Abstract
Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders characterized by sustained and otherwise unexplained overproduction of eosinophils with organ involvement and consecutive dysfunction. Recent reports document the efficacy of imatinib mesylate in a large proportion of HES patients (65%). Rearrangements involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), both tyrosine kinase receptors, have been demonstrated to be pathogenetically linked to the dysregulated clonal overproduction of eosinophils. This refined hypothesis has been confirmed by the discovery of the novel FIP1L1–PDGFRA fusion gene, which is a gain-of-function gene on chromosome 4q12. Its product is an imatinib-sensitive tyrosine kinase, which can be found in a subset of patients with HES, particularly in those responding to treatment with imatinib mesylate. Here, we sum up recent knowledge of clinical features, pathophysiology and novel treatment aspects of HES by performing a comprehensive search of the available literature and report on 94 patients. We particularly address the issue of organ involvement and specific characteristics of the variable clinical pictures. In addition, two cases will be presented, which illustrate typical clinical scenarios and treatment outcome.
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Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM (2002) Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347(7):481–487
Ascione L, De Michele M, Accadia M, Spadaro P, Rumolo S, Tuccillo B (2004) Reversal of cardiac abnormalities in a young man with idiopathic hypereosinophilic syndrome using a tyrosine kinase inhibitor. Eur J Echocardiog 5(5):386–390
Bain B, Pierre R, Imbert M, Vardiman JW, Brunnung RD, Flandrin G (2001) Chronic eosinophilic leukaemia and the hypereosinophilic syndrome. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, pp 29–31
Bain BJ (2003) Cytogenetic and molecular genetic aspects of eosinophilic leukaemias. Br J Haematol 122(2):173–179
Brito-Babapulle F (1997) Clonal eosinophilic disorders and the hypereosinophilic syndrome. Blood Rev 11(3):129–145
Chusid MJ, Dale DC, West BC, Wolff SM (1975) The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 54(1):1–27
Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG (2003) 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 348(13):1201–1214
Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, Kutok JL, Lee BH, Williams IR, Coutre SE, Stone RM, DeAngelo DJ, Marynen P, Manley PW, Meyer T, Fabbro D, Neuberg D, Weisberg E, Griffin JD, Gilliland DG (2003) PKC412 overcomes resistance to imatinib in a murine model of FIP1L1–PDGFRalpha-induced myeloproliferative disease. Cancer Cell 3(5):459–469
Cools J, Quentmeier H, Huntly BJ, Marynen P, Griffin JD, Drexler HG, Gilliland DG (2004) The EOL-1 cell line as an in vitro model for the study of FIP1L1–PDGFRA-positive chronic eosinophilic leukemia. Blood 103(7):2802–2805
Corradi D, Vaglio A, Maestri R, Legname V, Leonardi G, Bartoloni G, Buzio C (2004) Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death. Hum Pathol 35(9):1160–1163
Cortes J, Ault P, Koller C, Thomas D, Ferrajoli A, Wierda W, Rios MB, Letvak L, Kaled ES, Kantarjian H (2003) Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 101(12):4714–4716
Coutre S, Gotlib J (2004) Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Semin Cancer Biol 14(4):307–315
Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH (1982) NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 97(1):78–92
Frickhofen N, Marker-Hermann E, Reiter A, Walz C, Jung B, Bauer H, Hochhaus A (2004) Complete molecular remission of chronic eosinophilic leukemia complicated by CNS disease after targeted therapy with imatinib. Ann Hematol 83(7):477–480
Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH (2002) Treatment of hypereosinophilic syndrome with imatinib mesylate. Lancet 359(9317):1577–1578
Gotlib J, Malone JM, De Angelo DJ, Stone RM, Gilliland DG, Clark J, Tefferi A, Alam R, Schrier SL, Coutre SE (2002) Imatinib mesylate (Gleevec) induces rapid and complete hematological remissions in patients with idiopathic hypereosinophilic syndrome (HES) without evidence of BCR–ABL or activating mutations in c-kit and platelet-derived growth factor receptor-beta (PDGFR-β). Blood 100(11):abstr. 3152
Gotlib J, Cools J, Malone JM, Schrier SL, Gilliland DG, Coutre SE (2004) The FIP1L1–PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 103(8):2879–2891
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17(12):3835–3849
Ishii Y, Ito Y, Kuriyama Y, Tauchi T, Ohyashiki K (2004) Successful treatment with imatinib mesylate of hypereosinophilic syndrome (chronic eosinophilic leukemia) with myelofibrosis. Leuk Res 28(S1):79–80
Karnak D, Kayacan O, Beder S, Delibalta M (2003) Hypereosinophilic syndrome with pulmonary and cardiac involvement in a patient with asthma. CMAJ 168(2):172–175
Klion AD, Noel P, Akin C, Law MA, Gilliland DG, Cools J, Metcalfe DD, Nutman TB (2003) 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 101(12):4660–4666
Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, Metcalfe DD, Dunbar C, Nutman TB (2004) Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 103(2):473–478
Koury MJ, Newman JH, Murray JJ (2003) Reversal of hypereosinophilic syndrome and lymphomatoid papulosis with mepolizumab and imatinib. Am J Med 115(7):587–589
La Starza R, Specchia G, Cuneo A, Beacci D, Nozzoli C, Luciano L, Aventin A, Sambani C, Testoni N, Foppoli M, Invernizzi R, Marynen P, Martelli MF, Mecucci C (2005) The hypereosinophilic syndrome: fluorescence in situ hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but not genomic rearrangements of other tyrosine kinases. Haematologica 90(5):596–601
