The University of Southampton
University of Southampton Institutional Repository

Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia

Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia
Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia
The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophilia-associated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%). To determine response kinetics following imatinib, real-time quantitative-polymerase chain reaction (RQ-PCR) assays were developed and evaluated in samples accrued from across the European LeukemiaNet. The FIP1L1-PDGFRA fusion transcript was detected at a sensitivity of 1 in 10(5) in serial dilution of the EOL-1 cell line. Normalized FIP1L1-PDGFRA transcript levels in patient samples prior to imatinib varied by almost 3 logs. Serial monitoring was undertaken in patients with a high level of FIP1L1-PDGFRA expression prior to initiation of imatinib (100 mg/d-400 mg/d). Overall, 11 of 11 evaluable patients achieved at least a 3-log reduction in FIP1L1-PDGFRA fusion transcripts relative to the pretreatment level within 12 months, with achievement of molecular remission in 9 of 11 (assay sensitivities 1 in 10(3)-10(5)). In 2 patients, withdrawal of imatinib was followed by a rapid rise in FIP1L1-PDGFRA transcript levels. Overall, these data are consistent with the exquisite sensitivity of the FIP1L1-PDGFRalpha fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.
growth, dna, prevalence, expression, mrna cleavage and polyadenylation factors, chemistry, remission induction, platelet-derived growth factor alpha, chronic disease, Great Britain, humans, human, administration & dosage, drug therapy, protein, myeloproliferative disorders, time factors, cell line, hypereosinophilic syndrome, antineoplastic agents, pyrimidines, exons, agents, leukemia, treatment outcome, therapy, polymerase chain reaction, biosynthesis, dna primers, alpha, patients, kinetics, research, london, laboratories, receptor, platelet-derived growth factor, genetics, research support, piperazines
0006-4971
4635-4640
Jovanovic, J.V.
92ddc8f4-238a-4c32-8f06-f14fb1b5f294
Score, J.
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Waghorn, K.
60a6a26d-556b-41fc-84ee-dab95d63ab68
Cilloni, D.
8e050e5e-0690-4f0c-8013-235ff258b4c0
Gottardi, E.
9ee3bb1a-aca6-4f98-8145-349477de8e56
Metzgeroth, G.
ce361b67-c4da-471c-95aa-acb1dd0d1b04
Erben, P.
50e7cc94-7147-4f08-9a95-86b4aade442c
Popp, H.
9c3546a1-fb83-4fbd-97b6-55acbf1bb255
Walz, C.
03a7b61b-bebd-4510-8f08-ec6b65a36809
Hochhaus, A.
4c0b9da4-adfa-4253-8af7-78cec9e9a24f
Roche-Lestienne, C.
b14a6275-0a49-450d-9d0a-0750986d2060
Preudhomme, C.
1db28c45-3add-43f1-96b7-09d2c8442c66
Solomon, E.
9c5a1d66-b71f-4f11-9f00-92ff6488c709
Apperley, J.
622c945c-74c1-4773-a80f-2bdafe8dfe14
Rondoni, M.
65e47ce9-1770-434d-8b9f-1e88197a5b71
Ottaviani, E.
76295991-0c99-42c8-8170-52db831a6ef1
Martinelli, G.
3949da7a-7efe-4ebd-b1f7-92f1ca150d66
Brito-Babapulle, F.
14baad75-e681-4df6-9908-02537f00bd1d
Saglio, G.
73d6fc31-81e4-4e8d-9ea3-e08db4d00f10
Hehlmann, R.
753d719b-7bf8-4f74-bfdc-6d5d47e5d2c7
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, A.
8fc082eb-6b46-4412-86b2-f4c7669f0650
Grimwade, D.
ffb05d2d-ba42-4841-a002-3c80c3b26961
Jovanovic, J.V.
92ddc8f4-238a-4c32-8f06-f14fb1b5f294
Score, J.
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Waghorn, K.
60a6a26d-556b-41fc-84ee-dab95d63ab68
Cilloni, D.
8e050e5e-0690-4f0c-8013-235ff258b4c0
Gottardi, E.
9ee3bb1a-aca6-4f98-8145-349477de8e56
Metzgeroth, G.
ce361b67-c4da-471c-95aa-acb1dd0d1b04
Erben, P.
50e7cc94-7147-4f08-9a95-86b4aade442c
Popp, H.
9c3546a1-fb83-4fbd-97b6-55acbf1bb255
Walz, C.
03a7b61b-bebd-4510-8f08-ec6b65a36809
Hochhaus, A.
4c0b9da4-adfa-4253-8af7-78cec9e9a24f
Roche-Lestienne, C.
b14a6275-0a49-450d-9d0a-0750986d2060
Preudhomme, C.
1db28c45-3add-43f1-96b7-09d2c8442c66
Solomon, E.
9c5a1d66-b71f-4f11-9f00-92ff6488c709
Apperley, J.
622c945c-74c1-4773-a80f-2bdafe8dfe14
Rondoni, M.
65e47ce9-1770-434d-8b9f-1e88197a5b71
Ottaviani, E.
76295991-0c99-42c8-8170-52db831a6ef1
Martinelli, G.
3949da7a-7efe-4ebd-b1f7-92f1ca150d66
Brito-Babapulle, F.
14baad75-e681-4df6-9908-02537f00bd1d
Saglio, G.
73d6fc31-81e4-4e8d-9ea3-e08db4d00f10
Hehlmann, R.
753d719b-7bf8-4f74-bfdc-6d5d47e5d2c7
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, A.
8fc082eb-6b46-4412-86b2-f4c7669f0650
Grimwade, D.
ffb05d2d-ba42-4841-a002-3c80c3b26961

