiesis.

The most common cytogenetic abnormalities in CMML are trisomy 8 and various abnormalities of chromosome 7 [1]. Mutations in epigenetic modifiers and regulators of mRNA splicing occur in up to 80 percent of cases of CMML [2]. The most common mutations involve epigenetic modifiers (eg, TET2, ASXL1, EZH2), splicing factors (eg, SRSF2, SF3B1, ZRSF2), cytokine signaling (eg, NRAS, KRAS, CBL, JAK2), transcription factors (eg, RUNX1), and mediators of DNA damage response (eg, TP53, PHF6) [3-7]. Mutations in SRSF2 and ASXL1 are present in approximately 40 percent of cases of CMML [5,7-9].

The genetic determinants of the myeloproliferative and myelodysplastic features of CMML are uncertain. A large proportion of cases display hypersensitivity to GM-CSF in vitro, which likely contributes to the monocytic phenotype [10-14]. Mutations in RAS pathway genes appear to skew the phenotype toward the myeloproliferative variant of CMML [3,15]. As with myeloproliferative neoplasms, the bone marrow in CMML is characterized by an inflammatory cytokine microenvironment [16].

Importantly, certain mutations that are associated with myelodysplastic syndromes exclude the diagnosis of CMML, as described below. (See 'Diagnosis' below.)

EPIDEMIOLOGY — The incidence of CMML is poorly defined, in part because CMML had previously been categorized as either a myeloproliferative neoplasm (MPN) or myelodysplastic neoplasms/syndromes (MDS).

CMML occurs most commonly in older adults, with a median age at diagnosis of 65 to 75 years and a male:female ratio of 1.5 to 3.1 [17-19]. A study that used centralized morphologic review of a well-defined population reported a prevalence of 1 to 2 cases per 100,000 population per year [20]. Another study reported a similar incidence and also noted the highest incidence in patients >80 years of age [21]. The actual incidence may be higher because of the nonspecific clinical presentation, misclassification (as either MDS or MPN), and because a diagnostic bone marrow examination may not be performed in some older or frail patients [22].

CMML is not known to be an inherited disorder. No environmental exposure has been definitively linked to CMML, but some cases occur in patients after treatment with chemotherapy or ionizing radiation. Such therapy-related CMML represents approximately one-tenth of all cases [23-25]. In one study, secondary CMML (ie, CMML arising from antecedent MDS) accounted for approximately 6 percent of CMML [26].

CLINICAL FEATURES — Clinical findings of CMML are nonspecific, but patients may present with myeloproliferative-type symptoms and/or findings related to cytopenias; other patients are asymptomatic at presentation.

Clinically, CMML can be divided into dysplastic (white blood cell [WBC] count <13,000/microL; 13 x 10⁹/L) versus proliferative (WBC >13,000/microL) subtypes [27-30]. Patients with proliferative-type CMML are more likely to have constitutional symptoms (eg, weight loss, fever, night sweats), whereas the dysplastic subtype is more often associated with consequences of cytopenias (eg, fatigue, infection, bleeding/bruising) [17-19]. Individuals may have a combination of dysplastic and proliferative symptoms.

Splenomegaly and hepatomegaly, which may present with early satiety or abdominal fullness, is noted in up to one-half of patients with proliferative-type CMML but is less common with dysplastic-type CMML [17]. Nodular cutaneous leukemic infiltrates or gingival infiltration are seen occasionally, while central nervous system involvement or life-threatening hyperleukocytosis are rare [31,32]. Renal insufficiency, especially in the proliferative subtype of CMML [33], may be related to renal infiltration by monocytes and/or lysozyme secretion [34,35].

Many patients are initially asymptomatic, such as when CMML is first suspected because a routine blood count revealed mild anemia, neutropenia, monocytosis, and/or thrombocytopenia. Other patients present with an antecedent autoimmune illness (eg, rheumatoid arthritis) or other inflammatory condition [36,37].

PATHOLOGIC FEATURES

Peripheral blood — The hallmark of CMML is peripheral blood clonal monocytosis; in addition, at least one-half of cases manifest an elevated total white blood cell (WBC) count at presentation.

●Monocytes and blasts – CMML is associated with increased circulating monocytes.

A defining feature of CMML is an absolute monocyte count (AMC) ≥500/microL (0.5 x 10⁹/L) with monocytes accounting for ≥10 percent of peripheral blood WBCs [2,38]. The AMC is usually 2000 to 5000/microL but can be >80,000/microL in rare cases. It should be noted that the previous diagnostic threshold for AMC was ≥1000/microL [39].

