Approaches to the treatment of hypereosinophilic syndromes: A workshop summary report
2006; Elsevier BV; Volume: 117; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2006.02.042
ISSN1097-6825
AutoresAmy D. Klion, Bruce S. Bochner, Gerald J. Gleich, Thomas B. Nutman, Marc E. Rothenberg, Hans‐Uwe Simon, Michael E. Wechsler, P F Weller, THEHYPEREOSINOPHILICSYNDROMESW,
Tópico(s)Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ResumoHypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized. Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized. Hypereosinophilic syndromes (HESs), including idiopathic hypereosinophilic syndrome (IHES), platelet-derived growth factor receptor α (PDGFRA)–associated HES, lymphocytic variant HES (L-HES), familial hypereosinophilia, Churg-Strauss Syndrome (CSS), and eosinophil-associated gastrointestinal disease (EGID), are a heterogeneous group of uncommon disorders that are characterized by marked eosinophilia in the peripheral blood, tissues, or both, often without an identifiable cause. Although corticosteroids are the first-line treatment for many of these disorders, therapy for patients whose symptoms cannot be maintained with low doses of corticosteroids is poorly standardized, in large part because of the low prevalence of these disorders and the lack of published series comparing different agents. Recent advances in our understanding of the causes of eosinophilic disorders coupled with the availability of new agents targeting specific components of the immune response have already changed our approach to therapy in some cases (eg, the use of imatinib in PDGFRA-associated HES), highlighting the need for a rational therapeutic approach. A 2-day workshop was convened on May 25 and 26, 2005, in Bern, Switzerland, in conjunction with the biannual meeting of the International Eosinophil Society to discuss (1) the state of currently available therapies for 3 eosinophil-mediated disorders (HES, CSS, and EGID), taking into account recent developments in diagnostic testing and advances in the understanding of the pathogenesis of hypereosinophilic conditions, and (2) novel strategies for the treatment of eosinophilic disorders (for agenda, see the Web site at http://www.pharmacology.unibe.ch/eos2005). The workshop was funded by the Office of Rare Diseases Research of the National Institutes of Health, GlaxoSmithKline (Philadelphia, Pa), and the American Partnership for Eosinophilic Disorders. Thirty-seven clinicians and scientists from varied disciplines with expertise in the treatment of eosinophilic disorders participated in the discussions. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 of the disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized. Central to any discussion of therapy for eosinophilic disorders is the differential diagnosis of the eosinophil-associated conditions. In the past, many of these conditions were lumped together as IHES, defined by the following: (1) the presence of eosinophilia (>1500 eosinophils/mm3 for at least 6 months) that remains unexplained despite a comprehensive evaluation for known causes of eosinophilia (including parasitic helminth infections, HIV, drug hypersensitivity, nonhematologic malignancies, lymphomas, and primary allergic disorders) and (2) evidence of organ dysfunction directly attributable to the eosinophilia or otherwise unexplained in the clinical setting.1Hardy W.R. Anderson R.E. The hypereosinophilic syndromes.Ann Intern Med. 1968; 68: 1220-1229Crossref PubMed Scopus (400) Google Scholar In addition, IHES was distinguished from other idiopathic eosinophilic disorders that involved limited organs, such as the eosinophilic pneumonias, EGID, and eosinophilic cystitis.2Weller P.F. Bubley G.J. The idiopathic hypereosinophilic syndrome.Blood. 1994; 83: 2759-2779PubMed Google Scholar More recently, the heterogeneous group of disorders defined by Hardy and Anderson have begun to be reclassified, as clinical subtypes have been recognized and new molecular and immunologic markers are described.3Bain B.J. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis.Am J Hematol. 2004; 77: 82-85Crossref PubMed Scopus (66) Google Scholar, 4Roufosse F. Cogan E. Goldman M. Recent advances in the pathogenesis and management of hypereosinophilic syndromes.Allergy. 