CAR-T cell-associated neurotoxicity during therapy of hematologic malignancies: incidence, clinical features, predictive biomarkers and management measures

Chimeric antigen receptor T-cell therapy (CAR-T cell therapy)-associated neurotoxicity includes a range of neurological side effects following CAR-T cell infusion. While ICANS is already a well-recognized, widely described neurological complication, the spectrum of neurological toxicities associated with CAR-T cell therapy has widened to include other, less common but emerging neurotoxicity syndromes. These have been observed with its broader use and the development of new agents. Movement and neurocognitive toxicity represent a recently described and challenging syndrome associated with BCMA-directed CAR-T cell therapies. Cranial and peripheral neuropathies, as well as myelopathy have increasingly been identified. Rare forms of cerebellar toxicity have been described with under development agents as well. Furthermore, strokes or tumor inflammation-associated syndrome (TIAN) in patients with CNS disease may elicit an emergency consultation. Finally, classical forms of acute toxic leukoencephalopathy have been described in a few patients receiving fludarabine as lymphodepleting treatment before CAR-T cell infusion. These forms of neurotoxicity vary in severity, with some cases being severe and even life-threatening in the context of CAR-T cell therapy. The present review summarizes several types of neurotoxicity associated with CAR-T cell therapy in patients with hematologic malignancies, focusing on available data on incidence, clinical presentation, prediction, diagnostics and therapeutic management.