Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome

Kuang, Fei Li; Fay, Michael P.; Ware, JeanAnne; Wetzler, Lauren; Holland-Thomas, Nicole; Brown, Thomas; Ortega, Héctor; Steinfeld, Jonathan; Khoury, Paneez; Klion, Amy D.

doi:10.1016/j.jaip.2018.04.033

Cited by 75 publications

(58 citation statements)

References 23 publications

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“…No response was seen in the two patients with myeloproliferative HES ( JAK2 V617F‐positive) and three out of four patients with lymphocyte variant HES relapsed after an initial response. The lack of response of myeloproliferative HES to benralizumab is similar to the mepolizumab experience . Benralizumab is not currently approved by the FDA for HES.…”

Section: Risk‐adapted Therapysupporting

confidence: 55%

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

2019

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Disease overview: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage.Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 10 9 /L, and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ-hybridization, flow immunophenotyping, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the MPN subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.Risk-adapted therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, <1.5 × 10 9 /L) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), as well as other targets on eosinophils remains an active area of investigation.

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Section: Risk‐adapted Therapysupporting

confidence: 55%

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

2019

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“…14,25,26 Although the mechanism by which cytokines inhibit GC-mediated eosinophil apoptosis is incompletely understood, recent data suggest that resistance to GC in the setting of high IL-5 levels may be due to up-regulation of nuclear factor interleukin-3 (NFIL3). 14 Consistent with previously published data, 27 serum IL-5 levels were increased prior to GC treatment in HES subjects in the current study compared to healthy volunteers. Although IL-5 levels…”

Section: Dysregulated Expression Of a Variety Of Th2 And Inflammatorysupporting

confidence: 91%

Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes

Stokes

Yoon

Makiya

et al. 2019

Clin Experimental Allergy

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Background Glucocorticoids (GC) are considered first‐line therapy for most patients with hypereosinophilic syndrome (HES). Although response rates are generally high, many patients require moderate to high doses for control of eosinophilia and symptoms, and up to 15% of patients do not respond at all. Despite this, little is known about the mechanisms of GC resistance in patients with HES. Objective To explore the aetiology of GC resistance in HES. Methods Clinical data and samples from 26 patients with HES enrolled on a prospective study of GC responsiveness and 23 patients with HES enrolled on a natural history study of eosinophilia for whom response to GC was known were analysed retrospectively. Expression of GC receptor isoforms was assessed by quantitative RT‐PCR in purified eosinophils. Serum cytokine levels were quantified by suspension array assay in multiplex. Results Despite an impaired eosinophil response to GC after 7 days of treatment, the expected rise in absolute neutrophil count was seen in 7/7 GC‐resistant patients, suggesting that GC resistance in HES is not a global phenomenon. Eosinophil mRNA expression of glucocorticoid receptor (GR) isoforms (α, β, and P) was similar between GC‐sensitive (n = 20) and GC‐resistant (n = 9) patients with HES. Whereas geometric mean serum levels were also comparable between GC‐r (n = 11) and GC‐s (n = 19) for all cytokines tested, serum IL‐5 levels were >100 pg/mL only in GC‐r patients. Conclusions and Clinical Relevance These data suggest that the mechanism of GC resistance in HES is not due to a global phenomenon affecting all lineages, but may be due, at least in some patients, to impairment of eosinophil apoptosis by increased levels of IL‐5.

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“…Mepolizumab is an anti‐IL‐5 monoclonal antibody and is reportedly effective in treating severe bronchial asthma . In addition, the efficacy of mepolizumab in treating several other eosinophilic diseases, including eosinophilic granulomatosis with polyangiitis, has been reported . Although there are a few reports suggesting the effectiveness of mepolizumab in treating EP, it still remains unclear .…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of mepolizumab for eosinophilic pneumonia following bronchial thermoplasty

Otoshi

Baba

Komatsu

et al. 2019

Respirology Case Reports

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A 57-year-old woman with poorly controlled diabetes was admitted to our hospital for additional treatment of severe asthma. Although bronchial thermoplasty was performed in the both upper lobes, cough and dyspnoea gradually appeared 2 weeks later. High-resolution computed tomography revealed thickness of intralobular septa and a diffuse ground-glass attenuation in the lung fields. Laboratory examination revealed elevated levels of serum eosinophils and total immunoglobulin E. Bronchoalveolar lavage fluid showed a remarkable increase of eosinophils as high as 48.5%, then eosinophilic pneumonia was diagnosed. Although treatment with steroids resulted in an improvement of eosinophilic pneumonia, the treatment was discontinued after 4 days because it worsened her diabetic condition. Since eosinophilic pneumonia recurred after discontinuing steroid, mepolizumab was administered, which subsequently improved her disease condition. Clinicians should be aware that bronchial thermoplasty can lead to eosinophilic pneumonia and mepolizumab might be an effective treatment in this setting.

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Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome

Cited by 75 publications

References 23 publications

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes

Effectiveness of mepolizumab for eosinophilic pneumonia following bronchial thermoplasty

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