Chronic Myelomonocytic Leukemia (CMML)

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Chronic Myelomonocytic Leukemia (CMML)

Identity

Note The nosology of CMML is controversial. The FAB classification categorized this disorder as a myelodysplastic disorder. Others view this disease as predominantly a myeloproliferative disorder, or recognize both myeloproliferative and myelodysplastic forms of CMML. The recent World Health Organization (WHO) classification places CMML into a separate category along with juvenile myelomonocytic leukemia (JMML, JCML) of disorders with both myelodysplastic and myeloproliferative features.

Clinics and Pathology

Disease The defining features of CMML are an absolute monocytosis of >1X10⁹/l, increased numbers of monocytes in bone marrow, and a variable degree of dyplasia in all three lineages. Myeloblasts and promonocytes comprise less than 5% of nucleated cells in peripheral blood and less than 20% of cells in bone marrow. Roughly half of patients present with an elevated white cell count that is commonly associated with hepatomegaly and splenomegaly, the so-called myeloproliferative form of the disease. Patients lacking these features are generally considered to have the myelodysplastic form of the disease.

Phenotype / cell stem origin Presumably a multipotential stem cell.

Epidemiology CMML is usually a disease of older adults althought the disease also occurs in children, where distinction from juvenile chronic myelogenous leukemia (JCML, also known as juvenile myelomonocytic leuekmia) is difficult, and at times impossible. In one series the median age for the myelodysplastic type was 70 and for the myeloproliferative form 72 years. The disease shows a distinct male predominance of 1.6-2.1:1.

Clinics CMML patients may present with hepatomegaly or splenomegaly, serous effusions or other sites of extramedullary involvement such as skin or, less commonly, gums.

Cytology
Blood: The peripheral blood count may be increased or decreased. By definition monocytes and promonocytes exceed 1X109 /l. Dyplastic monocytes or neutrophils are usually evident. Normocytic or macrocytic anemia is common as is thrombocytopenia, which is usually mild. Serum lysozyme is usually elevated and immunoglobulin elevations occur in about a third of patients, with monoclonal gammopathy in about 5-10% of patients.
Bone marrow: The bone marrow is almost always hypercellular, often with trilineage dysplasia. Myeloblasts and monoblasts are less than 20% of the total cellularity. About 30% of cases show significant reticulin fibrosis. Cases associated with the t(5;12) (see below) are commonly associated with eosinophilia.

Treatment Although CMML often initially respond to conventional chemotherapy, complete responses are rare. Allogeneic bone marrow transplantation is potentially curative for those patients who are eligible.

Prognosis The median survival for patients with CMML is about 24 months. There does not appear to be a difference in survival between patients with the myeloproliferative versus the myelodysplastic forms of the disease nor are the number of blasts of prognostic value. Of adult patients who underwent allogeneic bone marrow transplantation the disease-free survival was 39% at 3 years.

Cytogenetics

Cytogenetics Morphological By definition CMML cases do not show the Philadelphia chromosome. Overall 20-30% of cases show cytogenetic abnormalities. These include numerical and structural abnormalities such as +8, del(20q), -7, del(11q), all of which may be seen in other myelodysplastic and myeloproliferative disorders. Rarely translocations have been identified in CMML. Cases associated with eosinophilia commonly show t(5;12)(q33;p13) which fuses TEL to the platelet-derived growth factor receptor ( PDGFbR)(about 2-5% of all CMML cases). Fusions of the Huntington interacting protein 1 ( HIP1) gene to PDGFbR have also been described in CMML associated with t(5;7)(q33;q11.2). Occasional cases of therapy-associated CMML are associated with the t(11;16)(q23;p13) which fuses MLL to CBP. Rare reports of CMML associated with t(1;13)(p36;q21), t(7;11)(p15;p15) and t(8;9)(p11;q34) have been reported.

Genes involved and Proteins

Note Mechanisms of Oncogenesis: In most cases of CMML the critical genetic lesions have not been identified. In the case of the TEL-PDGFRb fusion the TEL HLH region mediates oligomerization of the PDGFR that appears to be required for it's mitogenic properties. Roughly half of CMML cases show mutations of K-RAS and N-RAS, usually glycine to aspartic acid substitutions at the 12th or 13th codons.