Le Coutre P, Baskaynak G, Tamm I, Westermann J, Duyster J, Bonin M, Pursche S, Mayer P, Manley P, Mestan J, Schleyer E, Dorken B (2004) Activity and induction of apoptosis of the specific tyrosine kinase inhibitor AMN107 in bcr–abl + cell lines and in imatinib resistant primary cells from CML patients. Blood 104(11):abstr. 762
Lefebvre C, Bletry O, Degoulet P, Guillevin L, Bentata-Pessayre M, Le Thi Huong D, Godeau P (1989) Prognostic factors of hypereosinophilic syndrome. Study of 40 cases. Ann Med Interne (Paris) 140(4):253–257
Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM, Deangelo DJ, Gary Gilliland D, Cools J (2005) KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Leukemia 19(1):27–30
Martinelli G, Malagola M, Ottaviani E, Rosti G, Trabacchi E, Baccarani M (2004) Imatinib mesylate can induce complete molecular remission in FIP1L1–PDGFR—a positive idiopathic hypereosinophilic syndrome. Haematologica 89(2):236–237
Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, Minervini MM, Cascavilla N, Dell’Olio M, La Sala A, Mantuano S, Melillo L, Nobile M, Scalzulli PR, Bisceglia M, Carella AM (2004) Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis. Leuk Lymphoma 45(6):1219–1222
Nolasco I, Carvalho S, Parreira A (2002) Rapid and complete response to imatinib mesylate in a patient with idiopathic hypereosinophilia. Blood 102(11):abstr. 4940
Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ, Witzig TE, Cross NC, Tefferi A (2003) Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 101(9):3391–3397
Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, Tefferi A (2003) Imatinib for systemic mast-cell disease. Lancet 362(9383):535–536
Pardanani A, Tefferi A (2004) Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 104(7):1931–1939
Plötz SG, Simon HU, Darsow U, Simon D, Vassina E, Yousefi S, Hein R, Smith T, Behrendt H, Ring J (2003) Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med 349(24):2334–2339
Pitini V, Arrigo C, Azzarello D, La Gattuta G, Amata C, Righi M, Coglitore S (2003) Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes. Blood 102(9):3456–3457
Roche-Lestienne C, Lepers S, Soenen-Cornu V, Kahn JE, Lai JL, Hachulla E, Drupt F, Demarty AL, Roumier AS, Gardembas M, Dib M, Philippe N, Cambier N, Barete S, Libersa C, Bletry O, Hatron PY, Quesnel B, Rose C, Maloum K, Blanchet O, Fenaux P, Prin L, Preudhomme C (2005) Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Leukemia 19(5):792–798
Roufosse F, Cogan E, Goldman M (2004) Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy 59(7):673–689
Salem Z, Zalloua PA, Chehal A, Bitar N, Abboud M, Kadri A, Chami B, Bazarbachi A (2003) Effective treatment of hypereosinophilic syndrome with imatinib mesylate. Hematol J 4(6):410–412
Schaller JL, Burkland GA (2001) Case report: rapid and complete control of idiopathic hypereosinophilia with imatinib mesylate. MedGenMed 3(5):9
Schooley RT, Flaum MA, Gralnick HR, Fauci AS (1981) A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations. Blood 58(5):1021–1026
Schwartz RS (2003) The hypereosinophilic syndrome and the biology of cancer. N Engl J Med 348(13):1199–1200
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682):399–401
Shah NP, Branford S, Hughes TP, Nicoll JM, Decillis AP, Sawyers CL (2004) Major cytogenetic response to BMS-354825 in patients with chronic myeloid leukemia are associated with a one to two log reduction in bcr–abl transcript. Blood 104(11):abstr. 1008
Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, Gilliland DG, Tefferi A (2005) The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome. Blood. 28. DOI 10.1182/blood-2005-03-1183
Stone RM, Gilliland DG, Klion AD (2004) Platelet-derived growth factor receptor inhibition to treat idiopathic hypereosinophilic syndrome. Semin Oncol 31(2 Suppl 6):12–17
Tan D, Hwang W, Ng HJ, Goh YT, Tan P (2004) Successful treatment of idiopathic hypereosinophilic syndrome with imatinib mesylate: a case report. Int J Hematol 80(1):75–77
Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D, Herregods MC, Van Hoof A, Selleslag D, Roufosse F, Maerevoet M, Verhoef G, Cools J, Gilliland DG, Hagemeijer A, Marynen P (2004) Clinical and molecular features of FIP1L1–PDFGRA (+) chronic eosinophilic leukemias. Leukemia 18(4):734–742
Vardiman JW, Harris NL, Brunning RD (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100(7):2292–2302
Ueno NT, Zhao S, Robertson LE, Consoli U, Andreeff M (1997) 2-Chlorodeoxyadenosine therapy for idiopathic hypereosinophilic syndrome. Leukemia 11(8):1386–1390
Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Neuberg D, Wright RD, Gilliland DG, Griffin JD (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr–Abl. Cancer Cell 7(2):129–141
Weller PF, Bubley GJ (1994) The idiopathic hypereosinophilic syndrome. Blood 83(10):2759–2779
Winn RE, Kollef MH, Meyer JI (1994) Pulmonary involvement in the hypereosinophilic syndrome. Chest 105(3):656–660
Zabel P, Schlaak M (1991) Cyclosporin for hypereosinophilic syndrome. Ann Hematol 62(6):230–231
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A.M.S. Müller and U.M. Martens contributed equally to the paper.
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Müller, A.M.S., Martens, U.M., Hofmann, S.C. et al. Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the literature. Ann Hematol 85, 1–16 (2006). https://doi.org/10.1007/s00277-005-1084-7
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DOI: https://doi.org/10.1007/s00277-005-1084-7