Hemophagocytic Syndrome Associated with CAR-T Cell Therapy
Authors: Tan Yanqing , Zhou Li , Zhai Zhimin 
Published: December 2024

Hemophagocytic lymphohistiocytosis, also known as hemophagocytic syndrome, is a rare clinical syndrome characterized by excessive inflammation due to the overproduction of cytokines in the body, leading to multiple organ and systemic involvement. The disease can be divided into two main categories, primary HLH and secondary HLH, depending on the presence of related genetic defects. Secondary HLH can occur secondary to infections, tumors, inflammation, and connective tissue diseases. In recent years, with the application of cell therapy in clinical practice, it has been found that HLH can also occur in patients who have received cell therapy. Chimeric antigen receptor T cell immunotherapy involves obtaining T cells using biotechnology methods and modifying them to express chimeric antigen receptors on their surface through processes like in vitro expansion and special cultivation. These engineered CAR-T cells become specific cytotoxic cells that, when infused back into the body, aim to treat the disease. Currently, this therapy has shown promising results in the treatment of hematologic malignancies and solid tumors. In a small number of patients, HLH-like toxicity may occur after receiving the infusion of engineered cells. The American Society for Transplantation and Cellular Therapy Expert Group has proposed the term “immune effector cell-associated HLH-like syndrome” to describe this urgent toxicity. In order to understand the incidence, mechanisms, diagnosis, and treatment of cell therapy-related HLH, we conducted a search of databases like PubMed and summarized relevant articles for review. This article mainly focuses on the incidence, mechanisms, and treatment progress of HLH associated with CAR-T cell therapy. We also searched for articles on cell therapy methods such as Chimeric Antigen Receptor Macrophage Immunotherapy, Chimeric Antigen Receptor NK Cell Immunotherapy, and T Cell Receptor Engineered T Cell Therapy for the treatment of diseases, but due to limited clinical trials conducted, there have been no reports. Patients receiving cell therapy exhibit HLH-like features, with the main clinical manifestations including fever, hepatosplenomegaly, liver function abnormalities, decreased blood cell counts, elevated triglycerides, elevated serum ferritin (≥five hundred ug/L) and decreased fibrinogen levels, with serum ferritin being the most commonly reported marker. According to the literature, the mortality rate of CAR-T cell therapy-associated sHLH/MAS is about eighty percent. Viral infection, advanced age, methemoglobinemia, and thrombocytopenia may lead to poor prognosis. The mechanisms of CAR-T cell therapy-associated HLH include: high levels of IFN-γ and IFN-γ-induced chemokines play a critical role in MAS; activated CAR-T cells release various cytokines; infections; elevated ferritin levels (&gt;ten thousand µg/L) in the patient's body serve as inflammatory mediators; and a large amount of pro-inflammatory cytokines induces a cell-driven innate immune response, establishing a positive feedback loop of inflammation. In terms of treatment, according to the survey by Sandler et al. on the use of drugs for cell therapy-related HLH at EBMT centers, common clinical combinations include corticosteroids + chemotherapy, corticosteroids + monoclonal antibodies + chemotherapy, corticosteroids + chemotherapy + cytokine blockade, corticosteroids + cytokine blockade, and corticosteroids alone. We introduce commonly used specific medications, including etoposide, emapalumab, the IL-six monoclonal antibody siltuximab, the anti-interleukin (IL)-six receptor monoclonal antibody tocilizumab, the interleukin-1 receptor antagonist anakinra, and JAK-one and JAK-two blockers such as ruxolitinib and the JAK-one inhibitor itacitinib, among others.