Bibliography

Proposals for the classification of the myelodysplastic syndromes.

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C

British journal of haematology. 1982 ; 51 (2) : 189-199.

PMID 6952920

Chronic myelomonocytic leukemia: single entity or heterogeneous disorder? A prospective multicenter study of 100 patients. Groupe Franˆßais de Cytogˆ©nˆ©tique Hˆ©matologique.

Cancer genetics and cytogenetics. 1991 ; 55 (1) : 57-65.

PMID 1913608

Molecular genetic aspects of myelodysplastic syndromes.

Bartram CR

Hematology/oncology clinics of North America. 1992 ; 6 (3) : 557-570.

PMID 1613006

Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome?

Michaux JL, Martiat P

Leukemia & lymphoma. 1993 ; 9 (1-2) : 35-41.

PMID 8477199

The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group.

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, Sultan C, Cox C

British journal of haematology. 1994 ; 87 (4) : 746-754.

PMID 7986717

Problems in the classification of CMML--dysplastic versus proliferative type.

Germing U, Gattermann N, Minning H, Heyll A, Aul C

Leukemia research. 1998 ; 22 (10) : 871-878.

PMID 9766745

World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 ; 17 (12) : 3835-3849.

PMID 10577857

Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation.

Zang DY, Deeg HJ, Gooley T, Anderson JE, Anasetti C, Sanders J, Myerson D, Storb R, Appelbaum F

British journal of haematology. 2000 ; 110 (1) : 217-222.

PMID 10931002

Contributor(s)

Written 07-2001 Jay L. Hess

Citation

This paper should be referenced as such :
Hess JL . Chronic Myelomonocytic Leukemia (CMML). Atlas Genet Cytogenet Oncol Haematol. July 2001 .
URL : http://AtlasGeneticsOncology.org/Genes/CMMLID1098.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Dec 6 18:01:22 2008

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jlhuret@AtlasGeneticsOncology.org.

Disease	The defining features of CMML are an absolute monocytosis of >1X10⁹/l, increased numbers of monocytes in bone marrow, and a variable degree of dyplasia in all three lineages. Myeloblasts and promonocytes comprise less than 5% of nucleated cells in peripheral blood and less than 20% of cells in bone marrow. Roughly half of patients present with an elevated white cell count that is commonly associated with hepatomegaly and splenomegaly, the so-called myeloproliferative form of the disease. Patients lacking these features are generally considered to have the myelodysplastic form of the disease.
Phenotype / cell stem origin	Presumably a multipotential stem cell.
Epidemiology	CMML is usually a disease of older adults althought the disease also occurs in children, where distinction from juvenile chronic myelogenous leukemia (JCML, also known as juvenile myelomonocytic leuekmia) is difficult, and at times impossible. In one series the median age for the myelodysplastic type was 70 and for the myeloproliferative form 72 years. The disease shows a distinct male predominance of 1.6-2.1:1.
Clinics	CMML patients may present with hepatomegaly or splenomegaly, serous effusions or other sites of extramedullary involvement such as skin or, less commonly, gums.
Cytology	Blood: The peripheral blood count may be increased or decreased. By definition monocytes and promonocytes exceed 1X109 /l. Dyplastic monocytes or neutrophils are usually evident. Normocytic or macrocytic anemia is common as is thrombocytopenia, which is usually mild. Serum lysozyme is usually elevated and immunoglobulin elevations occur in about a third of patients, with monoclonal gammopathy in about 5-10% of patients. Bone marrow: The bone marrow is almost always hypercellular, often with trilineage dysplasia. Myeloblasts and monoblasts are less than 20% of the total cellularity. About 30% of cases show significant reticulin fibrosis. Cases associated with the t(5;12) (see below) are commonly associated with eosinophilia.
Treatment	Although CMML often initially respond to conventional chemotherapy, complete responses are rare. Allogeneic bone marrow transplantation is potentially curative for those patients who are eligible.
Prognosis	The median survival for patients with CMML is about 24 months. There does not appear to be a difference in survival between patients with the myeloproliferative versus the myelodysplastic forms of the disease nor are the number of blasts of prognostic value. Of adult patients who underwent allogeneic bone marrow transplantation the disease-free survival was 39% at 3 years.