Real-world incidence of HLH-like syndromes across CAR T-cell products: A multi-institutional cohort study using the trinetx network

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH)–like syndromes are rare but potentially life-threatening complications following chimeric antigen receptor (CAR) T-cell therapy. While cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are well-established immune-related toxicities, the real-world incidence of HLH-like syndromes across different CAR T-cell products remains poorly defined. Understanding product-specific risk is critical for early recognition and timely intervention. Methods: We conducted a retrospective cohort study using the TriNetX Research Network, a federated electronic health record platform encompassing over 100 academic and community healthcare organizations. Adult patients (aged ≥18 years) who received one of four U.S. Food and Drug Administration-approved CAR T-cell therapies—axicabtagene ciloleucel (Axi-cel), tisagenlecleucel (Tisa-cel), lisocabtagene maraleucel (Liso-cel), or idecabtagene vicleucel (Ide-cel) between 2017 and 2024 were included. HLH-like syndromes were identified using ICD-10 code D76.1, occurring within 30 days of CAR T-cell infusion. The primary outcome was the product-specific 30-day incidence of HLH. Results: Among 6,234 CAR T-cell recipients, 54 patients developed HLH-like syndromes within 30 days, yielding an overall incidence of 0.87%. Product-specific rates varied notably: idecabtagene vicleucel had the highest incidence at 2.01% (10/497), followed by tisagenlecleucel at 1.91% (10/524), lisocabtagene maraleucel at 1.70% (10/588), and axicabtagene ciloleucel at 0.79% (11/1,389). An additional 13 cases occurred among patients receiving unspecified or investigational CAR T-cell therapies. The incidence of HLH-like syndromes with idecabtagene vicleucel was nearly three times that of axicabtagene ciloleucel. Due to limitations of the TriNetX platform, data on HLH severity, intensive care unit admission, or mortality were unavailable. Conclusion: In this large, multi-institutional real-world study, HLH-like syndromes were observed following all CAR T-cell products, with notable variation in incidence by agent. Idecabtagene vicleucel and tisagenlecleucel were associated with the highest 30-day HLH incidence, while axicabtagene ciloleucel had the lowest. These findings highlight the need for product-specific clinical vigilance and may inform post-infusion monitoring protocols. Further prospective studies are warranted to validate these observations, explore predictive biomarkers, and guide standardized management approaches for HLH-like syndromes in the CAR T-cell therapy setting.