Background: Hypereosinophilic syndrome (HES) is characterized by blood and/or tissue eosinophilia resulting in end-organ damage. HES can be primary clonal (in which the eosinophil is part of clonal hematopoiesis), secondary (due to eosinophilic stimulating cytokines) or idiopathic (I-HES). A careful diagnostic work-up for primary causes, as well as vigilant surveillance for end-organ damage should be performed to establish an underlying and treatable diagnosis. Regardless of the cause, treatment of symptomatic HES is mandatory. Treatment may consist of steroids, tyrosine kinase inhibitors, hydroxycarbamide, or interferon, with variable responses. Long-term use of steroids leads to osteoporosis and infections, and treatment with steroid sparing drugs might be hampered by other side-effects. More aggressive treatments such as alemtuzumab is efficacious but severely immunosuppressive. Several antibodies targeting IL-5 or its receptor have been successfully applied for eosinophilic asthma but only mepolizumab is registered by the FDA and EMA for HES. Benralizumab, an anti-IL5R antibody, was efficacious and safe for treatment of HES in a phase-I/II trial. A randomized phase-III trial comparing benralizumab with placebo is currently recruiting. We have treated 15 patients with off-label benralizumab for severe refractory HES or HES with unacceptable steroid dependency. Methods: 15 adults (8 with I-HES, 6 with secondary (lymphocytic variant) HES and one patient with HES secondary to sarcoidosis; age range 19-69 years; 10 male, 5 female) from our institution were treated with benralizumab at a monthly dose of 30 mg after giving consent for off-label use. All had absent HES translocations by FISH, and no evident underlying diagnosis was present after extensive diagnostics including bone marrow examination with cytogenetics and molecular diagnostics. They all were refractory or had contra-indications to conventional treatment, or steroids could not be reduced to an acceptable dose. All had elevated eosinophil counts at diagnosis above 0.6 x 109/L (range 0.32-90 x109/L, median 8.3 x 109/L) except one patient who had a level of 0.32 while on 30 mg prednisolone per day. All patients had at least one organ affected by HES, including 2 patients with myocarditis. Three patients had previously received mepolizumab in a HES dose, 2 of whom were refractory and consequently stopped while one had an allergic reaction necessitating cessation. Median follow-up time after starting benralizumab was 22 months (range, 1-34 months). Results: In terms of efficacy, 13 patients had a reduction of their eosinophil count to below 0.05 x 109/L after one dose, one patient had a reduction from 8.13 to 0.72 x 109/L, with a count that is still decreasing while stopping all other medication. Eosinophil count decreased from 12.38 to 1.45 x 109/L in another patient, but benralizumab was stopped due to the development of MDS, which was most likely the cause of the eosinophilia despite normal cytogenetics and molecular diagnostics at time of diagnosis. All but 2 patients were off steroids completely after 4 months. All but 2 patients experienced a clinically relevant improvement of organ function, mostly to complete resolution of objective symptoms or signs. Interestingly, the 2 patients who did not experience clinically significant reduction of symptoms, despite reduction of peripheral eosinophil counts, both had colitis as one of the cardinal disease symptoms. In one, the diagnosis was revised to inflammatory bowel disease with secondary eosinophilia. In terms of safety, 2 patients experienced mild headache for a few days after the benralizumab dose, and 1 patient had a mild malar rash after the first dose. One patient stopped due to the development of MDS necessitating other treatment and one stopped due to refractoriness. Interestingly, this patient subsequently had an excellent response on mepolizumab, on both clinical symptoms as well as reduction of eosinophil counts. All patients with objective clinical benefit remain on treatment. Conclusions: We report on the largest single center cohort of patients treated with off-label benralizumab for HES. The use of this drug has proven a safe and effective treatment for HES regardless of the underlying cause. It reduces eosinophil counts, reverses organ-damage and use of steroids in most patients. Side effects are infrequent and mild and no severe adverse events were observed.

Mutsaers:GSK: Consultancy; Astra Zeneca: Research Funding; BMS: Consultancy.

Benralizumab is currently registered for eosinophilic asthma and is under investigation for HES in a phase-III trial after previous phase-I/II trials.

Author notes


Asterisk with author names denotes non-ASH members.

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