Cytokine-mediated hypersensitivity reactions to carboplatin in early triple-negative breast cancer with neoadjuvant pembrolizumab plus chemotherapy.

Abstract

e12589 Background: High-grade fevers exceeding 40°C after administration of carboplatin and paclitaxel have occasionally been observed in early triple-negative breast cancer (TNBC) patients who are receiving neoadjuvant therapy based on KEYNOTE-522 trial. Methods: We retrospectively reviewed 102 TNBC patients who initiated KEYNOTE-522-based therapy at our institution between October 2022 and October 2024. We assessed the incidence, timing, and clinical course of fevers occurring within 24 hours of carboplatin plus paclitaxel, with or without pembrolizumab, administration and lasting several days. Results: Among the 102 patients, 89 received weekly carboplatin and 13 received tri-weekly carboplatin. Febrile episodes (≥40°C) occurred in 10 of the 89 patients (11.2%) in the weekly group, whereas none of the 13 patients in the tri-weekly group developed fever. Fever onset occurred after the third dose of carboplatin and paclitaxel in 4 patients, the fourth in 1, the seventh in 3, the ninth in 1, and the eleventh in 1. Febrile episodes recurred with subsequent doses. Two patients were hospitalized for monitoring: both had hypotension responsive to fluids, elevated inflammatory markers (CRP, IL-6), and headaches. Other symptoms included hypoxia, nausea, facial flushing, and edema. Neutropenia was not observed, ruling out febrile neutropenia. Infection was excluded based on consistently negative culture results and the absence of suspicious findings on imaging. Fever resolved after carboplatin was discontinued, suggesting these episodes were likely carboplatin hypersensitivity reactions. Discussion: Carboplatin hypersensitivity reactions (HSRs) can be mediated by both IgE-dependent and cytokine-driven mechanisms. IgE-mediated HSRs typically arise after multiple exposures (around six to eight cycles) and present with allergic reactions, whereas cytokine-mediated HSRs often involve high-grade fevers. In our series, high fever was the primary symptom, and some cases developed after only a few administrations, with elevated IL-6 levels suggesting a predominantly cytokine-mediated etiology. These HSRs occurred only in the weekly carboplatin group, indicating that more frequent carboplatin exposure may heighten sensitization. However, tri-weekly dosing was introduced after July 2024, resulting in only 13 patients receiving it. This small sample size limits our ability to draw conclusions regarding its safety. Conclusions: To our knowledge, this is the first report to summarize cytokine-mediated carboplatin HSRs as a distinct adverse event of KEYNOTE-522-based regimen. Given that approximately 10% of patients experienced these severe reactions, appropriate management strategies are essential.