An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Outdated allergens are similar to unexpired extracts for the detection of allergen sensitization.

Background: Allergen extracts have relatively short shelf lives, which limits their use and increase financial loss and waste on unused extracts. It is thus important to determine if efficacy persists beyond the expiration date. Objective: To determine the in vivo efficacy and bioavailability of outdated allergen extracts for diagnosis of allergic sensitizations. Methods: We enrolled 34 participants with allergic rhinitis and 5 participants with Hymenoptera hypersensitivity. After confirming allergen sensitization with the unexpired extracts, each participant had a second skin test with the matched outdated one (up to 7 years after the expiration date). All pairs of extracts were from the same company, stored under identical conditions, and tested for microbiologic contamination. The results of 356 skin-prick tests between expired and 111 unexpired extracts were compared. Results: None of the extracts had bacterial or fungal contamination. All outdated extracts produced a positive wheal reaction, with an average of 9.4 mm, which was not significantly different than the unexpired allergens. Seven years outdated lyophilized Hymenoptera extracts showed no significant differences in the wheal's size for the intradermal test at 1 µg/mL, between 5 and 9 mm. Conclusion: Outdated allergen extracts were safe and did not seem to differ in potency and bioavailability from unexpired extracts for the detection of allergen sensitization by skin-prick testing. These results supported our hypothesis that allergen extracts have efficacy and bioavailability that extend beyond the expiry date provided by the manufacturer. For the diagnosis of aeroallergens and Hymenoptera sensitization, it seemed that allergens can be used beyond the expiration date.

Targeting interleukin (IL) 5 for asthma and hypereosinophilic diseases.

Although glucocorticosteroids are still the first line of treatment for chronic asthma, over the last two decades great advances have been made in understanding the pathogenesis of asthma that enabled the identification of new therapeutic targets for asthma treatment. The interleukin (IL) 5: eosinophil axis is a hallmark pathway of allergic inflammation that has received much attention. Indeed, IL-5 is known to regulate eosinophil differentiation, proliferation, priming and activation. Therefore, therapeutic agents targeting IL-5 have been generated. In this review we will discuss the effects of IL-5 on eosinophils and outline the signaling mechanism involved in IL-5-mediated effects. Furthermore, recent results from clinical trials targeting IL-5 in asthma and hypereosinophilic syndrome will be discussed and an overview of newly developed patents aimed to target IL-5 will be reviewed.

Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy.

BACKGROUND: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. OBJECTIVE: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. METHODS: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. RESULTS: Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). CONCLUSION: This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

BACKGROUND: Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized. OBJECTIVE: We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects. METHODS: The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G. RESULTS: Twenty-three patients responded to anti-IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3(+) cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor alpha expression, and increased percentage of CD4(+) and CD8(+) cells producing intracellular IL-5 (P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo. CONCLUSIONS: Anti-IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3(+) cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor alpha and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.

Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is characterized by high numbers of eosinophils in the esophagus and epithelial hyperplasia, and is being increasingly recognized. IL-5 promotes eosinophil trafficking to the esophagus, and positively regulates eosinophil growth, activation, survival, and tissue recruitment. OBJECTIVE: We hypothesized that the humanized monoclonal IgG(1) antibody against human IL-5 (mepolizumab) may be useful in the control of EE. METHODS: An open-label phase I/II safety and efficacy study of anti-IL-5 in 4 adult patients with EE and longstanding dysphagia and esophageal strictures was conducted. Patients received 3 infusions of anti-IL-5 (750 mg intravenously monthly) without change in their current therapy. The levels of plasma IL-5, peripheral blood eosinophils, and CCR3+ cells in blood, quality of life measurements, and histological analysis of esophageal biopsies were determined before and 1 month after treatment. RESULTS: Peripheral blood eosinophilia and percent of CCR3+ cells decreased by 6.4-fold and 7.9-fold (P < .05), respectively, after anti-IL-5 treatment. Notably, mean and maximal esophageal eosinophilia decreased from 46 to 6 and from 153 to 28 eosinophils/high-power field (x400; average, 8.9-fold, P < .001, and 6-fold, P < .05), respectively. Patients reported a better clinical outcome and improved quality of life (P = .03). Therapy was generally well tolerated, and responsiveness to anti-IL-5 therapy did not correlate with plasma IL-5 levels. CONCLUSION: Anti-IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes. CLINICAL IMPLICATIONS: Anti-IL-5 is a promising therapeutic intervention for EE.

Hypereosinophilic syndromes and new therapeutic approaches including anti-IL-5.

Eosinophilia syndromes are heterogenous disorders possessing different clinical manifestations characterized by peripheral blood eosinophilia and end organ damage. Treatment includes glucocorticoids, hydroxyurea (hydroxycarbamide), chemotherapy and interferon-alpha. Recently, an explanation for the eosinophilia has been found in many patients who would previously have been regarded as having an idiopathic hypereosinophilic syndrome. Such cases have fallen into myeloproliferative and lymphoid categories with some cases remaining unexplained. A subgroup of patients with the myeloproliferative variant carry the new gene rearrangement FIP1L1-PDGFRA, which produces a constitutively active tyrosine kinase often responsive to antityrosine kinase therapy with imatinib mesylate. A newly developed drug currently being tested in clinical trials is the humanized monoclonal antibody against human interleukin-5. Interleukin-5 positively regulates eosinophil growth, activation, survival and tissue recruitment. As such, anti-interleukin-5 therapy is expected to be very useful, especially for patients with the clonal T-cell variant that secretes high levels of interleukin-5. This review will analyze the etiology, classification and new options for the treatment of the hypereosinophilic syndromes, with particular emphasis on anti-interleukin-5 therapy.