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Previous Volume 348:1201-1214 March 27, 2003 Number 13 Next

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ABSTRACT

Background Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.

Methods We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.

Results Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFR (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFR is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.

Conclusions The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase — FIP1L1-PDGFR — that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFR is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

Source Information

From Brigham and Women's Hospital and Harvard Medical School, Boston (J. Cools, E.H.S., J.K., J. Clark, D.G.G.); the Dana–Farber Cancer Institute, Boston (D.J.D., J. Clark, I.G., J.D.G., R.S., D.G.G.); Stanford University School of Medicine, Stanford, Calif. (J.G., J.M., S.L.S., S.E.C.); Women and Infants Hospital, Brown University School of Medicine, Providence, R.I., and Westerly Hospital, Westerly, R.I. (R.D.L.); M.D. Anderson Cancer Center, Houston (J. Cortes, H.K.); the Wessex Regional Genetics Laboratory, Salisbury, United Kingdom (N.C.P.C.); Mayo Clinic, Rochester, Minn. (A.T.); National Jewish Medical and Research Center, Denver (R.A.); Tulane University School of Medicine, New Orleans (J.S.); Yale University School of Medicine, New Haven, Conn. (M.R.); University Hospital Leuven, Leuven, Belgium (P.V., G.V., M.B.); Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium (J. Cools, P.M.); Center for Human Genetics, Leuven, Belgium (I.W.); and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston (D.G.G.).

Drs. Cools and DeAngelo contributed equally to this article.

Address reprint requests to Dr. Gilliland at the Harvard Institutes of Medicine, 4 Blackfan Cir., Rm. 418, Boston, MA 02115 (gilliland{at}hihg.med.harvard.edu) or to Dr. Stone at the Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115 (rstone{at}partners.org).

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Hypereosinophilic Syndrome
Roufosse F. E., Goldman M., Cogan E., Gilliland D. G., Stone R. M., Coutre S. E.
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N Engl J Med 2003; 348:2687, Jun 26, 2003. Correspondence

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