Background Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia ≥1.5 × 109 /L, absence of a secondary cause, and evidence of ...eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti–IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. Objective The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. Methods Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. Results Eighteen of 161 patients (11%) tested were Fip1-like 1–platelet-derived growth factor receptor α ( FIP1L1-PDGFRA ) mutation—positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-α (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). Conclusion This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.
Markedly increased blood eosinophilia (ie, ≥1.5 × 109 /L), whether discovered fortuitously or found with signs and symptoms of associated organ involvement, commands diagnostic evaluation and often ...therapeutic interventions. This degree of hypereosinophilia is often but not uniformly associated with eosinophilic infiltration of tissues that can potentially lead to irreversible, life-threatening organ damage. Initial approaches focus on ascertaining that eosinophilia is not secondary to other underlying disease processes, including helminthic parasite infections, varied types of adverse reactions to medications, and other eosinophil-associated syndromes, such as eosinophilic gastroenteritides, eosinophilic pneumonias, and Churg-Strauss syndrome vasculitis. If evaluations exclude eosinophilia attributable to secondary causes or other eosinophil-related syndromes or organ-specific diseases, attention must be directed to considerations of varied other forms of the hypereosinophilic syndromes, which include myeloproliferative variants, lymphocytic variants, and many of still unknown causes. Cognizant of the capacities of eosinophils to mediate tissue damage, the varied causes for hypereosinophilia are considered, and a contemporary stepwise practical approach to the diagnosis and treatment of patients with hypereosinophilia is presented.
Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, ...clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.
Refining the definition of hypereosinophilic syndrome Simon, Hans-Uwe, MD, PhD; Rothenberg, Marc E., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
07/2010, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming ...increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition.
The symptomatic hypereosinophilic patient must be approached in a stepwise manner, with thorough assessment to determine whether the hypereosinophilia itself is contributing to damage and disease ...manifestations (thereby defining a hypereosinophilic syndrome), and to identify an eventual cause of hypereosinophilia, followed by initiation of treatment directed against the underlying condition or deleterious hypereosinophilic state. Situations encountered in the clinic are extremely heterogeneous because of the numerous potential causes of hypereosinophilia and the variable spectrum of eosinophil-mediated organ damage. A practical approach to many of these situations is presented in this review.
Background Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet ...many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA -negative, corticosteroid-responsive subjects with HESs. Objective We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. Methods MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. Results Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. Conclusion Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA -negative HES.
Novel targeted therapies for eosinophilic disorders Wechsler, Michael E., MD, MMSc; Fulkerson, Patricia C., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
09/2012, Letnik:
130, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic ...disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.
Sustained response to mepolizumab in refractory Churg-Strauss syndrome Kahn, Jean-Emmanuel, MD; Grandpeix-Guyodo, Catherine, MD; Marroun, Ibrahim, MD ...
Journal of allergy and clinical immunology,
2010, January 2010, 2010-Jan, 2010-01-00, 20100101, Letnik:
125, Številka:
1
Journal Article
Recenzirano
Etoposide was introduced (100 mg/d for 7 days every 3 weeks), and transient lowering of eosinophil counts was observed after the first course (Fig 1), but thoracic imaging remained unchanged (Fig 2, ...A), and complete alopecia occurred. Because the disease was not controlled, therapy with mepolizumab (750 mg/mo intravenous) was started in June 2007. Recent studies have suggested that ANCA-negative status in CSS is associated with a nonvasculitic pattern, including more frequent cardiac or pulmonary involvement (excluding pulmonary hemorrhage) and a low frequency of glomerulonephritis, purpura, and mononeuritis multiplex.1 The ANCA-negative CSS profile may be difficult to distinguish from hypereosinophilic syndrome, in which mepolizumab has a steroid sparing effect.2 The effectiveness of mepolizumab in our case is strengthened by the demonstration that the disease activity flares after spacing infusions, and that retreatment with monthly doses further controls the disease.
Background Mepolizumab, a monoclonal anti–IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor α fusion (F/P)–negative ...hypereosinophilic syndrome (HES). Lymphocytic variant hypereosinophilic syndrome (L-HES) is characterized by marked overproduction of IL-5 by dysregulated T cells. Objective To determine whether patients with L-HES respond to mepolizumab in terms of corticosteroid tapering and eosinophil depletion to the same extent as corticosteroid-responsive F/P-negative patients with HES and a normal T-cell profile. Methods Patients enrolled in the mepolizumab trial were evaluated for L-HES on the basis of T-cell phenotyping and T-cell receptor gene rearrangement patterns, and their serum thymus-and-activation-regulated chemokine (TARC) levels were measured. Response to treatment was compared in patient subgroups based on results of these analyses. Results Lymphocytic variant HES was diagnosed in 13 of 63 patients with HES with complete T-cell assessments. The ability to taper corticosteroids on mepolizumab was similar in patients with L-HES and those with a normal T-cell profile, although a lower proportion of patients with L-HES maintained eosinophil levels below 600/μL. Increased serum TARC levels (>1000 pg/mL) had no significant impact on the ability to reduce corticosteroid doses, but a lower proportion of patients with elevated TARC achieved eosinophil control on mepolizumab. Conclusion Mepolizumab is an effective corticosteroid-sparing agent for patients with L-HES. In some cases however, eosinophil levels remain above 600/μL, suggesting incomplete neutralization of overproduced IL-5 or involvement of other eosinophilopoietic factors.
Lymphocytic variant hypereosinophilic syndromes Roufosse, Florence; Cogan, Elie; Goldman, Michel
Immunology and allergy clinics of North America,
08/2007, Letnik:
27, Številka:
3
Journal Article
Recenzirano
A large body of evidence establishing the existence of an underlying T-cell disorder in a subset of patients fulfilling hypereosinophilic syndrome (HES) diagnostic criteria has accumulated over the ...past decade, resulting in the definition of a novel HES variant termed "lymphocytic" HES. Although end-organ complications of hypereosinophilia are generally benign, with predominant cutaneous manifestations, long-term prognosis is overshadowed by an increased risk of developing T-cell lymphoma, as a result of malignant transformation of aberrant T cells years after HES diagnosis. Therapeutic strategies should target pathogenic T cells in addition to eosinophils, but the practical implications remain largely unexplored.
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