Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias

Leukemia volume 18, pages 734–742 (2004)Cite this article

Abstract

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (−) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-α, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B12 was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Bain BJ . Eosinophilic leukaemias and the idiopathic hypereosinophilic syndrome. Br J Haematol 1996; 95: 2–9.

    CAS  PubMed  Google Scholar 

  2. Bain BJ . Hypereosinophilia. Curr Opin Hematol 2000; 7: 21–25.

    Article  CAS  Google Scholar 

  3. Chusid MJ, Dale DC, West BC, Wolff SM . The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54: 1–27.

    Article  CAS  Google Scholar 

  4. Bain B, Pierre R, Imbert M, Vardiman JW, Brunning RD, Flandrin G . Chronic eosinophilic leukemia and the hypereosinophilic syndrome. In: Jaffe ES, Harris NL, Vardiman JW (eds) WHO Classification of Tumours: Pathology and Genetics. Tumors of Haematopoietic and Lymphoid tissues. Lyon: IARC Press, 2001, pp 29–31.

    Google Scholar 

  5. Zittoun J, Farcet JP, Marquet J, Sultan C, Zittoun R . Cobalamin (vitamin B12) and B12 binding proteins in hypereosinophilic syndromes and secondary eosinophilia. Blood 1984; 63: 779–783.

    CAS  PubMed  Google Scholar 

  6. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH . NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982; 97: 78–92.

    Article  CAS  Google Scholar 

  7. Weller P, Bubley G . The idiopathic hypereosinophilic syndrome. Blood 1994; 83: 2759–2779.

    CAS  Google Scholar 

  8. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes 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.

    Article  CAS  Google Scholar 

  9. Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. PG-459-69. Cancer Cell 2003; 5: 459–469.

    Article  Google Scholar 

  10. Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH . Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002; 359: 1577–1578.

    Article  CAS  Google Scholar 

  11. Pardanani A, Reeder T, Porrata LF, Li C-Y, Tazelaar HD, Baxter EJ et al. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003; 101: 3391–3397.

    Article  CAS  Google Scholar 

  12. Cortes J, Ault P, Koller C, Thomas D, Ferrajoli A, Wierda W et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 2003; 101: 4714–4716.

    Article  CAS  Google Scholar 

  13. Malbrain ML, Van den Bergh H, Zachee P . Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. Br J Haematol 1996; 92: 176–183.

    Article  CAS  Google Scholar 

  14. Mitelman F, ISCN. An International System for Human Cytogenetic Nomenclature. Basel: S Karger, 1995.

    Google Scholar 

  15. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3, RESEARCH0034.1-0034.11.

  16. Cools J, Quentmeier H, Huntly BJ, Marynen P, Griffin JD, Drexler HG et al. The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA positive chronic eosinophilic leukemia. Blood 2003, Nov 20 [Epub ahead of print], in press.

  17. Martin-Subero JI, Harder L, Gesk S, Schlegelberger B, Grote W, Martinez-Climent JA et al. Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci. Int J Cancer 2002; 98: 470–474.

    Article  CAS  Google Scholar 

  18. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003; 102: 3093–3096.

    Article  CAS  Google Scholar 

  19. Klion AD, Noel P, Akin C, Law MA, Gilliland DG, Cools J 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 2003; 101: 4660–4666.

    Article  CAS  Google Scholar 

  20. Roufosse FE, Goldman M, Cogan E . Hypereosinophilic syndrome. N Engl J Med 2003; 348: 2687.

    Article  Google Scholar 

  21. Valent P, Horny HP, Li CY, Longley BJ, Metcalfe DD, Parwaresch RM et al. Mastocytosis. In: Jaffe ES, Harris NL, Vardiman JW (eds) WHO Classification of Tumours: Pathology and Genetics. Tumors of Haematopoietic and Lymphoid tissues. Lyon: IARC Press, 2001, pp 292–302.

    Google Scholar 

Download references

Acknowledgements

We thank Dr C Peeters-De Wolf for critical reading and helpful discussions, Ursula Pluys for technical assistance with FISH, Drs H Van Keer, J Billiet and M Pilet for retrieving laboratory data and G Verbeke for statistical advice. This paper presents research results of the Belgian Programme of Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The scientific responsibility is assumed by the authors. PV is a senior clinical investigator, JC a postdoctoral research fellow of Fonds voor Wetenschappelijk Onderzoek Vlaanderen. LM is partially supported by the Salus Sanguinis Foundation. This work was supported by grant G.0120.00 of the Fonds voor Wetenschappelijk Onderzoek Vlaanderen.

Author information

Authors and Affiliations

  1. The Center for Human Genetics, University Hospital Leuven, Leuven, Belgium

    P Vandenberghe, I Wlodarska & A Hagemeijer

  2. Cliniques Universitaires St-Luc, UCL, Brussels, Belgium

    L Michaux & M Maerevoet

  3. Algemeen Ziekenhuis Stuivenberg, Antwerp, Belgium

    P Zachée

  4. The Division of Hematology, University Hospital Leuven, Leuven, Belgium

    M Boogaerts & G Verhoef

  5. Virga Jesse Ziekenhuis Hasselt, Belgium

    D Vanstraelen

  6. The Division of Cardiology, University Hospital Leuven, Leuven, Belgium

    M-C Herregods

  7. AZ St-Jan, Brugge, Belgium

    A Van Hoof & D Selleslag

  8. Hôpital Erasme, ULB, Brussels, Belgium

    F Roufosse

  9. Division of Hematology, Harvard Medical School, Boston, USA

    J Cools & D G Gilliland

  10. Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

    P Marynen

Authors
  1. P Vandenberghe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Wlodarska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Michaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Zachée
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Boogaerts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Vanstraelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M-C Herregods
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Van Hoof
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Selleslag
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Roufosse
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Maerevoet
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G Verhoef
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Cools
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D G Gilliland
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. A Hagemeijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P Marynen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to P Vandenberghe or P Marynen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vandenberghe, P., Wlodarska, I., Michaux, L. et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 18, 734–742 (2004). https://doi.org/10.1038/sj.leu.2403313

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403313

Keywords

This article is cited by

Search

Advanced search

Quick links