Correspondence

Hypereosinophilic Syndrome

N Engl J Med 2003; 348:2687June 26, 2003

Article

To the Editor:

In some patients with idiopathic hypereosinophilic syndrome, Cools et al. (March 27 issue)1 detected a FIP1L1-PDGFRA fusion gene that was associated with a dramatic response to imatinib mesylate. Along with the recent description of the “lymphocytic variant” of the hypereosinophilic syndrome,2 their observation will provide clinicians with cornerstones for tailoring the management of this heterogeneous disease according to the underlying pathogenic mechanisms.

In their discussion, Cools et al. state that the hypereosinophilic syndrome is a myeloproliferative syndrome, thereby ignoring the involvement of interleukin-5–producing T cells in the pathogenesis of hypereosinophilia in approximately one fourth of patients with the syndrome.3 The 91 percent rate of response to imatinib in their study suggests either recruitment bias in favor of the myeloproliferative variant of the hypereosinophilic syndrome or an unexpected effect of imatinib in patients with an unsuspected lymphocytic variant. Inclusion of data concerning the T-cell phenotype and clonality would have been interesting in this regard. Incidentally, in a series of our own, one patient who had hypereosinophilia with clonal CD3–CD4+ T cells had a negative test for the FIP1L1-PDGFRA fusion gene (unpublished data).

Florence E. Roufosse, M.D.
Michel Goldman, M.D.
Elie Cogan, M.D.
Hôpital Erasme, B-1070 Brussels, Belgium
ecogan@ulb.ac.be

3 References

1. 1

   Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201-1214
   Full Text | Web of Science | Medline

2. 2

   Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med 2003;54:169-184
   CrossRef | Web of Science | Medline

3. 3

   Simon H-U, Plotz S, Dummer R, Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341:1112-1120
   Full Text | Web of Science | Medline

Author/Editor Response

We thank Roufosse et al. for their perspective. The phenotypic characterization of the hypereosinophilic syndrome as a myeloproliferative disease does not presuppose a primary or secondary cause. FIP1L1-PDGFRα is a primary cause of the hypereosinophilic syndrome, and the fusion gene provides a genetic tool with which to dissect involvement of the myeloid and lymphoid lineages. We agree that clonally derived T cells may cause a secondary, polyclonal expansion of eosinophils as a result of interleukin-5 production in some patients with the syndrome, as discussed by Schwartz in the Perspective article1 accompanying our report. However, T-cell clonality associated with hypereosinophilia appears to be relatively infrequent, occurring in 8 of 60 patients (13 percent) in the series2 cited by Roufosse et al. That study may also have overestimated the true frequency of T-cell clonality in the hypereosinophilic syndrome, because many patients had indolent disease with dermatologic manifestations.3

These considerations emphasize the potential for selection bias in studies of the hypereosinophilic syndrome2,4 because of the rarity and heterogeneity of the disease. However, we reported the FIP1L1-PDGFRA fusion gene in four of six untreated patients (including five from Belgium), a proportion similar to that observed in treated patients. Similar frequencies have been observed by Klion et al.5 and correlate with the high frequency of responses to imatinib reported by Gleich et al.6

The hypereosinophilic syndrome is indeed a heterogeneous disease, as exemplified in part by the observation that although 10 of 11 patients with the syndrome (91 percent) had a response to imatinib, only 6 of those 10 patients (60 percent) harbored the FIP1L1-PDGFRA fusion gene.4 Further investigation is necessary to elucidate the molecular bases of the hypereosinophilic syndrome for diagnostic, prognostic, and therapeutic purposes.

D. Gary Gilliland, Ph.D., M.D.
Brigham and Women's Hospital, Boston, MA 02115
gilliland@hihg.med.harvard.edu

Richard M. Stone, M.D.
Dana–Farber Cancer Institute, Boston, MA 02115

Steven E. Coutre, M.D.
Stanford University School of Medicine, Stanford, CA 94305

6 References

1. 1

   Schwartz RS. The hypereosinophilic syndrome and the biology of cancer. N Engl J Med 2003;348:1199-1200
   Full Text | Web of Science | Medline

2. 2

   Simon H-U, Plotz SG, Dummer R, Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341:1112-1120
   Full Text | Web of Science | Medline

3. 3

   Bain BJ. Eosinophilia -- idiopathic or not? N Engl J Med 1999;341:1141-1143
   Full Text | Web of Science | Medline

4. 4

   Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med 2003;54:169-184
   CrossRef | Web of Science | Medline

5. 5

   Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood (in press).
   

6. 6

   Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH. Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002;359:1577-1578
   CrossRef | Web of Science | Medline