Monocytes are generally mature with minimal morphologic atypia, but atypical monocytes with abnormalities of nuclear segmentation, unusually fine chromatin, or abnormal cytoplasmic granules can be present (picture 1). These atypical monocytes should be distinguished from promonocytes, which are considered blast equivalents in CMML. Immature cells, including monoblasts, promonocytes, and blasts may be present in the blood smear. Importantly, acute myeloid leukemia (AML) should be diagnosed if such immature forms account for ≥20 percent of leukocytes.

As discussed separately, staging of CMML requires accurate quantitation of blasts. (See "Chronic myelomonocytic leukemia: Management and prognosis", section on 'Disease stage'.)

●Neutrophils – Neutrophilia contributes to leukocytosis in CMML, but neutrophil precursors (eg, promyelocytes, myelocytes) usually account for <10 percent of leukocytes [17,40-42]. It can be difficult to distinguish dysplastic monocytes from hypogranular neutrophils; in many cases, distinctive mononuclear cells with features intermediate between myelocytes and monocytes ("paramyeloid cells") are apparent. Neutrophil dysplasia (eg, hypersegmented or abnormally segmented nuclei or abnormal cytoplasmic granulation) is easily apparent in the dysplastic subtype of CMML but may be subtle in the proliferative subtype [40,43]. The subtypes of CMML are discussed separately. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

●Red blood cells and platelets – Mild normocytic or macrocytic anemia is common and platelet counts vary, but there is often moderate thrombocytopenia. Nucleated red blood cells and atypical, large platelets may be seen on the blood smear [40,44].

●Eosinophils – In rare cases with ≥1500 eosinophils/microL, CMML must be distinguished from myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions, as described below. (See 'Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion' below.)

Cytochemical staining, flow cytometry, cytogenetics, and molecular features of blood cells are described below. (See 'Bone marrow' below.)

Bone marrow

Microscopy — There is no pathognomonic morphologic feature of CMML, but bone marrow is generally hypercellular with dysplasia and it contains abundant mononuclear cells, granulocytes, and myeloid progenitors.

Bone marrow is hypercellular in >75 percent of cases, but some cases are normocellular or occasionally hypocellular [19,45-47]. Bone marrow has <20 percent blasts (including myeloblasts, monoblasts, and promonocytes); by definition, blast counts >20 percent establish a diagnosis of AML. Mature monocytes should be excluded from the blast count, although the distinction between atypical monocytes and immature forms can be challenging when there is substantial dysplasia. (See 'Peripheral blood' above.)

Monocytic and granulocytic cells are abundant, but these lineages may be difficult to distinguish by morphology alone [42,45]. Bone marrow dysplasia resembles that of myelodysplastic neoplasms/syndromes (MDS), but dysplastic features in CMML can be subtle. Ring sideroblasts have also been reported in CMML, but the biologic and prognostic significance is unclear. Nodules of plasmacytoid dendritic cells that are clonally related to the CMML can be seen in the bone marrow in 20 percent of patients; this finding may be associated with adverse prognosis [48]. Other dysplastic features of CMML cells are described above. (See 'Peripheral blood' above.)

Megakaryocyte dysplasia is present in >80 percent of the cases; in occasional cases, megakaryocytes are the only lineage that manifests overt dysplasia. Dysplastic forms may include micromegakaryocytes and small hypolobate forms [39]. Clustering of megakaryocytes is usually not seen. Bone marrow fibrosis can be seen in CMML, but its significance is unclear.

Cytochemistry — Cytochemical studies are valuable for characterizing CMML [46].

Monocytes are positive for alpha-naphthyl butyrate esterase or alpha-naphthyl acetate esterase (with fluoride inhibition), alone, or in combination with naphthol AS-D [39]. Chloroacetate esterase (CAE) staining may be useful for distinguishing monocytes from granulocytic precursors.

Immunophenotype — Immunophenotyping can aid quantitation of monocytes and reveal antigenic abnormalities of monocytic forms, myeloid blasts, and maturing myelomonocytic cells. Multicolor flow cytometry is more sensitive than immunohistochemistry for characterizing the immunophenotype.

The bulk of bone marrow cells in CMML express typical myelomonocytic antigens (CD33, CD13) and variably express CD14, CD68, and CD64 [49-52]. In virtually all cases of CMML there is a relative increase in classical monocytes (defined by expression of CD14 and absence of CD16) in bone marrow and peripheral blood [13].