2004; 59: 673-689Crossref PubMed Scopus (144) Google Scholar Currently recognized subtypes include PDGFRA-associated HES, L-HES, chronic eosinophilic leukemia, and familial eosinophilia (Fig 1). Indeed, the term idiopathic is no longer a useful modifier of the term hypereosinophilic syndrome, and there was a general consensus to use the term hypereosinophilic syndrome to define these heterogeneous conditions associated with high-grade peripheral eosinophilia often accompanied by eosinophilic infiltration of organ tissue. From a diagnostic point of view, many of the entities can now be reliably distinguished from other conditions associated with high-grade eosinophilia through a combination of routine and specialized testing.4Roufosse F. Cogan E. Goldman M. Recent advances in the pathogenesis and management of hypereosinophilic syndromes.Allergy. 2004; 59: 673-689Crossref PubMed Scopus (144) Google Scholar In some instances better clinical definition has guided treatment options, the most dramatic being the use of imatinib in the PDGFRA-associated HES.5Cools J. DeAngelo D.J. Gotlib J. Stover E.H. Legare R.D. Cortes J. et al.A novel tyrosine kinase created by the fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003; 348: 1201-1214Crossref PubMed Scopus (1476) Google Scholar Unfortunately, for the majority of individuals with HES, no definitive basis underlying their disease has been identified. Moreover, there are known clinical entities (CSS, EGID, and systemic mastocytosis) that can be associated both with marked peripheral eosinophilia and tissue-organ dysfunction or damage that must be distinguished from HES as the approach to therapy differs. With the knowledge that treatment options for many of the eosinophil-associated conditions are targeting underlying defects, the HES Working Group examined approaches to therapy of HES and 2 defined entities (CSS and EGID) that can present in a manner that is difficult to distinguish clinically from HES. CSS is associated with significant peripheral eosinophilia, constitutional symptoms, and eosinophilic tissue infiltration but is different from HES in that it is a complex disease characterized by the presence of eosinophilic vasculitis that might involve multiple organ systems.6Lanham J.G. Elkon K.B. Pusey C.D. Hughes G.R. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.Medicine (Baltimore). 1984; 63: 65-81Crossref PubMed Scopus (1020) Google Scholar Previously referred to as allergic angiitis and granulomatosis,7Churg J. Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa.Am J Pathol. 1951; 27: 277-301PubMed Google Scholar the hallmark diagnostic criteria of CSS include eosinophilic vasculitis in addition to one or more of the following: asthmatic airway obstruction, pulmonary infiltrates, sinusitis, and neuropathy.8Masi A.T. Hunder G.G. Lie J.T. Michel B.A. Bloch D.A. Arend W.P. et al.The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).Arthritis Rheum. 1990; 33: 1094-1100Crossref PubMed Scopus (1723) Google Scholar Although the cause of this disorder that affects 4 to 6 subjects per million per year9Lane S.E. Watts R. Scott D.G. Epidemiology of systemic vaculitis.Curr Rheumatol Rep. 2005; 7: 270-275Crossref PubMed Scopus (91) Google Scholar is unknown, CSS has both allergic and autoimmune features. These include increased numbers of circulating T cells, the presence of immune complexes, and increased serum levels of rheumatoid factor, IgE, and eosinophil cationic protein. Anti-neutrophil cytoplasmic antibodies (ANCAs) are present in about 50% of patients with CSS, but there is no direct evidence for a pathogenic role for ANCAs in patients with CSS.10Hellmich B. Csernok E. Gross W.L. Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome.Ann N Y Acad Sci. 2005; 1051: 121-131Crossref PubMed Scopus (89) Google Scholar Of note, there is increasing recognition that some patients given diagnoses of chronic eosinophilic pneumonia are either exhibiting early manifestations of CSS or will ultimately progress to CSS. Primary eosinophil-associated gastrointestinal disorders (now referred to by the acronym EGID) are defined as disorders that affect the gastrointestinal tract with eosinophil-rich inflammation in the absence of known causes of eosinophilia (eg, drug reactions, parasitic infections, and