Objectives: Immune effector cell-associated neurotoxicity syndrome (ICANS) is typically a monophasic condition with a variable onset after chimeric antigen receptor T-cell (CAR T-cell) therapy. We report an exceedingly rare case of late-onset ICANS relapse, highlighting challenges in its recognition and management. Methods: A patient receiving CAR T-cell therapy for large B-cell lymphoma was monitored for neurotoxicity. Clinical, neuroimaging, and laboratory evaluations were performed to assess symptom progression and guide treatment. Results: The first ICANS episode occurred 14 days after infusion, presenting as grade 4 ICANS with coma, requiring intubation and intensive care. The patient was treated with methylprednisolone and anakinra, resulting in full recovery. A second episode occurred on day 40, characterized by disorientation, confabulation, and focal seizures (grade 3 ICANS). Treatment with levetiracetam, anakinra, and dexamethasone led to resolution. Discussion: This case highlights the potential for delayed ICANS relapse beyond typical time frames, underscoring the need for prolonged monitoring. These findings support a possible biphasic course of ICANS, warranting further research on its pathophysiology and optimal long-term management.
