Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS): A Review of Pharmacovigilance
Authors: Ebinama Ugochi , Prakash Rishab , Strati Paolo , Ahmed Sairah , Adkins Sherry , Srour Samer A. , Wang Michael L. , Jain Preetesh , Shpall Elizabeth J. , Lionel Anath , Lui Meng , Neelapu Sattva S. , Patel Krina K. , Iyer Swami P. 
Published: December 2023

Background: CAR-T cell therapies have revolutionized cancer therapeutics with durable responses in hematologic malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are well-established off-target effects of CAR-T therapy. Immune effector cell (IEC) therapy can result in hemophagocytic lymphohistiocytosis (HLH)-like events, which are now understood as separate entities. Rare and fatal, HLH is characterized by abnormal activation of natural killer (NK) cells, macrophages, and cytotoxic T-lymphocytes; this leads to supraphysiologic production of cytokines and immune-mediated organ system damage. Expert consensus review defines IEC-HS as the development of pathologic features of HLH/macrophage activation independent from CRS and ICANS attributed to IEC therapy, including new onset or worsening cytopenia, hyperferritinemia (&gt;2 times the upper limit of normal), coagulopathy with hypofibrinogenemia, and elevated transaminases. Few clinical studies have shown IEC-HS in Acute Lymphocytic Leukemia (ALL), especially in the pediatric and adolescent populations. However, the incidence and risk of IEC-HS exposure to CD19 and BCMA CAR-T are yet to be determined in B-cell lymphomas and Myelomas. The FDA Adverse Event Reporting System (FAERS) contains circumstantial case reports and serious post-CAR-T therapy IEC-HS. This retrospective analysis from the FAERS aims to address these questions and estimate the risk of IEC-HS with CAR-T cell therapies.
Methods: FAERS is a publicly accessible database of adverse event reports associated with various therapies, including CAR-T cell therapies. To estimate the risk of HLH-like syndrome associated with CAR-T treatment, we analyzed the reporting of four CD19 CAR-T therapies (Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel) and BCMA CAR-T (Idecabtagene Vicleucel) from the database between 2016 and 2023. Statistical analysis involved a disproportionality analysis using a reported odds ratio (ROR). OpenVigil, a software package used to analyze pharmacovigilance data, enabled the calculation of the ROR with a 95% confidence interval (CI). ROR greater than one, p&lt;0.05, and a confidence interval not including one was considered significant.
Results: Between 2016 and April 2023, the FAERS database recorded 8,302 CD19 CAR-T therapies (axicabtagene ciloleucel, n = 4,496; brexucabtagene autoleucel, n = 713; tisagenlecleucel n = 27,51; lisocabtagene maraleucel; n = 342) and 472 BCMA CAR-T therapies, Idecabtagene Vicleucel. We identified 177 reported HLH events as the primary events in patients receiving CAR-T therapies (CD19 CAR-T n = 165; BCMA n = 12). Thirty-six (20.3%) were reported as single IEC-HS, 96 (54.2%) as combined IEC-HS and CRS, 9 (5.1%) as combined IEC-HS and ICANS, and 36 (20.3%) as having all three IEC-related toxicities. The median age was 57 (4-89) years, and males &gt; females at a ratio of 2:1. The study's limitation is that medical personnel reported most of the adverse events (n = 166 of 177 [94%]), and it is unclear if the diagnosis of IEC-HS followed current diagnostic criteria. The CD19 CAR-T was primarily associated with B-cell lymphomas (n = 104, 60.0%), followed by R/R ALL (n= 39, 22.0%) and Chronic Lymphocytic Leukemia, CLL (n = 3, 1.7%). Their combined elevated risk for IEC-HS was greater than that of patients in the database who had not been exposed [ROR, 63.6; 95% CI 54.7-74.1] [p&lt;0.001]. In addition, we conducted a stratified analysis for each drug. Tisagenlecleucel had the highest risk for IEC-HS among the CD19 CAR-T drugs [ROR, 82.3; 95% CI 65.5-104.0] [p&lt;0.001]. The risk was also significant with Idecabtagene Vicleucel [ROR, 73.5; 95% CI 41.4-130.5]. Overall, the results of the study indicate a strong association between CAR-T cell therapy exposure and IEC-HS.
Conclusion: CAR-T cell therapy poses a risk for rare IEC-HS, CRS, and ICANS, necessitating early detection to minimize morbidity and mortality. The study's results will be compared to the institutional patient cohort for annual meeting. Understanding factors contributing to this rare complication is crucial for optimizing patient outcomes and ensuring safe CAR T cell therapy use.