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Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)

  • Last Modified: 04/11/2014

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Chronic Myelomonocytic Leukemia

Disease Overview
Treatment Overview for Myelodysplastic/ Myeloproliferative Neoplasms
Current Clinical Trials



Disease Overview

Note: Chronic myelomonocytic leukemia (CMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme.[1] The World Health Organization classification removed CMML from MDS, placing it in the new category Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).[2]

CMML is a clonal disorder of a bone marrow stem cell. Monocytosis is a major defining feature. CMML exhibits heterogenous clinical, hematological, and morphologic features, varying from predominantly myelodysplastic to predominantly myeloproliferative.

CMML is characterized pathologically by the following:[3,4]

  • Persistent monocytosis is greater than 1 × 109/L in the peripheral blood.
  • No Philadelphia chromosome or BCR/ABL fusion gene.
  • Fewer than 20% blasts in the blood or bone marrow.
  • Dysplasia involving one or more myeloid lineages or, if myelodysplasia is absent or minimal, either an acquired clonal cytogenetic bone marrow abnormality or at least 3 months of persistent peripheral blood monocytosis, if all other causes are ruled out.

Clinical features of CMML include the following:[3,4]

  • Fever, fatigue, night sweats, and weight loss. (Refer to the PDQ summaries on Hot Flashes and Night Sweats, Fatigue, and Nutrition in Cancer Care for more information.)
  • Infection.
  • Bleeding caused by thrombocytopenia.
  • Hepatomegaly (in some patients).
  • Splenomegaly (in some patients).
  • In patients with normal or slightly decreased white blood cell count, clinical features may be identical to MDS.
  • In patients with elevated white blood cell count, features are more like chronic myeloproliferative disorders (CMPD), including more frequent splenomegaly and hepatomegaly.

The median age at diagnosis of CMML is 65 to 75 years with a male predominance of 1.5 to 3.1.[3,4] Because CMML is grouped with chronic myeloid leukemia in some epidemiologic surveys and with MDS in others, no reliable incidence data are available for CMML.[5] Although the specific etiology of CMML is unknown, exposure to occupational and environmental carcinogens, ionizing radiation, and cytotoxic agents has been associated in some cases.[5]

Morphologically, the disease is characterized by a persistent peripheral blood monocytosis (always >1 × 109/L) that may exceed 80 × 109/L with monocytes typically accounting for more than 10% of the white blood cells.[3,4] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[6] Fewer than 20% blasts are seen in the blood or bone marrow. Neutrophilia occurs in nearly 50% of patients with neutrophil precursors (e.g., promyelocytes and myelocytes) accounting for more than 10% of the white blood cells.[7] Mild normocytic anemia is common. (Refer to the PDQ summary on Fatigue for more information on anemia.) Moderate thrombocytopenia is often present. Bone marrow findings include the following:[3,4,8,9]

  • Hypercellularity (75% of cases).
  • Blast count less than 20%.
  • Granulocytic proliferation (with dysgranulopoiesis).
  • Monocytic proliferation, dyserythropoiesis (e.g., megaloblastic changes, abnormal nuclear contours, ringed sideroblasts, etc.).
  • Micromegakaryocytes and/or megakaryocytes with abnormally lobated nuclei (as many as 80% of the cases).
  • Fibrosis (30% of the cases).

Hepatosplenomegaly may be present.[3,4] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[10] Care should be taken to identify cases of CMML with eosinophilia, a subtype of CMML, because of its association with severe tissue damage secondary to eosinophil degranulation. In CMML with eosinophilia, all criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 × 109.[5]

Although clonal cytogenetic abnormalities are found in 20% to 40% of patients with CMML, none is specific.[3,11,12] Point mutations of ras genes may occur in as many as 40% of patients with CMML.[3,12] The median survival time for CMML is 12 to 24 months.[12-14] Prognostic factors associated with shorter survival include the following:[12,14]

  • Low hemoglobin level.
  • Low platelet count; high white blood cell, monocyte, and lymphocyte counts.
  • Presence of circulating immature myeloid cells.
  • High percentage of marrow blasts.
  • Low percentage of marrow erythroid cells.
  • Abnormal cytogenetics.
  • High levels of serum LDH and beta-2-microglobulin.

Progression to acute leukemia occurs in approximately 15% to 20% of cases.[12,14]

Treatment Overview for Myelodysplastic/ Myeloproliferative Neoplasms

Various chemotherapy regimens for CMML have been used with only modest success.[13] In a study evaluating single-agent therapy with topotecan, a topoisomerase I inhibitor, 25 patients with CMML were treated with topotecan at doses that induce bone marrow aplasia (2.0 mg/m2/day by continuous infusion for 5 days). Complete hematologic remissions were induced in 28% of patients. Toxic effects were significant, and the median duration of remission was 8 months.[15][Level of evidence: 3iiiDiv] In a follow-up study, topotecan was used in combination with cytarabine, a pyrimidine-analog antimetabolite. This combination regimen induced complete remission in 44% of patients with CMML; median duration of complete response was 50 weeks, and patients required monthly maintenance therapy.[16][Level of evidence: 3iiiDiv]

