Hemophagocytic Lymphohistiocytosis Associated with Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of Spontaneous Reports

Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome increasingly reported with immune checkpoint inhibitors (ICIs). However, comparative real-world data across different ICI classes and treatment strategies are limited. This study aimed to characterize HLH reporting patterns associated with ICIs and to compare disproportionality signals among PD-1 inhibitors, PD-L1 inhibitors, and combination regimens using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A retrospective pharmacovigilance analysis was performed using FAERS reports submitted between 2013 and 2025. HLH-related cases were identified using core Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms. Reporting odds ratios (RORs) with 95% confidence intervals (Cis) were calculated to assess disproportionality across ICI treatment strategies, with ICI monotherapy as the reference. Restricted analyses compared PD-1 inhibitors, PD-L1 inhibitors, and ICI plus CTLA-4 inhibitor therapy. Results: A total of 733 HLH-related reports associated with ICIs were identified. The median age was 65 years (range 1–92), and 54.9% of patients were male. Lung cancer (34.4%) and melanoma (16.0%) were the most frequently reported malignancies. ICI monotherapy accounted for 34.7% of cases, while combination regimens included ICI plus chemotherapy (31.6%), ICI plus targeted therapy (17.8%), and ICI plus CTLA-4 inhibitors (15.9%). All cases were classified as serious adverse events; hospitalization occurred in 69.2% and death in 25.1%. Compared with monotherapy, combination regimens showed higher reporting odds of HLH, with the strongest signal for ICI plus targeted therapy (ROR 2.17, 95% CI 1.72–2.73). PD-1 inhibitors demonstrated higher reporting odds than PD-L1 inhibitors (ROR 1.86, 95% CI 1.41–2.46). Conclusions: This large real-world pharmacovigilance analysis demonstrates differential HLH reporting patterns across ICI classes and treatment strategies. Higher reporting odds with combination regimens and PD-1 inhibitors highlight the need for heightened clinical vigilance, particularly in combination treatment settings.