Dysphonia and dyspnea in idiopathic hypereosinophilic syndrome treated with Mepolizumab.
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SUBMITTER: Kay D
PROVIDER: S-EPMC6038714 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCurrent standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496).MethodsIn the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/μL at screening and ≥4 weeks' stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc, descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo.ResultsMepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32-96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3-31.4%) than placebo (35.7-74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22-0.68 vs 1.14-1.62). The proportion of patients who experienced ≥1 flare during Weeks 20-32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55-85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group.ConclusionsPatients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy.Clinical trial registration(https://clinicaltrials.gov/ct2/show/NCT02836496).
| S-EPMC9044076 | biostudies-literature
Project description: Not available
| S-EPMC7780009 | biostudies-literature
Project description:BackgroundMepolizumab, a monoclonal anti-IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor ? 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.ObjectiveTo 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.MethodsPatients 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.ResultsLymphocytic 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/?L. 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.ConclusionMepolizumab is an effective corticosteroid-sparing agent for patients with L-HES. In some cases however, eosinophil levels remain above 600/?L, suggesting incomplete neutralization of overproduced IL-5 or involvement of other eosinophilopoietic factors.
| S-EPMC2950246 | biostudies-literature
Project description:BackgroundHypereosinophilic syndrome (HES) is characterized by persistent elevated blood and/or tissue eosinophil levels and eosinophil-mediated organ damage. Presentation is highly heterogenous; patients may experience symptoms affecting multiple organ systems.ObjectivesTo assess the effects of mepolizumab, which targets interleukin-5, on HES-related symptom burden, based on HES daily symptoms (HES-DS) questionnaire data collected during the Phase III (ClinicalTrials.gov ID: NCT02836496) study of mepolizumab in patients with HES.MethodsEach of the six HES-related symptoms were rated (0-10) daily by patients, recalling worst symptom experience in the prior 24 hours; change from baseline at Week 32 was also calculated for mepolizumab versus placebo.ResultsMepolizumab versus placebo reduced HES-related symptom burden severity in patients with HES at Week 32. Improvements in the median change from baseline scores were seen across all symptom groups except skin for patients treated with mepolizumab; greatest improvement from baseline was observed for breathing symptoms.ConclusionThese data highlight the considerable symptom burden associated with HES and further support the clinical benefits of mepolizumab treatment for these patients.
| S-EPMC10090544 | biostudies-literature
Project description:In patients with hypereosinophilic syndrome (HES), mepolizumab reduces the incidence of HES-related clinical signs and symptoms (flares). However, reports characterizing flare manifestations are limited. The double-blind, parallel-group 200622 trial (NCT02836496) enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous year, and screening blood eosinophil count ≥1000 cells/μL. Patients maintained ≥4 weeks stable HES therapy, before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. This post hoc analysis investigated flare manifestations and duration by re-examining the Core Assessments form and narrative recorded for each flare during the study. Flare symptoms were retrospectively categorized into constitutional, dermatological, respiratory, nasal, gastrointestinal, neurologic and other. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares); flares reported in patients receiving mepolizumab compared with placebo were generally similar in terms of the frequency of symptoms reported. Mepolizumab was associated with a shorter median (range) duration of flares (10.0 [4, 126] days) versus placebo (26.0 [1, 154] days). In patients with HES, flares were associated with symptoms linked to multiple organ systems highlighting the challenges faced for treating flares.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02836496, identifier NCT02836496.
| S-EPMC9462399 | biostudies-literature
Project description:BackgroundAnti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear.ObjectiveWe sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES.MethodsThis 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.ResultsThe 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%]).ConclusionsCompared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.
| S-EPMC9579892 | biostudies-literature
Project description: Not available
| S-EPMC7665460 | biostudies-literature
Project description:BackgroundHypereosinophilic 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.ObjectiveWe evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES.MethodsMHE100901 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.ResultsSeventy-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.ConclusionMepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES.
| S-EPMC3558744 | biostudies-literature
Project description:Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.
| S-EPMC164673 | biostudies-literature
Project description:Knowledge of the multi-organ involvement in hypereosinophilic syndrome (HES) is important for the diagnosis and care of patients with this condition, even in cases with atypical presentation. This report aims to describe cerebral embolic infarction and intracardiac atypical linear-shaped thrombus in a patient with idiopathic HES and to discuss the approach of appropriate diagnosis and timely interventional management. A 55-year-old man presented with general weakness, including left-sided weakness, mild cognitive dysfunction, and mild exertional dyspnea for about 2 weeks. Initial magnetic resonance imaging for evaluating the brain showed multifocal acute to subacute infarction of both cerebral hemispheres and both cerebellums. Laboratory findings revealed leukocytosis (25,620 cells/mm3) and eosinophilia (54.9%). To evaluate the intracardiac embolic source, the patient underwent echocardiography, and a 1.5 cm linear thread-like and mobile mass was detected. Consequently, the patient was diagnosed with idiopathic HES. After bone marrow biopsy, corticosteroid and hydroxyurea were administered to control the eosinophilia. This case indicates that HES can present as a floating intracardiac atypical linear-shaped thrombus attached to the left ventricle. After appropriate diagnostic approaches, proper treatment could be given for the patient. <Learning objective: Idiopathic hypereosinophilic syndrome (HES) is a disorder characterized by persistent eosinophilia with heterogeneous clinical manifestations. Knowledge of the multi-organ involvement in HES is important for the diagnosis and care of patients with this condition, even in cases with atypical shaped thrombus as clinical presentation. Close monitoring combined with early treatment and diagnosis may help reduce mortality in HES patients.>.
| S-EPMC8103353 | biostudies-literature