Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Michele Fusaroli, Valentina Isgrò, Paola Maria Cutroneo, Carmen Ferrajolo, Valentina Cirillo, Francesca Del Bufalo, Emanuel Raschi, Elisabetta Poluzzi () and Gianluca Trifirò
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Michele Fusaroli: University of Bologna
Valentina Isgrò: University of Verona
Paola Maria Cutroneo: Sicilian Regional Pharmacovigilance Centre, University Hospital of Messina
Carmen Ferrajolo: Regional Centre of Pharmacovigilance and Pharmacoepidemiology
Valentina Cirillo: IRCCS Bambino Gesù Children’s Hospital
Francesca Del Bufalo: IRCCS Bambino Gesù Children’s Hospital
Emanuel Raschi: University of Bologna
Elisabetta Poluzzi: University of Bologna
Gianluca Trifirò: University of Verona

Drug Safety, 2022, vol. 45, issue 8, No 7, 908 pages

Abstract: Abstract Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017–September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2–4.4) and gastrointestinal perforations (2.9; 1.2–7.3), tisa-cel with hepatotoxicity (2.5; 1.1–5.7) and pupil disorders (15.3; 6–39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.

Date: 2022
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DOI: 10.1007/s40264-022-01194-z

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