malignancy).11Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-28Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar Patients with EGID have a variety of problems, including failure to thrive, abdominal pain, irritability, gastric dysmotility, vomiting, diarrhea, and dysphagia. Although the incidence of primary EGID has not been rigorously calculated, a miniepidemic of these diseases (especially eosinophilic esophagitis [EE]) has been noted over the last decade, with estimated prevalences of EE as high as 1:2500 among children12Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (691) Google Scholar and 1:4000 among adults.13Straumann A. Spichtin H.P. Grize L. Bucher K.A. Beglinger C. Simon H.U. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (632) Google Scholar Although the cause of EGID remains unproved, several lines of evidence support an allergic cause with environmental and genetic components.12Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (691) Google Scholar, 14Markowitz J.E. Liacouras C.A. Eosinophilic gastroenteritis.Gastroenterol Clinics. 2003; 32: 949-966Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar These include the finding that many patients with EGID are atopic and/or have evidence of food and aeroallergen hypersensitivity as defined by means of skin prick testing, allergen-specific IgE testing, and/or delayed skin patch testing and the observation that institution of an allergen-free diet often ameliorates the symptoms and might even induce remission of EGID. Although peripheral blood eosinophilia, the hallmark of HES, is an inexpensive and accessible measure with which to follow the response to treatment, the relationship between the absolute eosinophil count and eosinophil-mediated tissue damage is not consistent. Clearly there are subgroups of patients with eosinophil counts greater than 1500/mm3 who show no evidence of clinical disease, as well as symptomatic patients with HES and normal eosinophil counts on therapy. Although a number of potential markers of disease progression, including serum levels of eosinophil granule proteins and surface expression of eosinophil activation markers, granule proteins, or both have been suggested, none has been validated to date. Subtypes of HES for which specialized laboratory parameters might be useful to monitor the response to therapy include PDGFRA-associated HES (presence of the abnormal fusion gene, serum tryptase levels, or both5Cools J. DeAngelo D.J. Gotlib J. Stover E.H. Legare R.D. Cortes J. et al.A novel tyrosine kinase created by the fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003; 348: 1201-1214Crossref PubMed Scopus (1476) Google Scholar, 15Klion A.D. Noel P. Akin C. Law M.A. Gilliland D.G. 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: 4660-4666Crossref PubMed Scopus (323) Google Scholar) and L-HES (numbers of phenotypically aberrant lymphocytes, development of abnormal cytogenetics, or both16Simon H.U. Plotz S.G. Dummer R. Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia.N Engl J Med. 1999; 341: 1112-1120Crossref PubMed Scopus (404) Google Scholar, 17Roufosse F. Schandene L. Sibille C. Willard-Gallo K. Kennes B. Efira A. et al.Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome.Br J Haematol. 2000; 109: 540-548Crossref PubMed Scopus (154) Google Scholar). In most cases of HES, however, the current approach to the monitoring of therapy remains inexact based on a combination of clinical manifestations and absolute eosinophil counts. Corticosteroids have been used for decades in the treatment of HES and, with the exception of PDGFRA-associated HES, remain the first-line treatment for most patients (for a summary of treatment options for HES, see Table I). Adjunctive corticosteroids are also indicated, when initiating imatinib in patients with PDGFRA-associated HES and evidence of myocarditis, as suggested by electrocardiographic or echocardiographic assessment or by the presence of an increased serum troponin level.18Pitini V. Arrigo C. Azzarello D. La Gattuta G. Amata C. Righi M. et al.Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes.Blood. 