Genomics of PDGFR-rearranged hypereosinophilic syndrome.
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ABSTRACT:
SUBMITTER: Rheinbay E
PROVIDER: S-EPMC10250933 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
Publications
Genomics of PDGFR-rearranged hypereosinophilic syndrome.
Rheinbay Esther E Qi Meifang M Bouyssou Juliette M JM Oler Andrew J AJ Thumm Lauren L Makiya Michelle M Maric Irina I Klion Amy D AD Lane Andrew A AA
Blood advances 20230601 11
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Project description:Hypereosinophilic syndrome (HES) is defined by persistently elevated blood eosinophil levels and is associated with evidence of organ damage. Cardiovascular involvement in HES is most commonly associated with Loffler endocarditis (cardiac HES). Cardiac HES is typically characterized by progressive subendocardial fibrosis with overlying mural thrombus formation, leading to restrictive dysfunction of the left ventricle. The thrombus from cardiac HES could result in cardiogenic stroke; however, most of the stroke cases with HES were not associated with huge thromboembolism rather multiple infarcts in the watershed area. The major clinical features of 97 previously reported cases of stroke with HES are as follows: the median age was 52 years, of which 61 (63%) were men; the initial presenting symptoms were neurological (73%), followed by headache (16%), respiratory symptoms (9%), and visual symptoms (9%). Almost half of the cases were diagnosed with cardiac HES. The characteristics of cardiac findings were mural thrombi, endomyocardial fibrosis, and a restrictive pattern of heart failure. Cerebral findings revealed 78 cases (80%) were described as multiple infarctions and 55 cases (57 %) were involved with watershed areas, whereas 11 cases (11％) were described as embolic stroke for one proximal large-vessel occlusion. Regarding treatment, 71 (73%), 28 (29%), and 16 (16%) patients were treated with steroids, anticoagulants, and antiplatelets, respectively. The overall mortality and recovery rates were 11% and 89%, respectively. Physicians should know most cases of stroke with HES are characterized by multiple infarctions in the watershed area, and cardiac HES is not always associated with stroke.
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Project description:BackgroundHypereosinophilic 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.MethodsIn 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.ResultsDuring 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.ConclusionsIn 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.).
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Project description:RationaleChurg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy.MethodsA retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia > 1500/μl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR -positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n = 8), ≥4 ACR criteria (probable CSS; n = 21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n = 20), HES without asthma or sinusitis (HES; n = 18), and normal controls (n = 8). Serum biomarkers reported to be associated with CSS were measured using standard techniques.ResultsThere were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8, and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (P < 0.0001, r = 0.73), but not with prednisone dose.ConclusionsIn patients with a history of asthma and sinusitis, distinguishing between ANCA-negative CSS and PDGFR-negative HES is difficult because of significant overlap in clinical presentation and biomarker profiles.
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Project description:Glucocorticoids (GCs) are considered first-line treatment for platelet-derived growth factor ? (PDGFRA)-negative hypereosinophilic syndromes (HESs). Despite this, little is known about clinical predictors of GC responsiveness in HES.Knowledge of clinical and laboratory predictors of GC response before initiation of GC could lead to more rational selection of subjects with HES for whom earlier institution of second-line and alternative therapies would be appropriate.Response to GC, as defined by the reduction of the absolute eosinophil count to below 1000/mm3 and control of symptoms, was assessed by a retrospective chart review of subjects with PDGFRA-negative HES evaluated on an institutional review board-approved protocol. Demographic, clinical, and laboratory parameters obtained before institution of GC, as well as final diagnosis, were evaluated to determine predictors of GC response. Proportional odds models were used for univariate and multivariate assessment of predictors with permutation adjusted P values to correct for multiple comparisons.A total of 164 subjects with PDGFRA-negative HES were categorized according to GC response. Of them, 39% 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. The HES subtype diagnosis was the best predictor of response to GC with myeloid forms and lymphocytic variants of HES being the least responsive to GC.In a large cohort of well-characterized subjects with HES, the odds of response to GC was predicted by HES subtype. Using this model, clinicians may more readily proceed to second-line agents in subjects with confirmed lymphocytic or myeloid forms of HES.
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