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

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 (IC₀₂₅ , 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, IC₀₂₅  = 4.24), neurological disorders (n = 963, IC₀₂₅  = 2.42), hematological disorders (n = 532, IC₀₂₅  = 3.32), infections (n = 287, IC₀₂₅  = 2.38), cardiovascular disorders (n = 256, IC₀₂₅  = 2.81), pulmonary disorders (n = 186, IC₀₂₅  = 3.80), reno-metabolic disorders (n = 123, IC₀₂₅  = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC₀₂₅  = 5.01) and hepatic disorders (n = 32, IC₀₂₅  = 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.