2003; 102: 3456-3457Crossref PubMed Scopus (95) Google Scholar For non–PDGFRA-associated HES, the most appropriate initial corticosteroid dose and the duration of steroid therapy have not been studied, but it seems prudent to start with a moderate to high dose (≥40 mg of prednisone equivalent) and to taper very slowly while following the eosinophil count closely. Using this approach, most, but not all, patients will respond initially, and some will have their symptoms maintained on low doses of corticosteroids for long periods. For those patients requiring long-term corticosteroid treatment, evaluation of bone density, adjunctive therapies to prevent bone loss, and, in some cases, prophylaxis against opportunistic infection (notably Pneumocystis species–induced pneumonia) must be considered.Table ISummary of treatment options for HESDiagnosisTreatmentIndicationsDoseCommentsHESCorticosteroidsFirst-line therapy unless FIP1L1/PDGFRA-positiveVariedInitial dose ≥40 mg daily with slow taper to lowest effective doseHydroxyureaSecond-line therapy1-3 g/dSlow onset of action (1-2 wk)VincristineConsider for counts >100,000/mm3, including in children1-2 mg intravenouslyFor rapid reduction of eosinophilia, not for chronic therapyOther cytotoxic agents (including cyclophosphamide, 6-thioguanine, methotrexate, cytarabine, 2-CDA)Consider for refractory HES unresponsive to corticosteroids, hydroxyurea, IFN-αNAMyeleran and 6-mercaptopurine have been consistently ineffective in published studiesIFN-αSecond-line therapy1-2 mU sq dailySlow onset of action (1-2 wk), pegylated IFN-α appears to have comparable efficacyAnti–IL-5 antibodyResearch indication to date≤750 mg/kg monthlyCurrently unavailable except in clinical trials or for compassionate use (mepolizumab; GlaxoSmithKline)Other immunomodulatory therapy (including alemtuzumab, cyclosporine, IVIG)Consider for refractory diseaseNALittle published dataImatinib mesylateFirst-line therapy for FIP1L1/PDGFRA-positive and myeloproliferative variant, consider for other refractory disease100-400 mg dailyWith corticosteroids if cardiac involvement, not useful in lymphocytic variantBone marrow transplantFIP1L1/PDGFRA-positive and imatinib resistant FIP1L1/PDGFRA-negative with disease progression despite conventional therapiesNANonmyeloablativeCDA, Chlorodeoxyadenosine; NA, not applicable; IVIG, intravenous immunoglobulin. Open table in a new tab CDA, Chlorodeoxyadenosine; NA, not applicable; IVIG, intravenous immunoglobulin. Predictors of a prolonged response to corticosteroid therapy include episodic angioedema, a profound and sustained eosinopenic response 4 to 12 hours after challenge with 60 mg of prednisone, an increased serum IgE level, and the lack of hepatosplenomegaly.2Weller P.F. Bubley G.J. The idiopathic hypereosinophilic syndrome.Blood. 1994; 83: 2759-2779PubMed Google Scholar Over time, the toxicities of corticosteroid therapy become limiting in most patients, and alternative therapies must be considered. A number of cytotoxic therapies have been used for the management of corticosteroid-refractory HES. Of these, hydroxyurea has been the most extensively studied at doses of 1 to 3 g/d.19Parrillo J.E. Fauci A.S. Wolff S.M. Therapy of the hypereosinophilic syndrome.Ann Intern Med. 1978; 89: 167-172Crossref PubMed Scopus (229) Google Scholar As the dose increases, hematologic and gastrointestinal side effects become common, however, limiting the utility of hydroxyurea monotherapy in the treatment of HES. Low-dose (500 mg daily) hydroxyurea appears to act synergistically with IFN-α to lower the eosinophil count without increasing side effects and has been useful in some cases.20Butterfield J.H. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis.Acta Haematol. 2005; 114: 26-40Crossref PubMed Scopus (78) Google Scholar More recently, successful treatment of a single patient with a combination of hydroxyurea and imatinib has been reported. Hydroxyurea, a drug that acts by suppressing bone marrow eosinophilopoiesis, cannot be used to decrease the eosinophil count acutely because a therapeutic effect is generally not achieved for up to 2 weeks. Vincristine at a dose of 1 to 2 mg administered intravenously can be efficacious in rapidly decreasing eosinophilia in patients with extremely high eosinophil counts (>100,000/mm3) and might be useful in the treatment of children with aggressive disease who are unresponsive to other therapies.21Sakamoto K. Erdreich-Epstein A. deClerck Y. Coates T. Prolonged clinical response to vincristine treatment in two patients with hypereosinophilic syndrome.Am J Pediatr Hematol Oncol. 