Jovanovic, J.V., Score, J., Waghorn, K., Cilloni, D., Gottardi, E., Metzgeroth, G., Erben, P., Popp, H., Walz, C., Hochhaus, A., Roche-Lestienne, C., Preudhomme, C., Solomon, E., Apperley, J., Rondoni, M., Ottaviani, E., Martinelli, G., Brito-Babapulle, F., Saglio, G., Hehlmann, R., Cross, N.C., Reiter, A. and Grimwade, D. (2007) Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood, 109 (11), 4635-4640. (doi:10.1182/blood-2006-10-050054).

Record type: Article

Abstract

The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophilia-associated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%). To determine response kinetics following imatinib, real-time quantitative-polymerase chain reaction (RQ-PCR) assays were developed and evaluated in samples accrued from across the European LeukemiaNet. The FIP1L1-PDGFRA fusion transcript was detected at a sensitivity of 1 in 10(5) in serial dilution of the EOL-1 cell line. Normalized FIP1L1-PDGFRA transcript levels in patient samples prior to imatinib varied by almost 3 logs. Serial monitoring was undertaken in patients with a high level of FIP1L1-PDGFRA expression prior to initiation of imatinib (100 mg/d-400 mg/d). Overall, 11 of 11 evaluable patients achieved at least a 3-log reduction in FIP1L1-PDGFRA fusion transcripts relative to the pretreatment level within 12 months, with achievement of molecular remission in 9 of 11 (assay sensitivities 1 in 10(3)-10(5)). In 2 patients, withdrawal of imatinib was followed by a rapid rise in FIP1L1-PDGFRA transcript levels. Overall, these data are consistent with the exquisite sensitivity of the FIP1L1-PDGFRalpha fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.

This record has no associated files available for download.

More information

Published date: 2007
Keywords: growth, dna, prevalence, expression, mrna cleavage and polyadenylation factors, chemistry, remission induction, platelet-derived growth factor alpha, chronic disease, Great Britain, humans, human, administration & dosage, drug therapy, protein, myeloproliferative disorders, time factors, cell line, hypereosinophilic syndrome, antineoplastic agents, pyrimidines, exons, agents, leukemia, treatment outcome, therapy, polymerase chain reaction, biosynthesis, dna primers, alpha, patients, kinetics, research, london, laboratories, receptor, platelet-derived growth factor, genetics, research support, piperazines

Identifiers

Local EPrints ID: 59898
URI: http://eprints.soton.ac.uk/id/eprint/59898
ISSN: 0006-4971
PURE UUID: d6f6245e-fb7a-4f27-abec-ac66bf1818a5
ORCID for N.C. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 02 Sep 2008
Last modified: 16 Mar 2024 03:23

Export record

Altmetrics

Contributors

Author: J.V. Jovanovic
Author: J. Score
Author: K. Waghorn
Author: D. Cilloni
Author: E. Gottardi
Author: G. Metzgeroth
Author: P. Erben
Author: H. Popp
Author: C. Walz
Author: A. Hochhaus
Author: C. Roche-Lestienne
Author: C. Preudhomme
Author: E. Solomon
Author: J. Apperley
Author: M. Rondoni
Author: E. Ottaviani
Author: G. Martinelli
Author: F. Brito-Babapulle
Author: G. Saglio
Author: R. Hehlmann
Author: N.C. Cross ORCID iD
Author: A. Reiter
Author: D. Grimwade

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×