Complete hematologic response to sunitinib in an eosinophilia-associated chronic myeloproliferative disorder with an ETV6-FLT3 fusion gene


Walz, Christoph, Ritter, Michael, Haferlach, Claudia, Schnittger, Susanne, Schulte, Christoph, Haferlach, Torsten, Metzgeroth, Georgia, Hehlmann, Rüdiger, Hochhaus, Andreas, Cross, Nicholas C.P. and Reiter, Andreas (2007) Complete hematologic response to sunitinib in an eosinophilia-associated chronic myeloproliferative disorder with an ETV6-FLT3 fusion gene. Blood, 110, (11), p.1041A.

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Description/Abstract

Eosinophilia-associated chronic myeloproliferative disorders (Eos-MPD) in chronic or blast phase are associated with the constitutive activation of various tyrosine kinases caused by point mutations or fusion genes. Excellent long term responses to imatinib have been reported for patients with involvement of PDGFRA and PDGFRB. In contrast, FGFR1 and JAK2 fusion genes are imatinib-resistant and alternative tyrosine kinase inhibitors with potential activity are currently not yet available for clinical use. We here report on diagnosis and treatment of an Eos-MPD with a rearrangement of the receptor tyrosine kinase FLT3 with sunitinib (Sutent®), a small molecule tyrosine kinase inhibitor that inhibits VEGFR1-VEGFR3, PDGFRA, PDGFRB, KIT, CSF-1R and FLT3. A 60-years old male patient presented with marked eosinophilia in the peripheral blood, splenomegaly and ubiquitous peripheral lymphadenopathy. Leukocytes were elevated to 14,300/µl with 24% eosinophils, hemoglobin was 9.7 g/dl and platelets were 177 000/µl. Vitamin B12 level and serum tryptase activity were elevated. Bone marrow morphology displayed a CML-like MPD with marked eosinophilia and significantly increased numbers of loosely scattered, spindle-shaped mast cells. Conventional cytogenetic analysis revealed a complex translocation with involvement of chromosome bands 12p13 and 13q12. 3'-RACE-PCR with primers derived from ETV6 was performed as FISH analysis confirmed suspected involvement of ETV6 in 85 of 100 examined interphase nuclei. The sequencing of PCR products revealed a fusion between ETV6 exon 5 and a truncated FLT3 exon 14 with insertion of 11bp derived from ETV6 intron 5. This fusion is similar to the single other case of an ETV6-FLT3 fusion reported to date for which transforming activity was demonstrated (Vu et al., Leukemia 2006). Sunitinib was therefore initiated at a dose of 50 mg/day. The patient achieved rapid clinical and hematologic remission with normalization of eosinophil counts within one week, normalization of spleen size and complete disappearance of enlarged lymph nodes after 4 weeks. Treatment was well tolerated and no dose-limiting toxicities were observed. After 3 months a rearrangement of ETV6 was only detectable in 2 of 200 interphase nuclei by FISH analysis. Unexpectedly, a rapid increase of CD13/CD33+ myeloid blasts was seen after 5.5 months leading to the diagnosis of a blast phase. The karyotype was hyperploid with 51 chromosomes in addition to the complex translocation with involvement of chromosomes 12 and 13. None of the common FLT3 mutations could be detected. Combination treatment with conventional chemotherapy and sorafenib is now planned. In summary, we here demonstrate that FLT3 is not only involved in the pathogenesis of hematological malignancies via point mutations but also by the creation of tyrosine kinase fusion genes which are potential targets for recently developed FLT3 tyrosine kinase inhibitors such as sunitinib, sorafenib or PKC412.

Item Type: Article
Additional Information: ASH Annual Meeting Abstracts, Poster Session: Myeloproliferative Syndromes. Abstract 3558.
ISSNs: 0006-4971 (print)
Related URLs:
Keywords: gene, leukemia, hematology, england, germany, human, time
Subjects: R Medicine > RC Internal medicine
Q Science > QH Natural history > QH426 Genetics
Divisions: University Structure - Pre August 2011 > School of Medicine > Human Genetics
ePrint ID: 60394
Date Deposited: 11 Nov 2008
Last Modified: 27 Mar 2014 18:42
URI: http://eprints.soton.ac.uk/id/eprint/60394

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