Mepolizumab in patients with lymphoid variant hypereosinophilic syndrome: a multi-center prospective study

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 (L-)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⁺ L-HES, and the impact of treatment on aberrant cells and associated biomarkers.

Methods: A biomarker sub-study was conducted during two 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, sCD25 and/or detectable IL-5 were identified, and their treatment responses were compared to those without these anomalies.

Results: Of the 108 patients enrolled in 200622-205203, 103 consented to this study, including 17 with a CD3^-CD4⁺ T-cell subset. Presence of CD3^-CD4⁺ T cells or sCD25 levels ≥1500 pg/ml was associated with reduced eosinophil-lowering and corticosteroid-sparing effects of mepolizumab. None of the biomarkers were 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 impact on disease flares in patients with CD3^-CD4⁺ L-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.