1992; 14: 348-351Crossref PubMed Scopus (37) Google Scholar Prolonged vincristine use can be complicated by peripheral neuropathy, which is at times difficult to distinguish from underlying HES-associated neuropathies. Of the remaining cytotoxic agents for which there are published data, myeleran and 6-mercaptopurine have been consistently ineffective in the treatment of HES. Cyclophosphamide, 6-thioguanine, methotrexate, cytarabine, and 2-chlorodeoxyadenosine have each been tried in a small number of cases, with variable results. In some patients with corticosteroid-refractory HES or intolerable side effects of corticosteroid treatment, immunomodulatory agents with effects on type 2 cytokine (eg, IL-4 and IL-5) production and T-cell proliferation, which include IFN-α, cyclosporine, and alemtuzumab, have been shown to have a therapeutic effect. Of these, IFN-α is the only one for which sufficient clinical data are available.20Butterfield J.H. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis.Acta Haematol. 2005; 114: 26-40Crossref PubMed Scopus (78) Google Scholar Stable responses can often be achieved with relatively low doses of IFN-α (1-2 million U/d) and might persist for prolonged periods of time. Because the effects of IFN-α on eosinophil numbers in the peripheral blood might not become evident for several weeks, escalation to an effective dose could require several months. Rarely, patients have remained in remission for extended periods of time after cessation of IFN-α therapy, suggesting that IFN-α might be curative in a small subset of individuals. Even at low doses, systemic toxicity is common with IFN-α therapy and can be dose limiting. Low-dose hydroxyurea (500 mg daily) appears to potentiate the effect of IFN-α on suppressing eosinophilia without increasing toxicity and can be used in these situations. Monotherapy with IFN-α should be used with caution in L-HES, where in vitro data have demonstrated an inhibitory effect of IFN-α on spontaneous apoptosis of clonal CD3−CD4+ T cells.22Schandene L. Roufosse F. de Lavareille A. Stordeur P. Efira A. Kennes B. et al.Interferon alpha prevents spontaneous apoptosis of clonal Th2 cells associated with chronic hypereosinophilia.Blood. 2000; 96: 4285-4292PubMed Google Scholar In this instance the addition of corticosteroids should be considered because of their proapoptotic effect on the pathogenic T cells. It should be noted, however, that clinical data supporting the in vitro studies are not yet available. Although there are no published data regarding the use of pegylated IFN-α (0.5-1 μg/kg once weekly) in HES, responses appear to be similar to the standard IFN-α formulation, with pegylated IFN-α being better tolerated (J. Butterfield, G. Gleich, and M. E. Rothenberg, personal communication). Monoclonal anti–IL-5 antibody therapy for HES has a number of unique advantages related to the specificity of IL-5 for the eosinophil lineage. Preliminary studies with 2 different anti–IL-5 antibodies, SCH55700 (Schering-Plough, Deerfield, Ill) and mepolizumab (GlaxoSmithKline), demonstrated dramatic and prolonged decreasing of peripheral eosinophil counts in response to a single dose of antibody in a majority of patients with HES, regardless of the underlying cause or baseline IL-5 level.23Plotz S.G. Simon H.U. Darsow U. Simon D. Vassina E. Yousefi S. et al.Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis.N Engl J Med. 2003; 349: 2334-2339Crossref PubMed Scopus (234) Google Scholar, 24Klion A.D. Law M.A. Noel P. Haverty T.P. Nutman T.B. Safety and efficacy of the monoclonal anti-interleukin 5 antibody, SCH55700, in the treatment of patients with the hypereosinophilic syndrome.Blood. 2004; 103: 2939-2941Crossref PubMed Scopus (145) Google Scholar, 25Garrett J.K. Jameson S.C. Thomson B. Collins M.H. Wagoner L.E. Freese D.K. et al.Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.J Allergy Clin Immunol. 2004; 113: 115-119Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar These responses were sustained for up to a year after multiple infusions of anti–IL-5 in some patients. The therapy is extremely well tolerated, although a rebound in symptoms and eosinophilia associated with an increase in serum IL-5 levels was noted in one study as drug levels decreased.26Kim Y.J. Prussin C. Martin B. Law M.A. Haverty T.P. Nutman T.B. et al.Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL5 antibody SCH55700.J Allergy Clin Immunol. 2004; 114: 1449-1455Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar The safety and efficacy of anti–IL-5 therapy as a corticosteroid-sparing agent in HES is currently being assessed in a large, double-blind, placebo-controlled study of mepolizumab. The monoclonal anti-CD52 antibody alemtuzumab has been used successfully to treat 2 patients with HES, one of whom had a clonal population of T cells, and might provide an alternative therapy for patients with HES refractory to other therapies.27Pitini V. Teti D. Arrigo C. Righi M. Alemtuzumab therapy for refractory hypereosinophilic syndrome with abnormal T cells: a case report.Br J Haematol. 2004; 127: 477Crossref PubMed Scopus (75) Google Scholar, 28Sefcick A. Sowter D. DasGupta E. Russell N.H. Byrne J.L. Alemtuzumab therapy for refractory idiopathic hypereosinophilic syndrome.Br J Haematol. 2004; 124: 558-559Crossref PubMed Scopus (58) Google Scholar Imatinib mesylate is a tyrosine kinase inhibitor with activity against several receptor tyrosine kinases, including the fusion kinase FIP1L1/PDGFRA, which is responsible for PDGFRA-associated HES. Consequently, few experts would disagree with the use of imatinib as first-line therapy in patients in whom the FIP1L1/PDGFRA fusion gene has been demonstrated or in selected patients with the characteristic clinical and laboratory features of this myeloproliferative subtype of HES (eg, male sex, tissue fibrosis, and increased serum B12 and tryptase levels). Imatinib response rates in FIP1L1/PDGFRA-positive patients approach 100%, with only 2 reported cases of acquired drug resistance, both associated with a T6741 substitution in the ATP-binding domain of PDGFRA.5Cools J. DeAngelo D.J. Gotlib J. Stover E.H. Legare R.D. Cortes J. et al.A novel tyrosine kinase created by the fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003; 348: 1201-1214Crossref PubMed Scopus (1476) Google Scholar, 29Gleich G.J. Leiferman K.M. Pardanani A. Tefferi A. Butterfield J.H. Treatment of hypereosinophilic syndrome with imatinib mesilate.Lancet. 2002; 359: 1577-1578Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 30Klion A.D. Robyn J. Akin C. Noel P. Brown M. Law M.A. et al.Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome.Blood. 2003; 103: 473-478Crossref PubMed Scopus (217) Google Scholar, 31Pardanani A.D. Reeder T.L. Porrata L.F. Li C.Y. Tazelaar H.D. Baxter Witzig T.E. et al.Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders.Blood. 2003; 101: 391-397Crossref PubMed Scopus (166) Google Scholar Imatinib is the only commercially available tyrosine kinase inhibitor with activity against PDGFRA at the present time; however, additional agents now in development are likely to be effective in PDGFRA-associated HES. One of these, PKC412 (Novartis, Basel, Switzerland), has already been demonstrated to be effective against the T6741 resistance mutation in vitro.32Cools J. Stover E.H. Boulton C.L. Gotlib J. Legare R.D. Amaral S.M. et al.PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease.Cancer Cell. 2003; 3: 459-469Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Clinical responses to imatinib in FIP1L1/PDGFRA-positive patients are rapid, with normalization of eosinophil counts generally occurring within 1 week of initiation of treatment and reversal of signs and symptoms within 1 month. The exception is cardiac involvement, which is irreversible unless treatment is begun before fibrosis leads to permanent anatomic alterations.30Klion A.D. Robyn J. Akin C. Noel P. Brown M. Law M.A. et al.Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome.Blood. 2003; 103: 473-478Crossref PubMed Scopus (217) Google Scholar Although side effects of imatinib therapy are generally mild and rarely lead to discontinuation of therapy, acute cardiac decompensation has been observed in at least one patient at the onset of treatment with imatinib and has led to the recommendation that patients with evidence of potential cardiac involvement (eg, increased troponin levels) be pretreated with corticosteroids.18Pitini V. Arrigo C. Azzarello D. La Gattuta G. Amata C. Righi M. et al.Serum concentration of cardiac Troponin T in pat
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