Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome

• Published in: Transplantation and cellular therapy Vol. 29; no. 7; pp. 438.e1 - 438.e16
• Main Authors: Hines, Melissa R., Knight, Tristan E., McNerney, Kevin O., Leick, Mark B., Jain, Tania, Ahmed, Sairah, Frigault, Matthew J., Hill, Joshua A., Jain, Michael D., Johnson, William T., Lin, Yi, Mahadeo, Kris M., Maron, Gabriela M., Marsh, Rebecca A., Neelapu, Sattva S., Nikiforow, Sarah, Ombrello, Amanda K., Shah, Nirav N., Talleur, Aimee C., Turicek, David, Vatsayan, Anant, Wong, Sandy W., Maus, Marcela V., Komanduri, Krishna V., Berliner, Nancy, Henter, Jan-Inge, Perales, Miguel-Angel, Frey, Noelle V., Teachey, David T., Frank, Matthew J., Shah, Nirali N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023
• Subjects: Adult; Child; Chimeric antigen receptor T cell; Cytokine Release Syndrome - complications; Cytokine Release Syndrome - therapy; Hemophagocytic lymphohistiocytosis; Humans; Immunotherapy, Adoptive - adverse effects; Lymphohistiocytosis, Hemophagocytic - etiology; Lymphohistiocytosis, Hemophagocytic - therapy; Macrophage activation syndrome; Neurotoxicity Syndromes - etiology; T-Lymphocytes; United States; United States; Hemophagocytic lymphohistiocytosis; Chimeric antigen receptor T cell; Macrophage activation syndrome
• ISSN: 2666-6367; 2666-6375; 2666-6367
• DOI: 10.1016/j.jtct.2023.03.006

•Hemophagocytic lymphohistiocytosis (HLH)-like toxicities occur after CAR T-cells•This is now termed immune effector cell (IEC) associated HLH-like syndrome (IEC-HS)•Independent of cytokine release syndrome (CRS) and neurotoxicity, IEC-HS can be fatal•Consensus for identification and grading of IEC-HS has been developed by experts•Treatment, supportive care, and future research are imperative to improving outcomes of IEC-HS T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term “immune effector cell-associated HLH-like syndrome (IEC-HS)” to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.