Hematologic and lymphatic disorders associated with chimeric antigen receptor T-cell therapy: a pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database

Abstract

Background: As the application of Chimeric Antigen Receptor T-cell (CAR-T) therapy in cancer treatment becomes increasingly widespread, associated hematologic and lymphatic system adverse events pose significant challenges to its clinical use. Therefore, we aim to comprehensively investigate and summarize the hematologic and lymphatic system AEs associated with CAR-T therapy.

Methods: We extracted CAR-T-related adverse event reports from the FDA Adverse Event Reporting System (FAERS) database for the period from August 2017 to December 2023. Disproportionality analysis using the Reporting Odds Ratio (ROR) and Information Component (IC) was performed to identify CAR-T-associated hematologic and lymphatic system AEs. We employed LASSO regression analysis to identify hematologic and lymphatic system AEs associated with mortality.

Results: In the FAERS database, we identified 1,600 individual case safety reports of hematologic and lymphatic system AEs related to CAR-T therapy. The median age of patients was 57 years (interquartile range [IQR] 32-67), with fatal outcomes in 15.3% of cases. We identified 25 significant adverse event signals associated with CAR-T therapy. B-cell aplasia (ROR025 = 1054.56, IC025 = 4.74), cytopenia (ROR025 = 17.27, IC025 = 3.81), hypofibrinogenemia (ROR025 = 100.18, IC025 = 2.46), anemia (ROR025 = 1.87, IC025 = 0.59), febrile bone marrow aplasia (ROR025 = 55.32, IC025 = 2.70), and pancytopenia (ROR025 = 7.18, IC025 = 1.42) were the most significant hematologic and lymphatic system AEs for tisa-cel, axi-cel, brexu-cel, liso-cel, ide-cel, and cilta-cel, respectively. Most hematologic and lymphatic system AEs occurred within 10 days post-CAR-T infusion. Hematologic and lymphatic system AEs were associated with a mortality rate of 15.3%. Our analysis revealed 15 hematologic and lymphatic system AEs closely associated with mortality in CAR-T-treated patients, including splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia.

Conclusions: Our study found that hematologic and lymphatic system AEs were more closely associated with anti-CD19 CAR-T and CAR-T containing CD28. Splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia were identified as hematologic and lymphatic system AEs that, while less frequently reported clinically, were highly associated with mortality.

Keywords: Adverse events; CAR-T therapy; FAERS; Hematologic and lymphatic system toxicity.

Fig. 1

Flowchart of the study analysis process. Detailed description of the selection process for CAR-T hematologic and lymphatic system adverse events (AEs) from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)

Fig. 2

Statistical data on the incidence of hematologic and lymphatic system adverse events (AEs) in CAR-T reports from the FDA Adverse Event Reporting System (FAERS) database

Fig. 3

Hematologic and lymphatic system adverse events (AEs) in CAR-T reports from the FDA Adverse Event Reporting System (FAERS) database. A) Heatmap showing ROR025 and IC025 for 29 hematologic and lymphatic system AEs (with at least 3 reports) under different CAR-T treatment strategies in the FAERS database. B) Bar chart displaying the number of reports for 29 hematologic and lymphatic system AEs. C) Forest plot illustrating the signal values for hematologic and lymphatic system AEs associated with different CAR-T therapies

Fig. 4

Time to onset of CAR-T-related hematologic and lymphatic system adverse events (AEs). A) Cumulative distribution curves showing the time to onset of related hematologic and lymphatic system AEs under different CAR-T treatment strategies, with statistical testing performed using the non-parametric Kruskal-Wallis rank-sum test. B) Cumulative distribution curves showing the time to onset of related hematologic and lymphatic system AEs in fatal and non-fatal groups, with statistical testing performed using the non-parametric Wilcoxon rank-sum test

Fig. 5

Assessment of various hematologic and lymphatic system adverse events (AEs) associated with mortality after CAR-T therapy. A) Number and proportion of fatal reports for hematologic and lymphatic system AEs following treatment with different CAR-T products. B) Number of fatal reports and mortality rates for hematologic and lymphatic system AEs across different CAR-T products. C) K-fold cross-validation for selecting the optimal number of K-folds and Alpha parameter for LASSO regression