Chronic Myelomonocytic leukemia: 2020 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% over 3-5 years). Diagnosis: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 9 /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 × 10 9 /L, hemoglobin <10 g/dL, platelet count <100 × 10 9 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four 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~40%-50% 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.

An Unusual Treatment for Chronic Myelomonocytic Leukemia

“…For low risk patients the median survival is 6 years, for high risk patients it is just 5 months. 1 The most common mutations in CMML have differing mechanisms, including epigenetic control of methylation (TET2 60%), chromatin modulating (ASXL1 40%), cell signaling pathways (RAS pathway 30%) and mRNA splicing (SRSF2 50%). ASXL1 has been shown to correlate with survival.…”

“…7 Unfortunately, only 50% of patients respond to these agents, with less than 20% achieving complete response to these agents alone. 1 HMAs are also frequently used in patients with AML who are not candidates for standard chemotherapy induction. Unfortunately, response rates in most studies of patients with AML show a complete response in only approximately 20%.…”

“…Clonal cytogenetic abnormalities are found in approximately 30% of patients, most commonly trisomy 8, trisomy 21, monosomy 7 and del7q, and other complex karyotypes. 1 For younger, fit patients, treatment ideally involves bone marrow transplant. If not a candidate, cytoreductive strategies using hydroxyurea or hypomethylating agents (HMA) are the standard of care for symptomatic patients.…”

Evidence-Based Minireview: Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review

“…His complete blood count demonstrates a white blood cell (WBC) count of 44 × 10 9 /L, 25% monocytes, circulating myelocytes/metamyelocytes, hemoglobin of 8.5 g/dL, and a platelet count of 110 2 and is a clonal stem cell disorder that is characterized by sustained peripheral blood (PB) monocytosis (≥1 × 10 9 / L and ≥10% of WBC differential) and an inherent tendency for transformation to acute myeloid leukemia (AML; 15-20% over 3-5 years). 3 The median age at diagnosis for CMML is 73 years, with a male preponderance. 3 Histologically, CMML can be classified as CMML-0 (<2% PB blasts and <5% bone marrow [BM] blasts), CMML-1 (2-4% PB blasts and/or 5-9% BM blasts), and CMML-2 (5-19% PB blasts and/or 10-19% BM blasts or when…”

“…3 The median age at diagnosis for CMML is 73 years, with a male preponderance. 3 Histologically, CMML can be classified as CMML-0 (<2% PB blasts and <5% bone marrow [BM] blasts), CMML-1 (2-4% PB blasts and/or 5-9% BM blasts), and CMML-2 (5-19% PB blasts and/or 10-19% BM blasts or when…”