As with their morphology, blood and bone marrow monocytes have aberrant immunophenotypes, with two or more aberrant features by flow cytometry [53]. Decreased expression of CD14 may reflect immaturity of monocytes [13]. Other atypical immunophenotypic features include overexpression of CD56; aberrant expression of CD2; and decreased expression of HLA-DR, CD13, CD11c, CD15, CD16, CD64, and CD36 [13,53-55]. An increased fraction of CD34+ cells and/or an emerging population of blasts with an aberrant immunophenotype may suggest transformation to acute leukemia [56,57].

The most reliable immunohistochemical staining of tissue sections is for CD14, CD68R, and CD163 [46,58]. Lysozyme staining can complement CAE cytochemistry to identify monocytic cells (which are lysozyme positive, but CAE negative); this contrasts with granulocytic precursors, which are positive for both.

Cytogenetics — Cytogenetic abnormalities are identified in 20 to 40 percent of CMML cases, but no finding is specific to this disease [3]. Cytogenetic features are used in several of the CMML prognostic systems. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

The most common recurrent cytogenetic abnormalities in CMML are gain of chromosome 8, loss of chromosome 7, del(7q), -Y, and complex karyotypes [1,19,59-61]. A study of 414 patients with CMML reported a normal karyotype in 73 percent, 7 percent had trisomy 8, 4 percent had loss of chromosome Y, 3 percent had a complex karyotype, 1.5 percent had an abnormality of chromosome 7, and 10 percent had another aberration [62].

Molecular features — Somatic mutations are found in >90 percent of patients with CMML [2]. The most common mutations are TET2 (58 percent), SRSF2 (46 percent), ASXL1 (40 percent), RUNX1 (15 percent), NRAS (11 percent), CBL (10 percent), and others (<10 percent) [4,63]. Most cases have a mutation of either TET2, SRSF2, SETBP1, or ASXL1 [5,64,65]. Mutations of NPM1 are uncommon (<5 percent of cases). If an NPM1 mutation is present, this may indicate AML with monocytic differentiation or CMML with a high probability of progressing to AML [66].

As discussed below, when mutations are present at a variant allele frequency (VAF) >10 percent, they can be used as a marker of clonality; this can establish a diagnosis of CMML even in the absence of dysplasia and with a lower absolute monocyte count (>500/microL). (See 'Diagnosis' below.)

Somatic mutations are used in several CMML prognostic models. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

EVALUATION — Evaluation of a patient suspected to have CMML includes:

●Clinical – The history should elicit symptoms related to cytopenias (eg, weakness or fatigue from anemia; recurrent infections from neutropenia; bleeding/bruising from thrombocytopenia), splenomegaly (eg, early satiety or weight loss), and constitutional symptoms. Prior treatment with chemotherapy, transfusion history, and prior monocytosis should be documented.

●Blood counts/smear – A complete blood count (CBC) with differential count should be evaluated for monocytosis, cytopenias, and the percentage of blasts. The blood smear should be examined for dysplasia and blasts.

●Bone marrow examination – Bone marrow should be examined for cellularity, percentage of monocytes and monoblasts, and evidence of dysplasia, as described above. (See 'Microscopy' above.)

●Cytogenetics/molecular evaluation – Karyotype and genetic profiling can be performed with conventional cytogenetics and/or fluorescence in situ hybridization (FISH) of blood or bone marrow. A myeloid gene panel or other method for mutation analysis can document clonality and identify mutated genes.

Cytogenetics must exclude t(9;22) chromosomal translocation (ie, Philadelphia chromosome) and/or BCR::ABL1 rearrangement and abnormalities associated with myeloid/lymphoid neoplasms with eosinophilia (eg, PDGFRA- or PDGFRB-rearrangement, FGFR1-rearrangement, or PCM1::JAK2).

DIAGNOSIS — CMML should be considered in an adult with persistent, unexplained monocytosis, cytopenias, and/or proliferative symptoms.

Diagnostic criteria for CMML are evolving and current diagnostic systems differ subtly [2,38]. Note that, compared with the previous diagnostic threshold for monocytes (≥1000/microL), contemporary diagnostic criteria apply a lower threshold when there is evidence of clonality (described below).

International Consensus Classification (ICC) criteria — ICC criteria for diagnosis of CMML [2] are:

●Monocytosis – Absolute monocyte count (AMC) >500/microL (0.5 x 10⁹/L) with monocytes accounting for >10 percent of the white blood cell (WBC) differential count.

