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

Complete hematologic response to sunitinib in an eosinophilia-associated chronic myeloproliferative disorder with an ETV6-FLT3 fusion gene
Complete hematologic response to sunitinib in an eosinophilia-associated chronic myeloproliferative disorder with an ETV6-FLT3 fusion gene
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.
gene, leukemia, hematology, england, germany, human, time
0006-4971
p.1041A
Walz, Christoph
b8d235ac-2a38-41e7-a22f-e0bb78719b19
Ritter, Michael
fd959f38-f6a4-4a43-bb1e-7997d5eb2880
Haferlach, Claudia
0bf0896a-7b9c-451a-9e64-935ecdd7aa15
Schnittger, Susanne
5157942c-96eb-47cd-9837-3feea8ec8984
Schulte, Christoph
913319b1-58fa-4fc0-ab79-7aae4f2053f5
Haferlach, Torsten
fff2c7bf-3212-45e3-a731-19ea532c1137
Metzgeroth, Georgia
611ec46d-9a11-4e24-ae0f-5ac19dfd0237
Hehlmann, Rüdiger
790dac9f-3d0a-4388-b038-b5bbd07359c4
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede
Walz, Christoph
b8d235ac-2a38-41e7-a22f-e0bb78719b19
Ritter, Michael
fd959f38-f6a4-4a43-bb1e-7997d5eb2880
Haferlach, Claudia
0bf0896a-7b9c-451a-9e64-935ecdd7aa15
Schnittger, Susanne
5157942c-96eb-47cd-9837-3feea8ec8984
Schulte, Christoph
913319b1-58fa-4fc0-ab79-7aae4f2053f5
Haferlach, Torsten
fff2c7bf-3212-45e3-a731-19ea532c1137
Metzgeroth, Georgia
611ec46d-9a11-4e24-ae0f-5ac19dfd0237
Hehlmann, Rüdiger
790dac9f-3d0a-4388-b038-b5bbd07359c4
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede

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.

Record type: Article

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.

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More information

Published date: 16 November 2007
Additional Information: ASH Annual Meeting Abstracts, Poster Session: Myeloproliferative Syndromes. Abstract 3558.
Keywords: gene, leukemia, hematology, england, germany, human, time

Identifiers

Local EPrints ID: 60394
URI: http://eprints.soton.ac.uk/id/eprint/60394
ISSN: 0006-4971
PURE UUID: 684ce936-a433-4bb5-8146-8677704c491f
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 11 Nov 2008
Last modified: 23 Jul 2022 01:49

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Contributors

Author: Christoph Walz
Author: Michael Ritter
Author: Claudia Haferlach
Author: Susanne Schnittger
Author: Christoph Schulte
Author: Torsten Haferlach
Author: Georgia Metzgeroth
Author: Rüdiger Hehlmann
Author: Andreas Hochhaus
Author: Andreas Reiter

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