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Background: Hypereosinophilic syndrome (HES) is characterized by blood and tissue hypereosinophilia causing organ damage and/or dysfunction. Mepolizumab, an anti-IL-5 antibody, has recently been approved in this indication. In lymphoid-variant HES, eosinophil expansion is driven by IL-5-producing clonal CD3 - CD4 + T cells., Objective: This study aimed to elucidate the efficacy of mepolizumab in patients with CD3 - CD4 + lymphoid-variant HES, and the effect of treatment on aberrant cells and associated biomarkers., Methods: A biomarker substudy was conducted during 2 clinical trials evaluating mepolizumab in HES, a 32-week randomized placebo-controlled trial (200622) followed by a 20-week open-label extension (205203). Patients with CD3 - CD4 + and/or clonal T cells, elevated serum TARC/CCL17, soluble (s)CD25, and/or detectable IL-5 were identified, and their treatment responses were compared to those without these anomalies., Results: Of the 108 patients enrolled onto 200622 and 205203, 103 consented to the study, including 17 with a CD3 - CD4 + T-cell subset. Presence of CD3 - CD4 + T cells or serum sCD25 levels ≥1500 pg/mL was associated with reduced eosinophil-lowering and corticosteroid-sparing effects of mepolizumab. None of the biomarkers was associated with an increased likelihood of experiencing clinical flares. A mepolizumab-induced increase in serum IL-5 was observed that was significantly higher in patients with CD3 - CD4 + T cells. Treatment did not affect CD3 - CD4 + T-cell counts., Conclusion: Mepolizumab has a favorable effect on disease flares in patients with CD3 - CD4 + lymphoid-variant HES, although reduced eosinophil-depleting and corticosteroid-sparing effects are observed at the currently approved dose. Further studies are needed to validate these findings on larger patient cohorts, and to explore whether clinical activity other than flares is equally controlled in this disease variant., Competing Interests: Disclosure statement Funded by the Fonds Wetenschappelijk Onderzoek (FWO) and Fonds de la Recherche Scientifique (FRS)–National Fund for Scientific Research (FNRS) under the Excellence of Science (EOS) program (project G0H1222N); and FNRS grants F 5/4/150/5 (to F.R.), FC 54372 (to F.R.), and 1.A.094.21F (to J.C.). Disclosure of potential conflict of interest: F. Roufosse has received consultancy fees from AstraZeneca, GlaxoSmithKline, Menarini, and Merck; and royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are rare systemic inflammatory disorders with overlapping symptoms, elevated eosinophil counts, and heterogenous clinical presentations. Although progress has been made in recent years, there are substantial gaps in our understanding of the pathologic mechanisms involved in these diseases, as well as numerous unmet needs relating to both diagnosis and patient management. For example, in most cases of HES, the underlying cause of hypereosinophilia is unknown, while in EGPA, although a polygenic genetic susceptibility has been found, understanding of the pathogenic mechanisms remains largely elusive. Delineating differences between certain disease variants may be challenging, and there are no reliable predictive markers of disease course. In addition, the current diagnostic criteria for HES and classification criteria for EGPA are not easy to implement in a nonspecialist setting, and specialist referral pathways need to be signposted more clearly. Furthermore, disease-specific activity scores need to be developed to aid the assessment of treatment effects, and improved biomarkers are needed to aid with treatment stratification. In this review, we outline the limitations of our current understanding of HES and EGPA and highlight areas for future work, which ultimately should help improve patient management and outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear., Objective: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES., Methods: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed., Results: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%])., Conclusions: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Published by Mosby, Inc.)

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., (Published by Mosby, Inc.)

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., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Markedly increased blood eosinophilia (ie, > or =1.5 x 10(9)/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., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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.

Background: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/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 alpha (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-alpha (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.

The idiopathic hypereosinophilic syndrome is associated with expansion of an IL-5-producing T-cell subset in a subgroup of patients. Identification of such patients is critical to adequate management because there is some evidence that they present an increased risk for development of T-cell lymphoma. Although the T(H)2-like cells often bear an aberrant surface phenotype and can readily be detected with flow cytometry, we now show that lymphocyte phenotyping might be normal in some cases. In contrast, serum thymus and activation-regulated chemokine levels are consistently increased in such patients compared with others with persistent idiopathic hyper-eosinophilia and could therefore represent a useful diagnostic tool.