[Management of side effects of CAR T cells]

Chimeric antigen receptor (CAR) T cell therapy has significantly improved outcomes for patients with hematological neoplasms and the approval of six CAR T cell products has led to increasing routine use; however, CAR T cell therapy is associated with specific and sometimes severe side effects, which are summarized in this article. Cytokine release syndrome (CRS) is a frequent systemic inflammatory reaction triggered by the massive release of cytokines after CAR T cell activation. The symptoms range from mild fever to multiorgan failure. The management is stepwise using tocilizumab and corticosteroids depending on the severity, with recent data supporting the use of anakinra. Further targeted therapeutic agents appear to be promising. The immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is rare compared to CRS but life-threatening and is characterized by high ferritin levels, cytopenia and organ failure. Treatment includes anakinra, dexamethasone and other salvage medications, whereby recognition of the complication is essential. Immune effector cell-associated neurotoxicity syndrome (ICANS) is comparatively frequent, presenting with symptoms such as confusion, speech disturbances or seizures. The treatment depends on the severity and usually involves corticosteroids, anakinra and other immunosuppressants. Besides ICANS, a heterogeneous group of rarer neurological complications can also occur, which are often difficult to treat and not yet fully understood. Hematotoxicity with prolonged cytopenia (immune effector cell-associated hematotoxicity, ICAHT) is an increasingly recognized complication and its risk can be estimated before lymphocyte depletion using a simple score. Prolonged cytopenia substantially increases the risk of infections and explains why infections are the most frequent non-disease-related cause of death after CAR T cell treatment. In summary, since the first approval the management of CAR T cell-related side effects has markedly improved through a better understanding of the pathophysiology, identification of risk factors and especially early intervention strategies.