Chimeric antigen receptor (CAR)-T cell therapy is effective in the treatment of refractory/relapsed (r/r) hematological malignancies (r/r B-cell lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma). In addition, it is being explored as a treatment option for solid tumors. As of 31 March 2022, seven CAR-T therapies for hematological malignancies have been approved worldwide. Although CAR-T therapy is an effective treatment for many malignancies, it also causes adverse effects. The incidence of cytokine release syndrome (CRS), the most common adverse reaction after infusion of CAR-T cells, is as high as 93%.CRS, is the leading risk factor of immune effector cell-associated neurotoxicity syndrome (ICANS), as well as cardiovascular, hematological, hepatorenal, skin, pulmonary, and gastrointestinal toxicity. Severe adverse reactions complicated by CRS severely impede the widespread application of CAR-T therapy. The CAR-T product was initially approved in 2017; however, only limited studies have investigated the adverse reactions owing to CAR-T therapy compared to that of clinically approved drugs. Thus, we aimed to elucidate the mechanisms, risk factors, diagnostic criteria, and treatment of toxicities concurrent with CRS, thereby providing a valuable reference for the safe, effective, and widespread application of CAR-T therapy.

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.