Treatment with hydroxyurea is an option.[13] In a randomized clinical trial, 105 patients with advanced CMML were enrolled to compare treatment with hydroxyurea versus treatment with etoposide. Doses were scheduled to escalate to hydroxyurea 4 g/d and etoposide 600 mg/week in the absence of response and finally to adjust to maintain white blood cells between 5 × 109/L and 10 × 109/L. Median actuarial survival was 20 months in the hydroxyurea arm versus 9 months in the etoposide arm (P < .001). Main factors associated with poor survival were allocation to the etoposide arm, unfavorable karyotype (i.e., monosomy 7 or complex abnormalities), and anemia.[17][Level of evidence: 1iiA]

The nucleoside 5-azacitidine is an inhibitor of DNA methyltransferase that has been approved for the treatment of MDS, largely based on a Cancer and Leukemia Group B randomized trial.[18] This trial, in which patients were randomized to supportive care versus 5-azacitidine (75 mg/m2/day subcutaneously for 7 days every 28 days), included 10 patients with CMML.[18][Level of evidence: 1iiDii]

Bone marrow transplantation (BMT) or stem cell transplantation appears to be the only current treatment that alters the natural history of CMML. In a review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic BMT from matched unrelated donors, the actuarial probability of survival at 2 years for the 12 patients with CMML was 10%. Transplant-related mortality was influenced by the age of the patient (i.e., <18 years, 40%; 18–35 years, 61%; >35 years, 81%). This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[19][Level of evidence: 3iiiA] In a recent review of 50 allogeneic transplantations for CMML (i.e., median age 44, age range 19–61 years) from related (n = 43) or unrelated (n = 7) donors, the 5-year-estimated overall survival was 21%. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute graft versus host disease grade II through grade IV and for a higher relapse rate in patients with T cell-depleted grafts, suggesting a graft-versus-CMML effect. This latter series represents the largest cohort of patients with adult CMML and allogeneic stem cell transplantation to date.[20][Level of evidence: 3iiiA]

A case report suggests that targeted therapy with imatinib mesylate may be effective in a subset of patients with CMML related to PDGFβR fusion oncogenes.[21]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.  [PUBMED Abstract]

  2. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008.  [PUBMED Abstract]

  3. Onida F, Beran M: Chronic myelomonocytic leukemia: myeloproliferative variant. Curr Hematol Rep 3 (3): 218-26, 2004.  [PUBMED Abstract]

  4. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008.  [PUBMED Abstract]

  5. Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83 (1): 71-86, 1998.  [PUBMED Abstract]

  6. Kouides PA, Bennett JM: Morphology and classification of the myelodysplastic syndromes and their pathologic variants. Semin Hematol 33 (2): 95-110, 1996.  [PUBMED Abstract]

  7. Bennett JM, Catovsky D, Daniel MT, et al.: 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. Br J Haematol 87 (4): 746-54, 1994.  [PUBMED Abstract]

  8. Michaux JL, Martiat P: Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 9 (1-2): 35-41, 1993.  [PUBMED Abstract]

  9. Maschek H, Georgii A, Kaloutsi V, et al.: Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 48 (4): 208-14, 1992.  [PUBMED Abstract]

  10. Saif MW, Hopkins JL, Gore SD: Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 43 (11): 2083-92, 2002.  [PUBMED Abstract]

  11. Nösslinger T, Reisner R, Grüner H, et al.: Dysplastic versus proliferative CMML--a retrospective analysis of 91 patients from a single institution. Leuk Res 25 (9): 741-7, 2001.  [PUBMED Abstract]

  12. Onida F, Kantarjian HM, Smith TL, et al.: Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 99 (3): 840-9, 2002.  [PUBMED Abstract]

  13. Bennett JM: Chronic myelomonocytic leukemia. Curr Treat Options Oncol 3 (3): 221-3, 2002.  [PUBMED Abstract]

  14. Germing U, Kündgen A, Gattermann N: Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 45 (7): 1311-8, 2004.  [PUBMED Abstract]

  15. Beran M, Kantarjian H, O'Brien S, et al.: Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 88 (7): 2473-9, 1996.  [PUBMED Abstract]

  16. Beran M, Estey E, O'Brien S, et al.: Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol 17 (9): 2819-30, 1999.  [PUBMED Abstract]

  17. Wattel E, Guerci A, Hecquet B, et al.: A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood 88 (7): 2480-7, 1996.  [PUBMED Abstract]

  18. Kaminskas E, Farrell A, Abraham S, et al.: Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11 (10): 3604-8, 2005.  [PUBMED Abstract]

  19. Arnold R, de Witte T, van Biezen A, et al.: Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. European Blood and Marrow Transplantation Group. Bone Marrow Transplant 21 (12): 1213-6, 1998.  [PUBMED Abstract]

  20. Kröger N, Zabelina T, Guardiola P, et al.: Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 118 (1): 67-73, 2002.  [PUBMED Abstract]

  21. Magnusson MK, Meade KE, Nakamura R, et al.: Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood 100 (3): 1088-91, 2002.  [PUBMED Abstract]