Carboplatin‐induced severe hypersensitivity reaction: Role of IgE‐dependent basophil activation and FcεRI

Abstract

Basophil activation was observed in patients with a history of carboplatin-induced severe hypersensitivity reaction (HR). However, the precise mechanism by which carboplatin induces basophil activation and the associated surrogate markers remains to be elucidated. To investigate whether IgE-dependent mechanisms, including the overexpression of FcεRI, participate in carboplatin-induced basophil activation, 13 ovarian cancer patients were enrolled: 5 with a history of carboplatin-induced severe hypersensitivity reaction within the past 2 years, and 8 with no such history. The expression levels of FcεRI, IgE, and CD203c on basophils were measured using a flow cytometer. Immunoglobulin E-dependent basophil activation was evaluated by testing for IgE passive sensitization using lactic acid, and by testing for phosphatidylinositol 3-kinase inhibition, using wortmannin. In three patients positive for carboplatin hypersensitivity, pretreatment with wortmannin almost completely inhibited carboplatin-induced basophil activation (P < 0.05). In a healthy control subject, whose own IgE showed no response to carboplatin, acquired reactivity to carboplatin when exposed to plasma from patients positive for carboplatin hypersensitivity. This did not occur when the same experiment was carried out using plasma from the patients negative for carboplatin hypersensitivity. Moreover, pretreatment with omalizumab, a monoclonal anti-IgE antibody, almost completely blocked carboplatin-induced basophil activation in the plasma of patients positive for carboplatin hypersensitivity. On further investigation, the HR-positive group had significantly higher levels of FcεRI compared with the negative group (P < 0.05). In conclusion, an IgE-dependent mechanism incorporating FcεRI overexpression participates in carboplatin-induced severe HR. These results establish the relevance of monitoring the pharmacodynamic changes of basophils to prevent carboplatin-induced severe HR.

Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies

“…The BRCA status of our patients was not available for further analysis in this retrospective study. However, basophil activation has been observed in patients with a history of severe carboplatin hypersensitivity reaction (Iwamoto et al, 2014 ). Whether, BRCA 1/2 and HRD-related genes modulate Th2 gene expression and increase specific IgE to carboplatin is still unknown.…”

The Contribution of the Basophil Activation Test to the Diagnosis of Hypersensitivity Reactions to Oxaliplatin

“…Data analysis was performed by FlowJo (TreeStar, Ashland, OR, USA). BAT was considered positive when there was an SI ≥2 and/or a basophil activation percentage > 2% [16,17,[19][20][21]. We compared basophil activation percentage and SI (for CD63 and CD203c expression) between patients and controls.…”

“…BAT has also been studied as a possible diagnostic method, given the role of basophils and mast cells as key cells in immediate hypersensitivity reactions. Viardot-Helmer et al [15] found an increased expression of CD63 with exposure to cisplatin; Iwamoto et al [16][17][18] and Jean-Luc [19] detected increased expression of the CD203C marker after incubation with carboplatin and oxaliplatin, respectively; Giavina-Bianchi et al [20] evaluated CD63 and CD203c expression in patients submitted to rapid drug desensitization (RDD) with oxaliplatin and carboplatin, obtaining positive results in 73% of patients. Due to the existing limitations of skin tests, further studies are essential to ascertain the role of the in vitro diagnostic methods, particularly BAT, in hypersensitivity reactions to platinum compounds, as well as to make comparisons with controls in order to gain a better understanding of the underlying immunological mechanisms.…”

Basophil Reactivity as Biomarker in Immediate Drug Hypersensitivity Reactions—Potential and Limitations

“…They arise in up to 26.7% of patients and skin testing has been successfully performed although safety concerns exist regarding severe side-effects for the patient and risk of exposure of the medical personnel (Markman et al, 1999 ; Leguy-Seguin et al, 2007 ; Sugimoto et al, 2011 ). Consequently, the potential of BAT for predicting DHRs has been investigated using flow cytometric determination of CD203c (Iwamoto et al, 2012 , 2014 ). These authors verified the involvement of IgE in carboplatin-induced DHR, as the basophil activation could be inhibited by wortmannin and anti-IgE pretreatment by omalizumab.…”