Chronic Myelomonocytic Leukemia (CMML)

Definition, Etiology, Pathogenesis Top

Chronic myelomonocytic leukemia (CMML) is a rare (0.3/100,000 people per year) clonal hematologic disorder characterized by persistent monocytosis in peripheral blood, the absence of the Ph chromosome and BCR-ABL1 gene, and ≤20% blasts in bone marrow. CMML combines myeloid cell proliferation with myeloid cell dysplasia and ineffective hematopoiesis.

Clinical Features And Natural History Top

General symptoms are weakness, fatigue, weight loss, fever, and night sweats.

Signs and symptoms of cytopenias include features of anemia (easy fatigability, tachycardia, pale skin), neutropenia (increased susceptibility to infections), and thrombocytopenia (bleeding).

Signs and symptoms caused by extramedullary leukemic infiltrates: Hepatosplenomegaly, lymphadenopathy, cutaneous lesions; pleural, pericardial, and peritoneal effusions in patients with high monocyte counts.

Natural history depends on the stage of the disease (CMML-0, CMML-1, or CMML-2). The risk of transformation to acute myelogenous leukemia (AML) is 15% to 30%. The median survival is between 20 and 40 months.

Diagnosis Top

Diagnostic Tests

1. Complete blood count (CBC): Monocytosis >1×109/L, white blood cell (WBC) counts normal or slightly decreased (neutropenia) in ~50% of patients, otherwise slightly increased; mild basophilia and eosinophilia; moderate thrombocytopenia is frequent, and in some patients atypical giant platelets may be observed; normocytic (rarely macrocytic) anemia.

2. Bone marrow examination: In 75% of patients bone marrow aspiration reveals increased bone marrow cellularity, usually with dominant neutrophil or erythroid lineage and evident monocytic proliferation; >50% of patients have dysplastic changes, and in >80% of patients megakaryocytes with abnormal nuclear segmentation are observed. In ~30% of cases trephine biopsy also reveals bone marrow fibrosis.

3. Cytogenetic and molecular studies: Nonspecific clonal cytogenetic abnormalities are observed in 20% to 40% of patients. The most common cytogenetic abnormalities are trisomy 8, loss of the Y chromosome (−Y), monosomy 7 and del(7q), trisomy 21, and complex karyotypes (≥3 aberrations). Next-generation sequencing myeloid gene panels are suggested. The most common mutations found include TET2 (60%), SRSF2 (50%), and ASXL1 (40%). Approximately 10% of patients with CMML have the JAK2 mutation.

4. Imaging studies: Abdominal ultrasonography may reveal hepatosplenomegaly, lymphadenopathy, and ascites. Chest radiography may show pleural effusions. Echocardiography may reveal pericardial effusion.

Diagnostic Criteria

1. The World Health Organization (WHO) diagnostic criteria:

1) Persistent peripheral blood monocytosis ≥1×109/L with monocytes accounting for ≥10% of WBC count.

2) Not meeting WHO criteria for chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, or essential thrombocythemia. The presence of features of myeloproliferative neoplasm (MPN) in bone marrow (eg, increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei) and/or mutations in JAK2, CALR, or MPL tend to support MPN with monocytosis rather than CMML.

3) In cases with eosinophilia, no evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2.

4) Less than 20% blasts (myeloblasts, monoblasts, and promonocytes) in bone marrow and peripheral blood.

5) Dysplasia in ≥1 myeloid lineage.

6) If dysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are met and an acquired clonal cytogenetic or molecular genetic abnormality is present in myeloid cells or when the monocytosis has persisted for ≥3 months and all other causes of monocytosis have been excluded.

2. CMML subgroups:

1) CMML-0 (<2% blasts in peripheral blood and <5% in bone marrow).

2) CMML-1 (2%-4% in peripheral blood and/or 5% to 9% in bone marrow).

3) CMML-2 (5%-19% blasts in peripheral blood and/or 10%-19% in bone marrow and/or Auer rods present).

Differential Diagnosis

Other causes of monocytosis:

1) Infection: Bacterial infections (tuberculosis, syphilis, endocarditis), viral infections (cytomegalovirus, varicella/zoster, herpes simplex), fungal infections (acute and chronic).

2) Diseases of the gastrointestinal system: Inflammatory bowel disease (Crohn disease, ulcerative colitis), alcoholic liver disease, celiac disease.

3) Systemic connective tissue diseases, for instance, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis syndromes, polymyositis.

4) Granulomatous diseases, such as sarcoidosis.

5) Hematopoietic disorders: Acute monocytic and myelomonocytic leukemias, chronic myelogenous leukemia, myeloid neoplasms with the PDGFRB gene rearrangement, myeloproliferative neoplasms, and myelodysplastic syndrome.

6) Other: Glucocorticoid therapy, splenectomy, tetrachloroethane poisoning, convalescence phase of acute infections, bone marrow regeneration after radiotherapy or chemotherapy, use of granulocyte colony-stimulating factor (G-CSF) or granulocyte and macrophage colony-stimulating factor (GM-CSF).

Treatment Top

1. Supportive treatment as in myelodysplastic syndromes (eg, use of erythropoietic-stimulating agents, prophylactic antibiotics, and iron chelation).

2. Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment. It may be considered in younger patients with intermediate-2– or high-risk disease. It may also be considered for patients with lower-risk disease but with high-risk genetic features.

The results of HSCT are similar to those achieved in patients with myelodysplastic syndrome, with a median overall survival of 3 years.

3. Cytoreductive treatment: Usually with hydroxyurea (INN hydroxycarbamide) to control myeloproliferation.

4. Hypomethylating agents: Azacitidine or decitabine can be used in patients with CMML-1 with significant cytopenias or in patients with CMML-2.

Prognosis Top

Chemotherapy rarely achieves complete remission. Prognosis can be calculated using multiple risk stratification scores, including a CMML-specific prognostic scoring system that incorporates molecular information (the CPSS-Mol; simplified form available at QxMD).

This distinguishes low-, intermediate-1–, intermediate-2–, and high-risk groups with median overall survivals ranging from 17 to 68 months.