Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic
malignancies. Two CAR T-cell products are now approved for clinical use by the U.S.
FDA: tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse
large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR
T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical
activity has been generated. A barrier to widespread use of CAR T-cell therapy is
toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity. Manifestations
of CRS include fevers, hypotension, hypoxia, end organ dysfunction, cytopenias, coagulopathy,
and hemophagocytic lymphohistiocytosis. Neurologic toxicities are diverse and include
encephalopathy, cognitive defects, dysphasias, seizures, and cerebral edema. Our understanding
of the pathophysiology of CRS and neurotoxicity is continually improving. Early and
peak levels of certain cytokines, peak blood CAR T-cell levels, patient disease burden,
conditioning chemotherapy, CAR T-cell dose, endothelial activation, and CAR design
are all factors that may influence toxicity. Multiple grading systems for CAR T-cell
toxicity are in use; a universal grading system is needed so that CAR T-cell products
can be compared across studies. Guidelines for toxicity management vary among centers,
but typically include supportive care, plus immunosuppression with tocilizumab or
corticosteroids administered for severe toxicity. Gaining a better understanding of
CAR T-cell toxicities and developing new therapies for these toxicities are active
areas of laboratory research. Further clinical investigation of CAR T-cell toxicity
is also needed. In this review, we present guidelines for management of CRS and CAR
neurotoxicity.