Using a cohort of more than 500 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia. Microarray analysis was performed using PBMC RNA from 9 affected and 8 unaffected members of a previously described family with autosomal dominant familial eosinophilia (FE). Restricting the analysis to the probe sets for the 313 genes in the previously mapped region, the highest differential expression seen was for IL-5. To confirm these results, quantitative RT-PCR was performed using RNA from freshly isolated unstimulated PBMC from 10 affected and 9 unaffected family members. Whereas IL-5 mRNA expression was significantly increased in PBMC from affected family members, this was not accompanied by increased expression of other Th2 cytokines (IL4 or IL13). Serum levels of IL-5 and IL-5 receptor , but not IgE, were similarly increased in affected family members. Of note, IL-5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+ and ILC2 cells from affected family members, as were IL-5 protein levels in supernatants from 8 stimulated PBMC and ILC2 cultures. These data are consistent with a generalized dysregulation of IL-5 expression in FE and may reflect a novel mechanism of IL-5 regulation in humans (Prakash Babu et al. Allergy 2017). Therapy for eosinophilic disorders remains a primary focus of our group. In the past year, we completed enrollment in three clinical trials of targeted therapy for the treatment of HES. The first of these was a multicenter placebo-controlled, double-blind phase 3 clinical trial of mepolizumab (anti-IL-5 antibody; GlaxoSmithKline) for the treatment of refractory/relapsing eosinophilic granulomatosis with polyangiitis (EGPA). The study met both primary endpoints with 28% of subjects who received mepolizumab vs. 3% of those who received placebo achieving 24 weeks accrued remission and 32% vs. 3% in remission at Weeks 36 and 48. Annualized relapse rate and average daily prednisolone/prednisone dose were also significantly decreased in the mepolizumab group (Wechsler et al. N Engl J Med 2017). The second trial was a placebo-controlled, double-blind phase 2 trial of benralizumab (MedImmune/Astra Zeneca), an afucosylated antibody to IL-5 receptor alpha that has shown clinical efficacy in patients with eosinophilic asthma. The current trial stemmed, in part, from our prior pre-clinical work examining IL-5 receptor levels in patients with eosinophilia and/or mastocytosis (Wilson et al. J Allergy Clin Immunol 2011). Twenty adults with PDGFRA-negative HES and AEC 1000 cells/mm3 on stable background therapy were enrolled between April 2014 and January 2017 and randomized to receive benralizumab or placebo monthly for 3 months. while on stable background therapy. At week 12, subjects received open-label benralizumab, and AEC was unblended beginning at week 13. Depending on the results of the week 13 AEC, subjects were eligible to receive monthly benralizumab with tapering of background therapy. Only two subjects demonstrated a lack of response at 13 weeks and were taken off study. Twelve subjects remain on benralizumab for 6-35 months with AEC of 0/mm3. One additional subject has demonstrated a partial response and remains on therapy. Four subjects relapsed after 7-35 months of therapy and have been taken off protocol. The study met the primary endpoint with a >50% reduction in AEC in 9/10 subjects who received benralizumab compared to 3/10 who received placebo. Biopsies of affected tissues were performed in 7 subjects and showed resolution of tissue eosinophilia at week 24. The drug has been well-tolerated with only one serious adverse event (a ureteral stone) potentially related to benralizumab. Analyses are ongoing. The third trial was an open-label trial of dexpramipexole (Knopp Biosciences) in patients with steroid-resistant HES. Dexpramipexole was developed for the treatment of amyotrophic lateral sclerosis (ALS). Although it was well tolerated, dexpramipexole failed to show efficacy in a large phase 3 trial for this disease. It did, however, appear to selectively lower blood eosinophils, which prompted the current proof-of-concept open-label phase 2 trial in HES. All 10 subjects are enrolled, 4 subjects were able to taper prednisone to 50% of their pre-treatment dose, and both primary study endpoints were met. Three subjects continue on dexpramipexole for 10 to 34 months with AEC of 0 entirely off glucocorticoids. Tissue biopsies in two subjects confirmed resolution of eosinophilia. Adverse events related to drug have been limited to transient insomnia and palpitations in 3 subjects. Although the mechanism of action of dexpramipexole remains a mystery, bone marrow data is consistent with maturational arrest of the eosinophil lineage. In addition to the clinical trials described above, we continue to explore standard therapies for HES. In a retrospective study of glucocorticoid (GC) responsiveness, 164 subjects with PDGFRA-negative HES were categorized according to GC response. Thirty-nine percent of the subjects responded to low dose (<10 mg) prednisone, 9% did not respond to GC, and the remainder (52%) had variable responses to GC. HES subtype was the best predictor of response to GC with myeloid forms and lymphocytic variants of HES being the least responsive to GC (Khoury et al. J Allergy Clin Immunol Pract 2017). Helminth infections can be associated with dramatic eosinophilia and complications that are indistinguishable from HES. This is particularly true in loiasis where symptoms are associated with increased eosinophil granule protein levels (indicative of eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines (Herrick et al. Clin Inf Dis 2015;60:55-63). To explore more directly the role of eosinophils in post-treatment reactions in loiasis, 12 patients with loiasis and microfilarial counts <2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 g/kg) in Cameroon (Legrand et al. Clin Infect Dis 2017). Post-treatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours post-treatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum IL-5 levels, surface expression of CD69 and serum levels of eosinophil granule proteins, were increased post-treatment in both groups. These data suggest that the pathogenesis of posttreatment reactions is similar following DEC and IVM and that eosinophils play a significant role. Whether blocking post-treatment eosinophilia would reduce the severity of post-treatment reactions was addressed in a recently completed placebo-controlled, double-blind clinical trial of reslizumab (anti-IL-5 antibody) given 3-7 days prior to DEC treatment of 8 subjects with loiasis at the NIH Clinical Center. Preliminary results suggest that reslizumab had no effect on microfilarial clearance and that the post-treatment rise in eosinophilia was partially blocked. Unfortunately, the reduction in eosinophil count appears to have been insufficient to reduce post-treatment adverse events. Analysis of data pertaining to eosinophil activation and cytokine levels is ongoing.
| Kuang, Fei Li; Fay, Michael P; Ware, JeanAnne et al. (2018) Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome. J Allergy Clin Immunol Pract 6:1518-1527.e5 |
| Panch, Sandhya R; Bozik, Michael E; Brown, Thomas et al. (2018) Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes. Blood 132:501-509 |
| Khoury, P; Stokes, K; Gadkari, M et al. (2018) Glucocorticoid-induced eosinopenia in humans can be linked to early transcriptional events. Allergy 73:2076-2079 |
| Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83 |
| Groves, Daniel W; Klion, Amy D; Chen, Marcus Y et al. (2018) Swiss cheese heart. Eur Heart J 39:255-256 |
| Herrick, Jesica A; Legrand, Fanny; Gounoue, Raceline et al. (2017) Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection. Clin Infect Dis 64:1017-1025 |
| Ma, Chi A; Xi, Liqiang; Cauff, Brian et al. (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129:650-653 |
| Wechsler, Michael E; Akuthota, Praveen; Jayne, David et al. (2017) Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 376:1921-1932 |
| Khoury, Paneez; Makiya, Michelle; Klion, Amy D (2017) Clinical and Biological Markers in Hypereosinophilic Syndromes. Front Med (Lausanne) 4:240 |
| Kuang, Fei Li; Klion, Amy D (2017) Biologic Agents for the Treatment of Hypereosinophilic Syndromes. J Allergy Clin Immunol Pract 5:1502-1509 |
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