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); 46,XY.
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?
- Decitabine (Dacogen) 20 mg/m2 daily x five days per month for three months and then re-examine the bone marrow
- Continued observation until further disease progression
- Imatinib (Gleevec) 400 mg once daily
- Standard induction chemotherapy with daunorubicin (50 mg/m2 daily x three
days) and Ara-C (100 mg/m2 continuous infusion x seven days)
- Imatinib (Gleevec) 400 mg once daily
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
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.
- 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. 1994;87:746-54.
- Elliott MA. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined. Best Pract Res Clin Haematol. 2006;19:571-93.
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-302.
- Baranger L, Szapiro N, Gardais J, et al. Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation associated with a myeloid disorder with eosinophilia. Br J Haematol. 1994;88:343-7.
- Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion
of PDGF receptor beta to a novel ets-like gene, tel, in chronic
myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;77:307-16.
- Wlodarska I, Mecucci C, Marynen P, et al. TEL
gene is involved in myelodysplastic syndromes with either the typical
t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13). Blood. 1995;85:2848-52.
- Carroll M, Tomasson MH, Barker GF, et al. The
TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion
in chronic myelomonocytic leukemia is a transforming protein that
self-associates and activates PDGF beta R kinase-dependent signaling
pathways. Proc Natl Acad Sci USA. 1996;93:14845-50.
- Jousset C, Carron C, Boureux A, et al.
A domain of TEL conserved in a subset of ETS proteins defines a
specific oligomerization interface essential to the mitogenic
properties of the TEL-PDGFR beta oncoprotein. Embo J. 1997;16:69-82.
- Ritchie KA, Aprikyan AA, Bowen-Pope DF, et al. The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice. Leukemia. 1999;13:1790-803.
- Gunby RH, Cazzaniga G, Tassi E, et al. Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia. Haematologica. 2003;88:408-15.
- Han X, Medeiros LJ, Abruzzo LV, et al. Chronic myeloproliferative diseases with the t(5;12)(q33;p13): clonal evolution is associated with blast crisis. Am J Clin Pathol. 2006;125:49-56.
- Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood. 2002;100:1088-91.
- Carroll M, Ohno-Jones S, Tamura S, et al. CGP
57148, a tyrosine kinase inhibitor, inhibits the growth of cells
expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947-52.
- Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100-4.
- Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer. 2007;109:713-7.
- Wijermans PW, Rüter B, Baer MR, et al. Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2008;32:587-91.
- Han X, Medeiros J, et al. Chronic myeloproliferative diseases with the t(5;12)(q33;p13). American Journal of Clinical Pathology. 2006;125(1):49-56.
- Elliot M. Chronic neutrophilic leukemia and chronic
myelomonocytic leukemia: WHO defined. Best Practice & Research Clinical Haematology. 2006;19(3):571-593.
Case study submitted by Dale Bixby, MD, PhD, of the University of Michigan.
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