Chronic Myelomonocytic Leukemia (CMML)

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Chronic Myelomonocytic Leukemia (CMML)

Identity

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).

Clinics and Pathology

Note The WHO criteria include 1) stable increase in peripheral blood monocyte count (> 1 x 10⁹/L); 2) lack of Philadelphia chromosome and BCR-ABL fusion gene; 3) lack of gene rearrangement involving the Platelet-Derived Growth Factor Receptor Beta gene (PDGFRB); 4) blast cell percentage in the blood and the bone marrow lower than 20% and 5) cellular dysplasia of at least one myeloid cell line. This last criterion is not mandatory, as monocyte dysplasia can be difficult to assess in the bone marrow, and dysplasia of other lineages is inconstant. Thus, CMML may not always have a cytologically identifiable dysplastic component. When dysplasia is missing, diagnosis can be made if a clonal cytogenetic or molecular abnormality is identified in hematopoietic cells, or if peripheral blood monocyte count remains elevated at least 3 months without any other explanation.

Phenotype / cell stem 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.

Cytogenetics

Cytogenetics Morphological Conventional metaphase karyotyping of bone marrow mononucleated cells is normal in two thirds of patients. By definition CMML cases do not show the Philadelphia chromosome. Cases associated with eosinophilia and rearrangements that fuse the platelet-derived growth factor receptor (PDGFRB) to another gene such as TEL in t(5;12)(q33;p13) are excluded from the CMML group by the WHO classification as this separate entity is sensitive to tyrosine kinase inhibitors such as Imatinib mesylate. The recurrent aberrations observed in CMML include loss of the Y chromosome, monosomy 7, trisomy 8, and interstitial deletions of chromosomes 20q, 11q, and 12p, all of which may be seen in other myelodysplastic and myeloproliferative disorders. The proportion of patients showing large areas of uniparental disomy (UPD) in their blood cells, which is about 50% and could result from mitotic recombinations, is higher than in other myeloid malignancies.

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.

Other genes implicated (Data extracted from papers in the Atlas)

Genes ASXL1 CDKN2B ETV6 CCDC6 PDGFRB

Bibliography

Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia.

Droin N, Jacquel A, Hendra JB, Racoeur C, Truntzer C, Pecqueur D, Benikhlef N, Ciudad M, Guery L, Jooste V, Dufour E, Fenaux P, Quesnel B, Kosmider O, Fontenay M, Ducoroy P, Solary E.

Blood. 2010 Jan 7;115(1):78-88. doi: 10.1182/blood-2009-05-224352. Epub 2009 Oct 28.

PMID 19864642

Transcription intermediary factor 1 gamma is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.

Aucagne R, Droin N, Paggetti J, Lagrange B, Largeot A, Hammann A, Bataille A, Martin L, Yan KP, Fenaux P, Losson R, Solary E, Bastie JN, Delva L.

J Clin Invest. 2011 Jun;121(6):2361-70. doi: 10.1172/JCI45213. Epub 2011 May 2.

PMID 21537084

Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.

Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, Bouabdallah K, Vey N, Toma A, Recher C, Royer B, Joly B, Vekhoff A, Lafon I, Sanhes L, Meurice G, Orear C, Preudhomme C, Gardin C, Ades L, Fontenay M, Fenaux P, Droin N, Solary E; Groupe Francophone des Myelodysplasies.

Blood. 2011 Oct 6;118(14):3824-31. doi: 10.1182/blood-2011-05-352039. Epub 2011 Aug 9.

PMID 21828134

Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A.

Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F, Visconte V, Sugimoto Y, Prince C, O'Keefe C, Hsi ED, List A, Sekeres MA, Rao A, McDevitt MA, Maciejewski JP.

Blood. 2011 Oct 6;118(14):3932-41. doi: 10.1182/blood-2010-10-311019. Epub 2011 Aug 9.

PMID 21828135

A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.

Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, van De Walle I, Cathelin S, Trimarchi T, Araldi E, Liu C, Ibrahim S, Beran M, Zavadil J, Efstratiadis A, Taghon T, Michor F, Levine RL, Aifantis I.

Nature. 2011 May 12;473(7346):230-3. doi: 10.1038/nature09999.

PMID 21562564

SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias.

Damm F, Itzykson R, Kosmider O, Droin N, Renneville A, Chesnais V, Gelsi-Boyer V, de Botton S, Vey N, Preudhomme C, Clavert A, Delabesse E, Park S, Birnbaum D, Fontenay M, Bernard OA, Solary E.

Leukemia. 2013 Jun;27(6):1401-3. doi: 10.1038/leu.2013.35. Epub 2013 Feb 5.

