Real-world Hepatobiliary Toxicity After Bispecific T-Cell Engager Therapy: A 10-Year Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System and the World Health Organization's Global Individual Case Safety Report Database.

Abstract

Purpose: Relapsed/refractory hematological malignancies increasingly utilize bispecific T-cell engagers (BiTEs), yet their postmarketing hepatobiliary toxicity profiles remain inadequately characterized. This study aimed to bridge this knowledge gap by conducting the first comprehensive pharmacovigilance analysis of BiTE-associated hepatobiliary toxicity using real-world data from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the World Health Organization's global Individual Case Safety Report database (VigiBase).

Methods: Hepatobiliary reports were extracted from patients with hematological malignancy deposited in FAERS and VigiBase (2015-2024). Disproportionality analyses, multivariate logistic regression analyses, and time-to-onset analyses were employed to identify safety signals across CD19, non-CD19-targeting BiTE, and non-BiTE receivers, characterize hepatobiliary toxicity, and assess their impact on patients' survival.

Findings: Sixteen safety signals emerged, including four previously under-reported adverse events beyond package insert documentation: ascites, hepatobiliary disease, graft-versus-host disease in liver, and veno-occlusive liver disease. This analysis revealed that non-CD19 BiTEs were relatively safe in terms of hepatobiliary toxicities, whereas CD19 BiTE receivers had significantly earlier hepatobiliary toxicity onset (median: 6 vs 14 days; P = 0.002) and higher mortality rate compared with non-BiTE users (OR_FAERS = 3.28 [2.8-3.82]; P_FAERS = 2.05E-16; OR_VigiBase = 3.13 [2.60-3.76]; P_VigiBase = 2.0E-16).

Implications: These real-world insights complement clinical trial data; however, the disproportionality analyses employed are susceptible to reporting and utilization biases due to the lack of denominator data. The reported odds ratios and significance should be interpreted as measures of reporting association rather than true risk.