A Modified Basophil Activation Test for the Clinical Management of Immediate Hypersensitivity Reactions to Paclitaxel: A Proof-of-Concept Study

Abstract

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n = 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Tax^pos), and eleven were tolerant (iHSR-Tax^neg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Pl^pos), and fourteen were tolerant (iHSR-Pl^neg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02-4.11; n = 11) and -0.28 (range -4.88-0.07, n = 11) in iHSR-Tax^pos and iHSR-Tax^neg, respectively. The BAT median SI values were 4.45 (range, 0.1-26.7; n = 14) and 0 (range, -0.51-1.65; n = 12) in iHSR-Pl^pos and iHSR-Pl^neg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Tax^pos and iHSR-Tax^neg showed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Tax^pos patients and 90.91% of iHSR-Tax^neg patients. Comparing BAT results for iHSR-Pl^pos and iHSR-Pl^neg showed the area under the ROC curve to be 0.9286 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Pl^pos patients and 91.67% of iHSR-Pl^neg patients. Most iHSR-Tax^pos patients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Pl^pos patients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Tax^pos patients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes.

Keywords: BAT; MRGPRX2; basophils; flow cytometry; hypersensitivity; platinum; taxane.