Chronic Myelomonocytic Leukemia (CMML)

2013-07-01   Eric Solary 

1.Inserm UMR 1009, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif cedex, France
2.Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, 413b Stellar Chance Laboratories, Philadelphia, PA 19104, USA

Clinics and Pathology

Phenotype stem cell origin

The cell of origin is a multipotential stem cell.

Epidemiology

CMML is a relatively rare disease whose incidence is around 1 case/100000 inhabitants per year. CMML is a disease of older adults, with a strong male predominance. The median age at diagnosis is around 70 years, the disease is exceptionally diagnosed before 50 years of age.

Clinics

The onset of the disease is usually insidious and, diagnosis is fortuitous in many cases. Symptoms, when present, are the consequences of cytopenias (notably anemia, which is invalidating in a third of patients), and/or of extramedullary hematopoiesis, notably splenomegaly but also hepatomegaly, skin infiltration, gum infiltration, and serous (notably pleural) effusions. Extramedullary hematopoiesis is mostly restricted to patients with WBC > 13 G/L. Finally, auto-immune manifestations (seronegative arthritis, vasculitis) can be associated to CMML.

Cytology

Peripheral blood count indicates monocytosis (up to 80 x 109/L). Cells identified by cytologists as monocytes are heterogeneous, commonly including mature monocytes, dysplastic monocytes, and a variable fraction of dysplastic granulocytes (these cells do not express CD14 but express granulocytic markers CD15 and CD24, belong to the leukemic clone, and demonstrate immunosuppressive properties like myeloid-derived suppressive cells). An increase in neutrophils or eosinophils can be associated, as well as myelemia. Anemia is usually moderate, normocytic or macrocytic. Thrombocytopenia is inconstant and can be severe. Of note, an immune mechanism can contribute to these cytopenias. Hyperuricemia, increased B12 plasma level, increase serum and urine lysozyme, and polyclonal hypergammaglobulinemia can be observed.
Bone marrow: Bone marrow smears show a hypercellular tissue in which blast cell percentage (myeloblasts and monoblasts) remains lower than 20%. Monocyte proliferation is always present and often moderate (10 to 15% of mononuclear cells) and dysplastic changes can be observed in one or several lineages. A variable degree of myelofibrosis can be detected in up to 30% of patients.

Treatment

Allogeneic stem cell transplantation remains the only potentially curative option but is rarely feasible, due to the age of patients. In those ineligible for transplantation, the mainstay of CMML treatment is hydroxyurea, which is usually initiated when the disease becomes proliferative. The overall response rate reaches 60% but complete response is exceptional. The hypomethylating agent azacitidine (AZA) has been approved in Europe for CMML with WBC < 13 G/L and bone marrow blasts between 10 and 29%. The other hypomethylating agent, decitabine, is approved in US, not in Europe. An overall response rate of 40% is observed with these drugs. Prospective randomized comparisons of hypomethylating agents versus hydrxyurea have still to be performed.

Prognosis

The median survival for patients with CMML is 24-36 months. According to the WHO, the main prognostic factor is the percentage of blast cells in the blood and the bone marrow. Several prognostic scores have been proposed that rely on peripheral blood counts, serum lactate deshydrogenase values, and percentage of bone marrow blast cells and cytogenetic abnormalities. More recent data suggest that cytogenetic and molecular information could be prognostically useful. Cytogenetics is part of a recent Spanish score whereas a recent French prognostic score includes the presence of mutations in ASXL1 gene, which is an independent poor prognostic factor in CMML. An international staging system may be established in the coming years.

Genes Involved and Proteins

Note
Whole exome sequencing identifies a mean number of 16 mutations in peripheral blood monocytes of patients with a CMML, none of which is specific of this entity. The recurrently mutated genes encode signaling molecules (NRAS, KRAS, CBL, JAK2, FLT3, CSF3R, NOTCH, NCSTN, MAML1), epigenetic regulators (TET2, ASXL1, EZH2, UTX, IDH1, IDH2, DNMT3A, SETBP1), splicing factors (SF3B1, SRSF2, ZRSF2, U2AF1), and cohesins (STAG1, STAG2, RAD21, SMC1A, SMC3, PDS5B). Mutations in the transcription regulators RUNX1, NPM1 and TP53 have also been reported in CMML. The most frequently mutated genes are TET2 (50-60%), SRSF2 (40-50%), and ASXL1 (30-40%). TET2 and SRSF2 mutations are often combined. Most of the studies consistently report the poor prognosis of ASXL1 mutations.
Aberrant gene expression profiles can be identified in the absence of gene mutation. In particular, expression of TIF1γ (transcription intermediary factor 1 gamma) is repressed by aberrant promoter hypermethylation in 35% of CMML patients, and conditional invalidation of TIF1γ leads to a CMML-like syndrome in aging mice. No direct link was identified between the repression of TIF1γ and other genes such as INK4B and the epigenetic gene mutations.

Bibliography

Pubmed IDLast YearTitleAuthors
215370842011Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.Aucagne R et al
218281342011Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.Braun T et al
234433432013SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias.Damm F et al
198646422010Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia.Droin N et al
235585222013An evolutionary perspective on chronic myelomonocytic leukemia.Itzykson R et al
218281352011Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A.Jankowska AM et al
215625642011A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.Klinakis A et al
237746742013Mutation of the colony-stimulating factor-3 receptor gene is a rare event with poor prognosis in chronic myelomonocytic leukemia.Kosmider O et al
236904272013Importance of genetics in the clinical management of chronic myelomonocytic leukemia.Padron E et al
236328882013GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia.Padron E et al
233721642013Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia.Such E et al

Summary

Note

Chronic myelomonocytic leukemia (CMML) is the most frequent entity among myeloproliferative / myelodysplastic syndromes, as defined by the World Health Organization (WHO) classification of myeloid malignancies in 2008. The percentage of peripheral and marrow blast cells is the major prognostic factor identified at that time. Based on the percentage of blast cells in the bone marrow and peripheral blood, CMML is further stratified into CMML-1 (< 5% in blood, < 10% in the bone marrow) and CMML-2 (5 - 19% in the blood; 10 to 19% in the bone marrow, or less if Auer inclusions are present).

Citation

Eric Solary

Chronic Myelomonocytic Leukemia (CMML)

Atlas Genet Cytogenet Oncol Haematol. 2013-07-01

Online version: http://atlasgeneticsoncology.org/haematological/1098/cmmlid1098

Historical Card

2001-07-01 Chronic Myelomonocytic Leukemia (CMML) by  Jay L Hess 

Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, 413b Stellar Chance Laboratories, Philadelphia, PA 19104, USA

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