Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management

Abstract

Disease overview: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years).

Diagnosis: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10⁹ /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%) and the oncogenic RAS pathway (∼30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over-all survival.

Risk stratification: Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count > 10 × 10⁹ /L, hemoglobin <10 gm/dL, platelet count <100 × 10⁹ /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into 4 groups; high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.

Risk-adapted therapy: Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ∼30%-40% and complete remission rates of ∼7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.

Figure 1

A Schematic approach to the differential diagnosis of peripheral blood monocytosis. *: Peripheral blood abnormalities include unexplained anemia, thrombocytopenia, thrombocytosis, leukocytosis, eosinophilia, granulocytic dysplasia (pseudo Pelger Huët cells), circulating immature myeloid cells such as myelocytes, metamyelocytes and promyelocytes, promonocytes and blasts. **: FISH – fluorescence in-situ hybridization, PDGFRA and PDGFRB: Platelet-derived growth factor – A and Platelet-derived growth factor – B. FISH testing for PDGFRA and PDGFRB rearrangements is highly recommended if the peripheral blood monocytosis is associated with concomitant eosinophilia. The ETV6-PDGFRB fusion oncogene can give rise to clonal monocytosis mimicking CMML, but is in fact a unique molecularly defined myeloid neoplasm (not to be diagnosed as CMML). Similarly PDGFRA fusions are commonly associated with eosinophilia, but rarely can have associated monocytosis. Most PDGFRA fusions occur due to the karyotypically occult CHIC2 deletion (not detectable by metaphase cytogenetics) resulting in the FIP1L1-PDGFRA fusion oncogene. The World Health Organization also mandates FISH testing for FGFR1 rearrangements and the PCM1-JAK2 fusion, however, these abnormalities are very uncommonly associated with monocytosis. *** While estimating peripheral blood blasts in a patient with CMML, the blasts have to be summated with circulating promonocytes.

Figure Two

A. Peripheral blood smear demonstrating monocytes with well-defined nuclear lobes and mature chromatin. Wright-Giemsa 1000 X magnification. B. Peripheral blood smear demonstrating promonocytes with open chromatin, nuclear folds and less defined nuclear lobes. Wright-Giemsa 1000 X magnification. C. Bone marrow aspirate demonstrating monoblasts with open chromatin, lack of nuclear lobes and variable nucleoli. Wright-Giemsa 1000 X magnification.

Figure Three

Peripheral blood smear of a patient with chronic myelomonocytic leukemia demonstrating circulating promonocytes (black arrows) and dysplastic granulocytes (red arrows). Wright-Giemsa 100 X magnification.