●Cytopenia – At least one cytopenia:

•Anemia – Hemoglobin <13 g/dL in males, <12 g/dL in females

•Neutropenia – Absolute neutrophil count (ANC) <1.8 x 10⁹/L

•Thrombocytopenia – Platelets <150 x 10⁹/L

Patients with early stage CMML may show only borderline or no cytopenia; such cases require marrow morphology, flow cytometry, and molecular data to support a diagnosis of CMML [67].

●Blasts – Blasts (myeloblasts, monoblasts, and promonocytes) constitute <20 percent of cells in blood and marrow.

●Clonality – Abnormal cytogenetics and/or ≥1 myeloid neoplasm-associated mutation (with ≥10 percent variant allele frequency [VAF]).

In cases without evidence of clonality, CMML can be diagnosed by AMC >1.0 x 10⁹/L and >10 percent of WBC plus at least one of the following:

•Increased blasts plus promonocytes (≥5 percent in marrow or >2 percent in blood)

•Morphologic dysplasia

•Abnormal immunophenotype, consistent with CMML

●Bone marrow – Hypercellular marrow, often with increased monocytes, that lacks diagnostic features of acute myeloid leukemia, MPNs, or other conditions associated with monocytosis.

●Exclude other MPNs – No BCR::ABL1 or abnormalities associated with myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (ie, PDGFRA- or PDGFRB-rearrangement, FGFR1-rearrangement, or PCM1::JAK2).

World Health Organization 5th edition (WHO5) criteria — WHO5 criteria are [38]:

●Diagnosis requires:

•Prerequisite criteria (below) must be met in all cases:

-If monocytosis is ≥1 × 10⁹/L: One or more supporting criteria (below) must be met.

-If monocytosis is ≥0.5 and <1 × 10⁹/L: Supporting criteria 1 and 2 must be met.

•WHO5 prerequisite criteria (all are required):

-Monocytosis – AMC ≥500/microL (0.5 x 10⁹/L) and relative ≥10 percent monocytosis.

-Blasts – Blasts (myeloblasts, monoblasts, and promonocytes) constitute <20 percent of cells in blood and marrow.

-Exclude other MPNs – Not meeting diagnostic criteria for chronic myeloid leukemia (CML) or other MPNs.

-Exclude myeloid/lymphoid neoplasms with tyrosine kinase fusions – Not meeting diagnostic criteria of myeloid/lymphoid neoplasms with tyrosine kinase fusions.

•WHO5 Supporting criteria:

-1) Dysplasia (≥10 percent morphologic dysplasia of cells of a lineage) involving ≥1 myeloid lineages

-2) Acquired clonal cytogenetic or molecular abnormality

-3) Abnormal partitioning of peripheral blood monocyte subsets (ie, detection of increased classical monocytes [>94 percent] in the absence of known active autoimmune diseases and/or systemic inflammatory syndromes)

Note that the ICC and WHO5 diagnostic criteria for CMML differ subtly. The ICC includes a category called clonal monocytosis of undetermined significance (CMUS) [2] that the WHO5 would describe as CMML [38]. CMUS is defined by:

●AMC ≥0.5 x 10⁹/L with monocytes ≥10 percent of WBCs

●No MDS-defining cytopenias

●A myeloid-driver somatic mutation with VAF ≥2 percent

●No bone marrow morphologic findings of CMML [2]

Both ICC and WHO5 recognize dysplastic-type and proliferative-type CMML as distinct subtypes of CMML. All cases should be subclassified according to both the percentage of blasts in blood and bone marrow and the total WBC count, as described separately. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

DIFFERENTIAL DIAGNOSIS — CMML must be distinguished from other disorders associated with monocytosis and/or dysplasia, including reactive disorders, chronic myeloid leukemia (CML), other myeloproliferative neoplasms (MPN), and myelodysplastic neoplasms/syndromes (MDS).

Distinguishing CMML from other monocytosis — CMML can be difficult to distinguish from other causes of monocytosis. While there are no pathognomonic cytogenetic or molecular abnormalities associated with CMML, certain findings can support or exclude the diagnosis:

●Immunophenotype – One study suggested that when CD14+, CD16-negative monocytes account for >94 percent of total monocytes on flow cytometry, reactive monocytosis and most other hematologic malignancies can be excluded; using this criterion, the sensitivity and specificity for CMML were 94 and 92 percent, respectively [13].

