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

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. MethodsWe 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.

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

“…According to the FDA Adverse Event Reporting System for tisagenlecleucel in the post-marketing period for the pediatric population, infection was the second most frequent cause of death (11.3%) after disease progression [ 172 ]. Another post-marketing surveillance study of tisagenlecleucel in adults and children revealed a relatively small number of children undergoing CAR T-cell therapy (<0.5%) and higher fungal infection rates (5.4%) [ 173 ]. Not surprisingly, treatment of r/r ALL pediatric patients with other types of CD19-specific CAR T-cells documented comparable with tisagenlecleucel grade ≥3 infection rates (21–24%) [ 159 , 174 ].…”

CAR-T cells—Real-time experience applying CAR-T cells—What we have learned so far

“…Recognition, management, and differentiation of CAR-T cell toxicities are crucial for safe and broad employment of this therapy. Real world data confirmed the well-known adverse reactions of CAR-T cells and in some analyses lower severe CRS and ICANS rates were reported most likely due to the fact that clinical experience improved their early detection [6][7][8][9]. Furthermore, use of corticosteroids to mitigate toxicities by inhibiting the proliferation and/or inflammatory cytokine production from CAR-T cells and other immune cells has become more liberal with initiation at lower grades of CRS or ICANS [6,7].…”

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CD19-targeted chimeric antigen receptor-engineered (CAR)-T cells are novel therapies showing great promise for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma, mantle cell lymphoma, and follicular lymphoma. EMA-approved and commercially available CAR-T cell products have been used successfully by qualified CAR-T cell centers worldwide and these real world data compare favorably to pivotal study results with overall response rates (ORR) and complete response rates (CR) ranging from 51-93% and 40-64%, respectively [1][2][3][4][5][6][7][8][9].Recently, axicabtagene ciloleucel (axi-cel) received FDA approval based on results of a multicenter, randomized study comparing axi-cel to conventional salvage chemoimmunotherapy and autologous blood stem cell transplantation (ASCT) as second-line treatment in patients with relapsed or refractory DLBCL [10,11]. After a median follow-up of 24.9 months, median event-free survival (EFS) was more than 4-fold greater and ORR was 33% higher with double the CR rate in the axi-cel arm.

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“…CD19-targeted chimeric antigen receptor-engineered (CAR)-T cells are novel therapies showing great promise for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma, mantle cell lymphoma, and follicular lymphoma. EMA-approved and commercially available CAR-T cell products have been used successfully by qualified CAR-T cell centers worldwide and these real world data compare favorably to pivotal study results with overall response rates (ORR) and complete response rates (CR) ranging from 51-93% and 40-64%, respectively [1][2][3][4][5][6][7][8][9].…”

“…Furthermore, use of corticosteroids to mitigate toxicities by inhibiting the proliferation and/or inflammatory cytokine production from CAR-T cells and other immune cells has become more liberal with initiation at lower grades of CRS or ICANS [6,7]. More frequent use of CAR-T cells in the real world resulted in detection of so far, unexpected and unreported side effects such as cardiomyopathy, hepatic failure, and gastrointestinal perforation [9]. Limited reports demonstrated a low rate of secondary malignancies (SMNs) after CAR-T cell therapy; however longer follow-up times are needed to properly evaluate the cumulative incidence and type of SMNs, respectively [16,17].…”