PMID 23443343

Prognostic score including gene mutations in chronic myelomonocytic leukemia.

Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, Berthon C, Ades L, Fenaux P, Beyne-Rauzy O, Vey N, Braun T, Haferlach T, Dreyfus F, Cross NC, Preudhomme C, Bernard OA, Fontenay M, Vainchenker W, Schnittger S, Birnbaum D, Droin N, Solary E.

J Clin Oncol. 2013 Jul 1;31(19):2428-36. doi: 10.1200/JCO.2012.47.3314. Epub 2013 May 20.

PMID 23690417

Clonal architecture of chronic myelomonocytic leukemias.

Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, Ades L, Fenaux P, Platzbecker U, Gagey O, Rameau P, Meurice G, Orear C, Delhommeau F, Bernard OA, Fontenay M, Vainchenker W, Droin N, Solary E.

Blood. 2013 Mar 21;121(12):2186-98. doi: 10.1182/blood-2012-06-440347. Epub 2013 Jan 14.

PMID 23319568

An evolutionary perspective on chronic myelomonocytic leukemia.

Itzykson R, Solary E.

Leukemia. 2013 Jul;27(7):1441-50. doi: 10.1038/leu.2013.100. Epub 2013 Apr 5. (REVIEW)

PMID 23558522

Mutation of the colony-stimulating factor-3 receptor gene is a rare event with poor prognosis in chronic myelomonocytic leukemia.

Kosmider O, Itzykson R, Chesnais V, Lasho T, Laborde R, Knudson R, Gauthier A, Merlevede J, Ades L, Morabito M, Fontenay M, Tefferi A, Droin N, Solary E.

Leukemia. 2013 Sep;27(9):1946-9. doi: 10.1038/leu.2013.182. Epub 2013 Jun 18.

PMID 23774674

Importance of genetics in the clinical management of chronic myelomonocytic leukemia.

Padron E, Abdel-Wahab O.

J Clin Oncol. 2013 Jul 1;31(19):2374-6. doi: 10.1200/JCO.2013.48.9120. Epub 2013 May 20.

PMID 23690427

GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia.

Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, Kim E, Bebbington C, Baer M, Yarranton G, Lancet J, Komrokji RS, Abdel-Wahab O, List AF, Epling-Burnette PK.

Blood. 2013 Jun 20;121(25):5068-77. doi: 10.1182/blood-2012-10-460170. Epub 2013 Apr 30.

PMID 23632888

Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia.

Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, Nomdedeu B, Arenillas L, Luno E, Xicoy B, Amigo ML, Valcarcel D, Nachtkamp K, Ambaglio I, Hildebrandt B, Lorenzo I, Cazzola M, Sanz G.

Blood. 2013 Apr 11;121(15):3005-15. doi: 10.1182/blood-2012-08-452938. Epub 2013 Jan 31.

PMID 23372164

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

Contributor(s)

Written 07-2001 Jay L Hess

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

Updated 07-2013 Eric Solary

Inserm UMR 1009, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif cedex, France

Citation

This paper should be referenced as such :
Hess JL . Chronic Myelomonocytic Leukemia (CMML). Atlas Genet Cytogenet Oncol Haematol. July 2001 .

Solary E . Chronic Myelomonocytic Leukemia (CMML). Atlas Genet Cytogenet Oncol Haematol. July 2013 .

URL : http://AtlasGeneticsOncology.org/Anomalies/CMMLID1098.html

The various updated versions of this paper are referenced and archived by INIST as such :

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Feb 1 17:11:50 CET 2014

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Note	The WHO criteria include 1) stable increase in peripheral blood monocyte count (> 1 x 10⁹/L); 2) lack of Philadelphia chromosome and BCR-ABL fusion gene; 3) lack of gene rearrangement involving the Platelet-Derived Growth Factor Receptor Beta gene (PDGFRB); 4) blast cell percentage in the blood and the bone marrow lower than 20% and 5) cellular dysplasia of at least one myeloid cell line. This last criterion is not mandatory, as monocyte dysplasia can be difficult to assess in the bone marrow, and dysplasia of other lineages is inconstant. Thus, CMML may not always have a cytologically identifiable dysplastic component. When dysplasia is missing, diagnosis can be made if a clonal cytogenetic or molecular abnormality is identified in hematopoietic cells, or if peripheral blood monocyte count remains elevated at least 3 months without any other explanation.
Phenotype / cell stem 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.

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

Written	07-2001	Jay L Hess
		Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 413b Stellar Chance Laboratories, Philadelphia, PA 19104, USA
Updated	07-2013	Eric Solary
		Inserm UMR 1009, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif cedex, France