●Genetics – Somatic mutations are detectable in >90 percent of cases of CMML [67]. While mutations of TET2, SRSF2, ASXL1, or SETBP1 are supportive of a diagnosis of CMML, they are not sufficient to establish the diagnosis. A variant allele frequency (VAF) >10 percent may be helpful in distinguishing CMML from clonal hematopoiesis of indeterminate potential (CHIP) or related disorders. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

Importantly, the following genetic alterations exclude a diagnosis of CMML: BCR::ABL1, PDGFRA- or PDGFRB-rearrangements, FGFR1-rearrangment, PCM1::JAK2. (See 'Diagnosis' above.)

●Prior disorders – A prior history of an MPN excludes the diagnosis of CMML. The presence of mutations commonly seen in MPNs (JAK2, CALR, or MPL) favors a diagnosis of an MPN with associated monocytosis, rather than CMML.

Reactive monocytosis — Monocytosis, with or without associated neutrophilia, is a relatively nonspecific finding and reactive causes of monocytosis (ie, non-clonal monocytes) are often prominent in the differential diagnosis of CMML.

Conditions that cause monocytosis include pregnancy, asplenia, corticosteroids, myeloid growth factors, and inflammatory or autoimmune conditions (eg, sarcoidosis, inflammatory bowel disease). Reactive monocytosis can be associated with Hodgkin lymphoma (ie, the monocytes are not part of the malignant clone). Infections that have been associated with monocytosis include brucellosis, varicella-zoster, bacterial endocarditis, tuberculosis, malaria, typhoid fever, syphilis, and trypanosomiasis.

With extreme leukocytosis associated with a reactive cause (eg, severe infection, myeloid growth factors), even though the absolute monocyte count can be >1000/microL, monocytes account for only a small fraction of the total white blood cell (WBC) count. In contrast, despite a relative increase in monocytes, many cases of CMML do not have an elevated total WBC count. Evaluation of neutrophilia is discussed separately. (See "Approach to the patient with neutrophilia".)

Myelodysplastic syndromes — Dysplasia is present in both CMML and MDS. Dysplasia in CMML is generally more subtle and is typically seen in <10 percent of mononuclear cells, but higher degrees of dysplasia are compatible with the diagnosis. Although MDS may exhibit modest or fluctuating monocytosis, CMML has persistent peripheral blood monocytosis (ie, >500 monocytes/microL) and often manifests other proliferative features such as splenomegaly, leukocytosis, and constitutional symptoms (picture 1).

The mutations associated with CMML do not distinguish it from MDS, and vice versa. However, SETBP1 and/or SRSF2 mutations are more common in overlap disorders than in MDS and their presence may favor a diagnosis of CMML or another MDS/MPN.

Other diagnostic features of MDS are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Myeloproliferative neoplasms

Chronic myeloid leukemia — Both CML and CMML may manifest findings related to proliferative features (eg, splenomegaly, B symptoms), but the presence of the BCR::ABL1 rearrangement and/or t(9;22), the Philadelphia chromosome, confirms the diagnosis of CML and excludes CMML. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Other MPNs — Polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic neutrophilic leukemia (CNL) may present with proliferative features, including constitutional symptoms, splenomegaly, and leukocytosis; bone marrow is generally hypercellular in PV, the cellular phase of PMF, and CNL. These MPNs typically exhibit polycythemia and/or thrombocytosis and generally lack the persistent absolute monocytosis and dysplastic features of CMML. Although JAK2 V617F can be associated with both MPNs and CMML, the other characteristic mutations associated with MPNs (eg, MPL, CALR, CSF3R) are not seen with CMML.

Details of the characteristic features and diagnosis of these MPNs are presented separately. (See "Overview of the myeloproliferative neoplasms".)

Myeloproliferative/myelodysplastic syndromes

Juvenile myelomonocytic leukemia — Juvenile myelomonocytic leukemia (JMML) is a rare disorder of infancy and early childhood characterized by hepatosplenomegaly, lymphadenopathy, pallor, fever, and skin rash (table 1). Patients with JMML demonstrate clonal overproduction of maturing myeloid cells. Progression to acute leukemia is rare. The karyotype in JMML is often normal but sometimes shows monosomy 7. Although JMML and CMML share certain clinical and pathologic features, the ages of affected patients are clearly distinct. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia'.)

Atypical CML — Atypical CML (aCML) is a BCR::ABL1-negative is an uncommon MDS/MPN syndrome that, like CMML, is characterized by both dysplasia and myeloid proliferation. The entity is uncommon, but it can cause a considerable diagnostic challenge. Monocytosis is common in aCML but, by definition, monocytes are <10 percent of the blood differential count. aCML is characterized by profound dysgranulopoiesis, absence of the BCR::ABL1 fusion gene, and neutrophilia (table 2). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on '"Atypical CML"'.)

