Chronic myeloproliferative disorder with ETV6-PDGFRβ fusion gene
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- Tipirneni, E., Buttar, A., Brettler, D. et al. Ann Hematol (2012) 91: 637. doi:10.1007/s00277-011-1296-y
PDGFRα and PDGFRβ mutations result in a myeloproliferative state [1, 2]. These are BCR-ABL1 negative and referred as atypical CML or more broadly unclassifiable myeloproliferative or myelodysplastic/myeloproliferative disease. The PDGFRβ gene is located on chromosome 5q33. This gene can get disrupted by various chromosomal translocations involving 5q33 and other partner chromosomes. One of the translocation is (5:12), which causes fusion of ETV6 and PDGFRβ. Although very rare, some of the common features were the presence of eosinophilia or monocytosis in peripheral blood and bone marrow. It has been mostly reported in males. Blast crisis has been reported in a few. Interest in better characterizing this disease has increased recently with the potential of response to imatinib.
We have a 55-year-old female with no significant past medical history was found to have a white blood cell (WBC) count of 22.7 × 109 on routine laboratory testing. She was asymptomatic at the time of this presentation, and her most recent WBC 2 years prior was normal. She worked as a housekeeper, was a nonsmoker, and used alcohol occasionally. Physical examination was normal. Repeat lab work after 4 weeks revealed a WBC count of 32.4 × 109/L with a normal hemoglobin level (12.2 g/dL) and platelet count (202 × 109/L). The differential was normal except for neutrophilia (83%). Leukocyte alkaline phosphatase score was low at 5 (20–100). BCR ABL1 fusion and JAK2 mutation were negative. The bone marrow was hypercellular with normal maturation of the myeloid series and increased myeloid to erythroid ratio (8:1). Myelocytes, metamyelocytes, and neutrophils accounted for 83% of the cellularity, with normal amounts of eosinophils, lymphocytes, monocytes, and plasma cells. Cytogenetic analysis of bone marrow revealed a t(5;12)(q33;p13)/46,XX. FISH analysis with break apart probes for ETV6 at 12p13 and PDGFRβ at 5q33 demonstrated involvement of both genes and was consistent with an ETV6-PDGFRβ fusion (figure).
The patient was started on imatinib 400 mg/day. A week after starting the medication, she had significant nausea, vomiting, lower extremity swelling, and worsening shortness of breath. She stopped the medication after 7 days but had prolonged neutropenia. She recovered her counts 4 weeks after stopping the medication at which time imatinib 100 mg was started, which she tolerated very well. She had a complete hematologic response and significant cytogenetic response by peripheral blood analysis in about 1 month after starting the medication. The ETV6-PDGFRβ rearrangement originally observed in 86 of the 100 nuclei was present in only 4 of 500 nuclei after 3 months of treatment.
Response to imatinib has been examined in a small number of patients [3, 4]. In one series, four patients with ETV6-PDGFRβ rearrangement who were started on imatinib 400 mg daily all had a complete hematologic response 4 weeks after therapy. Three of the four had a complete cytogenetic response 12 weeks after initiating imatinib, and the fourth patient had a complete cytogenetic response at 36 weeks.
Our patient is unusual in several ways. She is a female with no organomegaly and did not have eosinophilia or monocytosis in the peripheral blood or bone marrow. She did not tolerate imatinib 400 mg but had an excellent response both hematologically and cytogenetically on 100 mg/day. Hence it is not unreasonable to treat these patients with a lower dose and assess response especially if they are not able to tolerate the higher dose.
The ETV6-PDGFRβ rearrangement was detected in this patient because of its association with a cytogenetically recognizable translocation, the t(5:12). PDGFRα rearrangements are cytogenetically cryptic and will go unidentified unless specifically tested by FISH. Because carriers of PDGFRα rearrangements also have the potential to respond to imatinib, FISH testing for this rearrangement should be considered before treatment is planned.