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Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.

ABSTRACT: Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ?50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/?L and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ?50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

SUBMITTER: Panch SR

PROVIDER: S-EPMC6073324 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.

Panch Sandhya R SR Bozik Michael E ME Brown Thomas T Makiya Michelle M Prussin Calman C Archibald Donald G DG Hebrank Gregory T GT Sullivan Mary M Sun Xiaoping X Wetzler Lauren L Ware JeanAnne J Fay Michael P MP Dunbar Cynthia E CE Dworetzky Steven I SI Khoury Paneez P Maric Irina I Klion Amy D AD

Blood 20180508 5

Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 tr ...[more]

PMID: 29739754

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Project description:Background:Brain metastases are common in advanced melanoma and often necessitate corticosteroids such as dexamethasone to control symptoms and reduce peritumoral edema. Immunotherapy improves survival in metastatic melanoma, but concomitant treatment with corticosteroids may reduce efficacy. Here, we report the use of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, as a steroid-sparing agent in melanoma patients with brain metastases treated with immunotherapy. Methods:Medical records and imaging were retrospectively analyzed for melanoma patients with brain metastases who received bevacizumab at our institution between 2012 and 2017. Results:12 melanoma patients with brain metastases received bevacizumab (5-7.5 mg/kg Q2-3 W; median 4 cycles, range 1-9). Patients were BRAF wild-type or resistant to BRAF/MEK inhibitor therapy. All had progressive intracranial disease after prior resection, stereotactic radiosurgery and/or whole brain radiotherapy, and up to four lines of previous systemic treatment. Prior to bevacizumab, all patients had radiologically defined peritumoral edema and nine required dexamethasone for symptom control. In 10 evaluable patients, six reduced their dexamethasone dose by more than 50%, and eight displayed reduced edema 4 weeks after bevacizumab. Seven patients experienced adverse events possibly related to bevacizumab, including intracranial hemorrhage, hypertension, and gastrointestinal bleeding. Ten patients received immunotherapy after bevacizumab. Five patients survived more than 6 months, including one who remained disease-free after 4 years and without neurological deficit despite being hemiplegic from edematous brain metastases prior to bevacizumab. Conclusion:In 12 very poor prognosis melanoma patients with brain metastases, bevacizumab was well-tolerated, associated with improved symptoms and reduced peritumoral edema despite weaning steroids, and facilitated treatment with immunotherapy that provided durable survival in a substantial proportion of cases.

Dataset Information

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.

Publications

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.

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