MDS/MPN unclassifiable — Both CMML and MDS/MPN, unclassifiable (MDS/MPN-U) have clinical and pathologic features that overlap MPNs and MDS. MDS/MPN-U includes cases that display MDS and MPN features but cannot be classified as aCML, CMML, or JMML. By definition, cases of MDS/MPN-U cannot have peripheral monocytes >1000/microL that corresponds to >10 percent of the differential count.

Systemic mastocytosis with associated hematologic neoplasm — Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is manifested by systemic mastocytosis and a second hematologic neoplasm [39]. The most common associated hematologic neoplasm with mastocytosis is CMML [68].

SM-AHN is characterized by mastocytosis-like symptoms (eg, diarrhea, pruritus, intermittent hypotension, nausea, ocular symptoms, anaphylaxis) and has a particularly aggressive natural history. Abnormal mast cell infiltrates in the bone marrow biopsy are often the sentinel finding. The activating mutation, KIT D816V, is present in most cases of SM-AHN (in both the mastocytes and the associated hematologic neoplasm cells).

Other aspects of the diagnosis of SM-AHN are presented separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion — Myeloid and lymphoid variants of eosinophilia include MPNs with certain molecular abnormalities, including those involving PDGFRA, PDGFRB, FGFR1, PCM1::JAK2, and other rare rearrangements; the presence of one of these molecular abnormalities excludes the diagnosis of CMML.

Details of these eosinophilic conditions are presented separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Myeloproliferative HES variants'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY

●Description – Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy with clinical and pathologic features of both myeloproliferative neoplasms (MPN) and myelodysplastic neoplasms/syndromes (MDS). CMML is characterized by peripheral blood monocytosis, cytopenia, and clonality, often accompanied by splenomegaly.

●Pathogenesis – Cytogenetic and molecular abnormalities are common in CMML, but none is diagnostic. Mutations in epigenetic modifiers or splicing factors are found in most cases. Genetic alterations appear to converge on a phenotype skewed towards hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocytopoiesis. (See 'Pathogenesis' above.)

●Presentation – Clinical findings are nonspecific, but patients can present with proliferative-type symptoms (eg, constitutional symptoms, splenomegaly) and/or findings related to cytopenias. (See 'Clinical features' above.)

●Pathology – Features include:

•Blood – Monocytosis (absolute monocyte count [AMC] ≥500/microL [≥0.5 x 10⁹/L]) is the hallmark of CMML; monocytes account for ≥10 percent of leukocytes. (See 'Peripheral blood' above.)

Monocytes are generally mature, but they can exhibit dysplasia with aberrant nuclear segmentation, disordered chromatin, or abnormal cytoplasmic granulation (picture 1).

•Bone marrow – Bone marrow is generally hypercellular, but it has <20 percent blasts; cytochemical, immunophenotypic, cytogenetic, and molecular findings are described above. (See 'Bone marrow' above.)

●Diagnosis – CMML should be considered in an adult with persistent, unexplained monocytosis, cytopenias, and/or proliferative symptoms. (See 'Diagnosis' above.)

Diagnostic criteria are evolving; criteria developed by the International Consensus Classification [2] are:

•Monocytosis – AMC >500/microL with monocytes accounting for >10 percent of the white blood cell (WBC) differential count

•Cytopenia – At least one affected lineage

•Blasts – Blasts (myeloblasts, monoblasts, and promonocytes) constitute <20 percent of cells in blood and marrow

•Clonality – Abnormal cytogenetics and/or ≥1 MPN-associated mutation (with ≥10 percent allele frequency)

•Bone marrow – Hypercellular marrow, often with increased monocytes, that lacks diagnostic features of acute myeloid leukemia, MPNs, or other conditions associated with monocytosis

•Exclude other MPNs – No BCR::ABL1 or abnormalities associated with myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (ie, PDGFRA- or PDGFRB-rearrangement, FGFR1-rearrangement, or PCM1::JAK2)

●Classification – All cases should be subclassified according to the WBC count and percentage of blasts in peripheral blood and bone marrow, as described separately. (See "Chronic myelomonocytic leukemia: Management and prognosis".)

●Differential diagnosis – CMML must be distinguished from other conditions associated with monocytosis and/or dysplasia, including reactive causes, MPNs, and MDS. Molecular rearrangements that exclude CMML are described above. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge David P Steensma, MD, who contributed to an earlier version of this topic review.