Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains one of the most clinically significant and potentially life-threatening toxicities, limiting the broader applicability of this otherwise promising modality. Current standard-of-care (SOC) management of ICANS relies heavily on corticosteroids, which are not always effective and at high doses and with prolonged exposure may carry substantial risks for infectious complications, steroid-induced hyperglycemia, acute steroid myopathy, and steroid-induced psychosis. Steroid-sparing strategies are thus urgently needed. In this article, we emphasize the role of immune cell activation and mitochondrial dysfunction as a feedforward amplifier of neuroinflammation during ICANS and describe a structured framework for identifying and selecting mitochondrial-targeting drugs suitable for repurposing in ICANS prophylaxis and treatment. These agents are recommended based on mechanistic relevance, central nervous system bioavailability, oncological safety, and translational precedent. We apply this framework to generate a candidate landscape and highlight leflunomide as a prototype example. This work details leflunomide's dihydroorotate dehydrogenase-centered mitochondrial pharmacology, summarizes evidence from adjacent neuroinflammatory disease contexts, and outlines a proposed staged clinical evaluation pathway.