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Case Study: A 78-Year-Old Man With Elevated Leukocytes and Anemia

The following case study focuses on finding the optimal treatment for a 78-year-old man. Test your knowledge by reading the question below and making the proper selection.

A 78-year-old man presents with a three-year history of an elevated leukocyte count with recent fatigue and anemia. He has received two red blood cell transfusions in the past two months. His past medical history includes coronary artery disease and hypertension. His physical examination is unremarkable. The patient’s white blood cell (WBC) count is 75,000/uL, hemoglobin is 9.3 g/dL, and platelet count is 71,000/uL with a WBC differential including 60 percent neutrophils, 19 percent lymphocytes, 15 percent monocytes, and 6 percent eosinophils. His bone marrow aspirate shows mild erythroid dysplasia, 1 percent blasts with an increase in monocytes (14 percent) and eosinophils (7 percent). Chromosomal analysis demonstrates 46XY, t(5;12)(q33;p13)[16]; 46,XY[4]. Fluorescence in situ hybridization (FISH) testing for the BCR-ABL translocation and quantitative RT-PCR for the BCR-ABL transcript were both negative. What is the optimal treatment for this patient?

  1. Decitabine (Dacogen) 20 mg/m2 daily x five days per month for three months and then re-examine the bone marrow
  2. Continued observation until further disease progression
  3. Imatinib (Gleevec) 400 mg once daily
  4. Standard induction chemotherapy with daunorubicin (50 mg/m2 daily x three days) and Ara-C (100 mg/m2 continuous infusion x seven days)

Answer

  1. Imatinib (Gleevec) 400 mg once daily

Explanation

Chronic myelomonocytic leukemia (CMML) is considered to be a clonal myeloid stem cell disorder.1-3 In 2001, the World Health Organization (WHO) classified CMML as a myelodysplastic-myeloproliferative disease with diagnostic criteria including: 1) persistent peripheral blood (PB) monocyte count >1X109/L; 2) absence of the Philadelphia chromosome; 3) < 20 percent blasts in the PB or bone marrow (BM); and 4) dysplasia in one or more hematopoietic cell lineages.2,3 The subcategory of CMML with eosinophilia was also established and is characterized by a PB eosinophilia of >1500 cells/uL.

Translocation (5;12)(q31-q33;p12-p13) is a recurring cytogenetic abnormality reported in patients with CMML, in particular those with eosinophilia.4 The t(5;12) translocation results in the fusion of the transmembrane and tyrosine kinase domains of the platelet-derived growth factor receptor-B (PDGFR-B) gene on chromosome 5 with the amino-terminal domain of the TEL/ETV6 gene of chromosome 12, a member of the ETS family of transcription factors.5,6 The resultant aberrant tyrosine kinase activity of this hybrid protein is potentially the transforming event in these cases of CMML.7-9 The overall incidence of t(5;12) in CMML is unknown but is presumed to be relatively rare. A retrospective analysis by Gunby, et al. demonstrated the translocation in only 1/27 patients with CMML.10 Others have indicated only 40 to 50 known cases of CMML involving t(5;12) or similar chromosomal abnormalities involving the PDGFR-B loci.11

Imatinib is a tyrosine kinase inhibitor with potent activity against BCR-ABL in chronic myeloid leukemia. Imatinib also inhibits a number of additional tyrosine kinases including PDGFRA, PDGFRB, and c-kit, providing the basis for its use in CMML involving the t(5;12) translocation.12-14 Recently, Han, et al. reviewed 13 cases from the literature of myeloproliferative diseases with evidence of PGDFR-B translocations treated with imatinib.11 An impressive number of complete responses were noted, encouraging further study of this agent in this CMML subgroup.

Given this patient’s age and absence of blastic transformation, intensive induction chemotherapy regimens such as daunorubicin and cytarabine would not be optimal. Such therapies can lead to significant treatment-related mortality in the elderly. The alternative plan of observation alone, while always an option for patients, would not be preferable for this symptomatic patient who has transfusion dependency and fatigue. Finally, hypomethylating agents, including decitabine have recently been evaluated in patients with CMML.15,16 Overall response rates of 25 percent to 70 percent have been reported, with complete response rates ranging from 12 percent to greater than 60 percent. Although this is a treatment option, given the identification of the t(5;12) translocation, oral imatinib, which is generally well tolerated even in the elderly, is a rational treatment option for this patient.

In summary, CMML associated with t(5;12) translocation is a relatively rare disorder. Responses to imatinib are variable, but this agent offers a unique treatment alternative in a disease with relatively few curative options in the elderly population. Therefore, identifying this translocation, especially in CMML patients presenting with eosinophilia, should be a priority.

References

  1. Bennett JM, Catovsky D, Daniel MT, et al. . Br J Haematol. 1994;87:746-54.
  2. Elliott MA. . Best Pract Res Clin Haematol. 2006;19:571-93.
  3. Vardiman JW, Harris NL, Brunning RD. . Blood. 2002;100:2292-302.
  4. Baranger L, Szapiro N, Gardais J, et al. . Br J Haematol. 1994;88:343-7.
  5. Golub TR, Barker GF, Lovett M, Gilliland DG. . Cell. 1994;77:307-16.
  6. Wlodarska I, Mecucci C, Marynen P, et al. . Blood. 1995;85:2848-52.
  7. Carroll M, Tomasson MH, Barker GF, et al. . Proc Natl Acad Sci USA. 1996;93:14845-50.
  8. Jousset C, Carron C, Boureux A, et al.. Embo J. 1997;16:69-82.
  9. Ritchie KA, Aprikyan AA, Bowen-Pope DF, et al. . Leukemia. 1999;13:1790-803.
  10. Gunby RH, Cazzaniga G, Tassi E, et al. . Haematologica. 2003;88:408-15.
  11. Han X, Medeiros LJ, Abruzzo LV, et al. . Am J Clin Pathol. 2006;125:49-56.
  12. Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. . Blood. 2002;100:1088-91.
  13. Carroll M, Ohno-Jones S, Tamura S, et al. . Blood. 1997;90:4947-52.
  14. Buchdunger E, Zimmermann J, Mett H, et al. . Cancer Res. 1996;56:100-4.
  15. Aribi A, Borthakur G, Ravandi F, et al. . Cancer. 2007;109:713-7.
  16. Wijermans PW, Rüter B, Baer MR, et al. . Leuk Res. 2008;32:587-91.

Additional Resources

  1. Han X, Medeiros J, et al. . American Journal of Clinical Pathology. 2006;125(1):49-56.
  2. Elliot M. . Best Practice & Research Clinical Haematology. 2006;19(3):571-593.

Case study submitted by Dale Bixby, MD, PhD, of the University of Michigan.

Citations