Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome

Abstract

Background: Conventional therapies for hypereosinophilic syndromes (HES) have variable efficacy and carry significant long-term toxicities. Anti-IL-5 (mepolizumab) therapy has a glucocorticoid (GC)-sparing effect in GC-sensitive HES, but the efficacy of mepolizumab in treatment-refractory HES patients with severe disease has not been examined to date.

Objective: To identify predictors of response to mepolizumab in subjects with severe treatment-refractory HES and compare long-term outcomes in these subjects with HES subjects treated with conventional therapies.

Methods: Retrospective analysis of clinical and laboratory data from 35 HES subjects treated with mepolizumab and 55 HES subjects on conventional therapy, all followed at a single center, was performed.

Results: Peak eosinophilia, GC sensitivity, pulmonary involvement, HES clinical subtype, and pretreatment serum IL-5 were correlated with mepolizumab response. Despite evidence of more severe disease at baseline, mepolizumab-treated subjects had comparable long-term clinical outcomes to HES subjects treated with conventional therapies and reported improvements in therapy-related comorbidities. Subjects managed with mepolizumab monotherapy had fewer disease flares than HES subjects on conventional therapies or mepolizumab-treated HES subjects requiring additional HES therapies.

Conclusions: This study confirms that mepolizumab is an effective and well-tolerated therapy for HES, but suggests that response is more likely in GC-responsive subjects with idiopathic or overlap forms of HES. A primary benefit of treatment is the reduction of comorbidity due to discontinuation or the reduction of conventional HES therapies. Although subjects who completely discontinued GC had the most benefit, high-dose mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.

Trial registration: ClinicalTrials.gov NCT00244686.

Keywords: Eosinophilia; Hypereosinophilic syndrome; Interleukin 5; Monoclonal antibody.

Conflict of interest statement

Conflicts of interest: H. Ortega and J. Steinfeld are GlaxoSmithKline employees and shareholders. The rest of the authors declare that they have no relevant conflicts of interest

Published by Elsevier Inc.

Figures

FIGURE 1.

Clinical response to mepolizumab. A, Schematic of clinical decision making and determination of response to mepolizumab. B, Numbers and percentages of HES subjects by response. C, Mepolizumab response by clinical subtype. Exact ANOVA testing was performed on clinical subtype and mepolizumab response (P =.0022). *Indicates significant differences in pairwise comparisons (adjusted P < .05). D, Pretreatment serum IL-5 levels in 19 subjects with active disease, categorized by response to mepolizumab. The horizontal line indicates the geometric mean. Red circles denote complete responders, gray squares partial responders, and orange triangles non-responders. Baseline percentage of subjects on GC therapy and mean dose are indicated. AEC, Absolute eosinophil count; ANOVA, analysis of variance; GC, glucocorticoid; HES, hypereosinophilic syndrome; IV, intravenous; LOD, limit of detection; NR, nonresponder.

FIGURE 2.

Study populations. EGPA, Eosinophilic granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; MPN, myeloproliferative neoplasm; NIH, National Institutes of Health; PDGFRA-platelet-derived growth factor receptor alpha

FIGURE 3.

The number of HES medications at baseline and last study visit (excluding mepolizumab) were enumerated for subjects treated with conventional HES therapy (CONTROL HES) and those treated with mepolizumab (MEPO HES). Bars indicate mean and the lines indicate the standard deviation of each group. Paired Wilcoxon signed rank test was performed in each group. HES, hypereosinophilic syndrome.

FIGURE E1.

Clinical response to mepolizumab by enrollment criteria. Clinical response to mepolizumab in the NIH study cohort as a whole (right) and based on enrollment criteria (left). Subjects who participated in a prior trial of mepolizumab in HES with clinical response are shown in the upper-left panel and subjects enrolled directly on the compassionate use protocol for treatment-refractory, life-threatening HES are shown in the lower left. HES, Hypereosinophilic syndrome; NIH, National Institutes of Health.

FIGURE E2.

Pretreatment serum cytokine levels by treatment response. Pretreatment serum cytokine levels in 19 subjects with active disease, categorized by response to mepolizumab. The horizontal bars indicate the geometric mean within each group. Dotted lines indicate the limit of detection for each assay. Samples below the limit of detection are assigned a value of 0.1 pg/ mL. Red circles denote complete responders, gray squares partial responders, and orange triangles nonresponders. CI, Confidence interval; GM-CSF, granulocyte-macrophage colony-stimulating factor; NR, nonresponder.