Chimeric antigen receptor T‐cells safety: A pharmacovigilance and meta‐analysis study

Abstract Chimeric‐antigen‐receptor T cells directed against CD19 (CAR‐T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse‐drug reactions (ADR) associated with CAR‐T. This observational, cross‐sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta‐analysis of data from CAR‐T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR‐T (axicabtagene‐ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility‐interval of information component (IC 025 , significance > 0). We also performed a systematic‐review and meta‐analysis of CAR‐T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR‐T: Cytokine release syndrome (CRS, n = 1378, IC 025 = 4.24), neurological disorders (n = 963, IC 025 = 2.42), hematological disorders (n = 532, IC 025 = 3.32), infections (n = 287, IC 025 = 2.38), cardiovascular disorders (n = 256, IC 025 = 2.81), pulmonary disorders (n = 186, IC 025 = 3.80), reno‐metabolic disorders (n = 123, IC 025 = 1.89), hemophagocytic‐lymphohistiocytosis (n = 36, IC 025 = 5.01) and hepatic disorders (n = 32, IC 025 = 2.49). ADR‐related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all‐cause mortality. These ADR‐related fatalities were associated with hemophagocytic‐lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta‐analyses, the most frequent any‐grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR‐T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic‐lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.