Comparative pharmacovigilance signals for PD-1,PD-L1,CTLA-4,and LAG-3 immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis in the FAERS database

Abstract

Background

Hemophagocytic lymphohistiocytosis (HLH) is a fulminant, hyperinflammatory syndrome increasingly recognized as a rare but devastating immune checkpoint inhibitors (ICI) toxicity. Given the lack of robust epidemiological data, a large-scale pharmacovigilance analysis was performed to characterize HLH reporting patterns across distinct ICI classes.

Methods

The FDA Adverse Events Reporting System (FAERS) was queried to identify HLH cases associated with FDA-approved PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors from Q4 2003  through Q3 2025. Disproportionality analysis was conducted to quantify safety signals relative to the full database.

Results

All major ICI classes were associated with HLH, with PD-L1 inhibitors (particularly atezolizumab) and CTLA-4 inhibitors showing the strongest signals; no single agent class appeared to be spared. Among PD-1 inhibitors, pembrolizumab exhibited the highest burden (n = 120; ROR 9.51, 95% CI 7.93–11.40), while cemiplimab demonstrated a high point estimate (ROR 10.56). In the PD-L1 class, atezolizumab showed the strongest signal among widely used agents (n = 76; ROR 14.48, 95% CI 11.54–18.18). The CTLA-4 inhibitor ipilimumab yielded substantial disproportionality (n = 54; ROR 12.77, 95% CI 9.76–16.70), and the LAG-3 inhibitor relatlimab showed a comparable signal (ROR 12.64) despite limited case numbers.

Conclusions

This analysis confirms HLH as a significant class-wide toxicity of immune checkpoint blockade, with robust safety signals observed for pembrolizumab, atezolizumab, and ipilimumab. These findings underscore the critical need for heightened clinical vigilance and rapid diagnostic evaluation for HLH in patients presenting with hyperinflammatory symptoms during immunotherapy.