04/05/03

 

 

 

 

 

 

 
   

Contents | Director | Case 1 | Case 2 | Review 1 | Review 2 | EKG 1 | Rad 1

AMR - March 2004

   

 

 

Review - Chronic Myelomonocytic Leukemia

Jeffrey Allen, MD

Myeloproliferative disorders (MPD) classically have been characterized as marrow proliferative where one cell lineage preferentially proliferates, while myelodysplastic syndromes (MDS) have been characterized by their excess rate of blast divisions (greater than 50%) and their high rate of dysplasia and increased apoptosis.1 Two diseases, chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia, bridge the divide between MPD and MDS.

CMML is a disease most commonly seen in patients greater than 75 years of age (although a childhood form is also occasionally seen) with an incidence of 1.5 per 100,000, a progression rate to acute myeloid leukemia of approximately 35%, and a median survival of only three years.1  There is a slight male predominance in the elderly population.  Presenting complaints are very similar to those of other leukemias and may be very non-specific.  CMML is defined clinically by having less than 20% of blasts in the bone marrow, less than 5% blasts in the peripheral smear, and greater than 1,000 monocytes per microliter in the peripheral blood.2  The French American British (FAB) classification scheme separates CMML patients based on the degree of peripheral leukocytosis.  There are two groups: those patients who present with peripheral leukocyte count of less than 13,000/microliter are classified as being predominantly dysplastic while those with peripheral leukocyte count greater than 13,000/microliter are classified as being predominantly proliferative.  It is believed that approximately 50% of those patients initially characterized as dysplastic will evolve to be proliferative.  This distinction may seem academic, but survival curves are dramatically different between those patients who present as predominantly dysplastic versus those who are predominantly proliferative (median survivals of 16 months and 12 months in one study, 30 months versus 11 months in a second study, respectively).1  The 2001 World Health Organization Classification paper suggested dividing CMML on the basis of the percentage of blasts seen in the bone marrow.  In this classification, those with less than 10% of blasts were classified as CMML-1 and those with 10-20% of blasts were classified as CMML-2.3  A similar conclusion regarding outcomes can be made using this classification as well, as those patients with a higher percentage of blasts fare considerably worse than those with fewer blasts. 

The distinction between CMML and chronic myelogenous leukemia (CML) or atypical CML can be difficult to make.  Granulocytic dysplasia was noted to be most prominent in atypical CML patients, while those with CMML were more likely to have a higher degree of peripheral monocytosis and a greater percentage of erythroid precursor cells in the bone marrow.1  Cytogenetic abnormalities seen in CMML are variable, with some patients having normal karyotypes while some may have monosomy 7, del 7q, or even balanced translocations such as t(5;12), t(9;12), or t(5;7).2  Fusion proteins involving the tyrosine kinase family can be seen in CMML, occasionally involving the platelet derived growth factor receptor beta (PDRFr-beta)

Management of patients with CMML is primarily guided by their separation into the dysplastic predominant or proliferative predominant group. Those patients who are categorized into being dysplastic are treated similarly to other patients with myelodysplastic syndromes (MDS). Anemia is supported with transfusions as necessary and erythropoietin appears to be of benefit, especially in those patients with decreased levels of endogenous hormone. There is some suggestion that thalidomide at doses of 100 mg to 200 mg may decrease the transfusion requirement in approximately 20% of patients.1 Thrombocytopenia is managed with transfusion support until such time as the patient becomes refractory to transfusions, at which time chemotherapy may be attempted. Combined agent chemotherapy may have as much as a 50% response rate, though durable responses or frank cure are very unlikely. Those patients with high functionality can be considered for bone marrow transplantation, and long term survivals of 20-59% have been seen in suitable candidates.1

Proliferative CMML is usually treated with hydroxyurea at doses of 1-4 gram orally per day titrated to maintain a white cell count between 5 and 10,000 per microliter. Patients treated with this regimen were noted to have a median survival of 24 months versus only 9 months in patients treated with etoposide.1 Those patients with complex chromosomal abnormalities were noted to have a worse prognosis. While other regimens are currently being investigated, to date, no regimen has proven as effective as hydroxyurea and overall survival is limited. Recent literature suggesting the use of imatinib mesylate (Gleevac), a selective inhibitor of tyrosine kinases such as ABL, KIT, and PDGFR-b, in those patients with translocations involving PDRFr-beta, has shown some success in producing durable responses (at 9 and 12 months).4

CMML is a disease which shares features of both myelodysplastic and myeloproliferative syndromes. The recent success of imatinib mesylate in isolated cases demonstrates the need for further research into the molecular genetics and pathology of CMML. However, further research is clearly indicated and the future of CMML will undoubtedly be marked by more targeted therapies and hopefully, an improvement in outcomes.

REFERENCES

  1. Bennett, John M. The Myelodysplastic/Myeloproliferative Disorders: the Interface. Hematology/Oncology Clinics of North America, Volume 17, Number 5, October 2003.
  2. Doll, Donald C and Landaw, Stephen A. Clinical manifestations and diagnosis of the myelodysplastic syndromes, Uptodate, Online Electronic Version 12.1.
  3. Bruming RD, Matutes E, Harris NL, Flandrin G, Vardiman J, Bennett J, et al. Acute myeloid leukaemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues Lyon: IARC Press; 2001. p. 77-80.
  4. Apperley, JF, Gardembas, M, Melo, JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. New Engl J Med. 2002; 347:481.