Understanding and Challenging of Taxane Hypersensitivity

Allergic reactions to chemotherapy agents are one of the leading causes of drug allergies. Hypersensitivity reactions (HSR) caused by taxanes, in particular, are common in chemotherapy drug allergies. Efforts have been made for decades through various studies to understand and overcome taxane allergies.¹ Immediate HSR caused by taxanes can be summarized into 3 main pathways: 1) specific antibody (immunoglobulin E [IgE]/immunoglobulin G [IgG])-mediated activation of mast cells or basophils, which can be initiated by either taxane moiety or the solubilizer (Cremophor) added to the medication, 2) direct activation of basophils by taxanes without IgE-mediated pathway, and 3) anaphylatoxins (C3a and C5a) produced by an IgG-mediated mechanism that triggers complement activation through the creation of immune complexes. These anaphylatoxins can then activate mast cells and basophils via their surface receptors.² Diagnosing taxane allergies may be limited due to reactions caused by additives and reactions mediated by complement activation compared to other drug allergies that primarily manifest through the IgE cascade. The absence of standardized diagnostic reagents for additives in clinical settings is one of the factors that complicate the diagnosis of taxane-induced HSRs.

In cases of taxane allergy, avoiding the causative agent is ideal, but changing the first-line chemotherapy, often taxane-based, is not always practical in cancer treatment. Therefore, desensitization methods are used to continue taxane therapy.³ In this issue of the Allergy Asthma Immunol Res, Bayrak Durmaz et al.⁴ showed the clinical outcomes and safety of rapid drug desensitization (RDD) through the multicenter study.

The authors retrospectively analyzed 75 patients with taxane (paclitaxel and docetaxel)-induced HSRs and demonstrated a total of 255 desensitization procedures performed on these patients. Most patients reacted to the first exposure (56%) and the second (30.7%). There was no statistically significant difference between paclitaxel and docetaxel in age, gender, numbers of responsible drug exposure, type of malignancy, initial HSR severity, and comorbid allergic disease history. Due to premedication agents before chemotherapy administration, skin testing was possible in only 64% of patients, with positive findings in 18.8% of them. The major RDD method used in this study was the 3-bag 12-step protocol primarily employed at Brigham and Women’s Hospital.⁵ In this study, 9 eligible patients with mild or moderate HSRs were successfully reduced in step from the 12-step RDDs. During the RDD procedure, breakthrough reactions (BTRs) occurred in 10.6% of RDDs, but all patients were ultimately able to complete the RDD. More BTRs occurred with docetaxel than paclitaxel; however, this difference lacked statistical significance. Of these BTRs, only one patient suffered from grade 3 BTR. Similar severity rates were observed between docetaxel and paclitaxel.

This study has several limitations. First, as previously mentioned regarding skin testing with implicated taxanes, it was not feasible to conduct skin tests on all enrolled patients. Secondly, existing literature suggests that challenges can be conducted if skin tests yield negative results in patients experiencing grade 2 reactions in severity. However, due to their local patient safety considerations, desensitization was preferred over challenge in these cases.

A Turkish research team published a similar taxane RDD study in 2023, where a total of 183 desensitization procedures were conducted in 45 subjects, reporting a success rate of 98.9%.⁶ In addition, various chemotherapy desensitization research is also being conducted in Korea. Among them, there is a study where RDD was performed with a single bag instead of multiple bags that have been traditionally used. It has been confirmed that there is no difference in safety compared to conventional desensitization methods. With no differences in the completion rate, incidence of BTR, or proportion of severe BTR, the administration time was significantly shorter in the 1-bag protocol group compared with the conventional multi-bag protocol group.⁷

Research on chemotherapy desensitization needs to evolve with the rapid development of new anticancer agents. In order to overcome allergies to the optimal drugs for cancer treatment, it is essential to conduct mechanistic studies on drug allergies and continually advance desensitization research.