Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome

Abstract

Background: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils.

Methods: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient's background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12.

Results: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse.

Conclusions: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.).

Conflict of interest statement

Dr. Lee reports being employed by MedImmune; Dr. Kolbeck, being employed by MedImmune and owning shares of stock in AstraZeneca; Dr. Newbold, being employed by and holding stock in AstraZeneca; and Dr. Goldman, being employed by AstraZeneca. No other potential conflict of interest relevant to this article was reported.

Copyright © 2019 Massachusetts Medical Society.

Figures

Figure 1.. Trial Design and Effect of Benralizumab on Eosinophil Counts.

Panel A shows the design of the trial, in which 20 patients with hypereosinophilic syndrome (HES) were randomly assigned to receive subcutaneous injections of benralizumab (30 mg) or placebo every 4 weeks for 12 weeks (open triangles). Patients continued to receive stable therapy (drugs or dietary changes) for hypereosinophilic syndrome, and the absolute eosinophil counts were blinded until week 13 of the trial. The placebo-controlled, randomized phase was followed by open-label and extension phases, during which all the patients received 30 mg of benralizumab every 4 weeks (closed triangles). Bone marrow biopsies (black arrows) and peripheral-tissue biopsies (gray arrows) were performed at the indicated time points. Panel B shows the eosinophil counts at baseline and at week 12 in patients in the two groups during the randomized phase of the trial. The dotted line indicates an eosinophil count of 500 cells per cubic millimeter. Panel C shows the percent change from baseline to week 12 in the eosinophil count for each patient after three doses of benralizumab or placebo (P = 0.02 by Fisher’s exact test). The dotted line indicates the cutoff for the primary end point (a reduction of ≥50% in the eosinophil count). Week 6 data were used for Patient 17, who had withdrawn from the trial before week 12 (open circle).

Figure 2. (facing page). Clinical Improvement and Resolution of Tissue Eosinophilia.

Panel A shows a 37-year-old woman with a lymphoid form of hypereosinophilic syndrome before and after treatment with benralizumab. At baseline, the patient’s severe spongiotic dermatitis was complicated by super-infections and bacteremia, resulting in multiple hospitalizations. Previous therapies included oral prednisone (40 mg daily), phototherapy, methotrexate, cyclosporine, mycophenolate, thalidomide, interferon alfa, and various topical agents, none of which adequately controlled her symptoms or eosinophilia. The baseline eosinophil count was 1650 cells per cubic millimeter while the patient was receiving subcutaneous pegylated interferon alfa (90 μg weekly). Since she had been assigned to the placebo group, she did not receive benralizumab until week 12 during the open-label phase of the trial. At week 13, the eosinophil count had dropped to 30 cells per cubic millimeter and declined further to 0 cells per cubic millimeter by week 15. After three monthly doses of benralizumab, during which the pegylated interferon alfa was discontinued, there was a great reduction in the number of skin lesions and associated infections. (A more detailed case vignette about this patient is provided in the Supplementary Appendix.) Panel B shows representative gastric and colonic biopsy samples (hematoxylin and eosin staining and immunostaining against eosinophil peroxidase [anti-EPX]) obtained from two patients with eosinophilic gastrointestinal disorders (Patients 7 and 13) at baseline (top row) and after benralizumab therapy at week 24 (bottom row). In the two patients, biopsy samples showed an eosinophil count of more than 200 cells per high-power field at baseline and a count of 0 at week 24.

Figure 3.. Effect of Benralizumab in Bone Marrow.

Panel A shows the numbers of eosinophils, basophils, and mast cells in bone marrow obtained from trial patients at baseline and at 12 weeks after the receipt of either benralizumab or placebo. Eosinophils and basophils are expressed as the percentage of total bone marrow (BM) cells in bone marrow aspirates. Mast cells were quantified as the average number of tryptase-positive cells in 10 high-power fields (HPF) at 40× magnification in bone marrow biopsy samples stained with antibody against tryptase. Two-sample t-testing (Welch’s method) of the within-patient differences was used to determine whether there was a treatment effect for benralizumab as compared with placebo. Unadjusted P values are shown. P values that were adjusted with the use of Holm’s correction for multiple comparisons are P = 0.07 for eosinophils, P