Neurotoxicity and cognitive outcomes in modern therapies for primary central nervous system lymphoma

PURPOSE OF REVIEW: Improved survival in primary CNS lymphoma (PCNSL) has increased the importance of delayed treatment-related neurotoxicity as a determinant of functional outcome and quality of life. This review summarizes contemporary evidence on neurocognitive outcomes across modern therapies and discusses the challenge of distinguishing neurotoxicity from relapse. RECENT FINDINGS: Neurotoxicity differs by treatment modality. Consolidation whole-brain radiotherapy (WBRT) after high-dose methotrexate-based induction remains most strongly associated with delayed cognitive decline, white matter injury, and cerebral atrophy. High-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) in fit patients and low-dose WBRT are effective consolidation strategies with better cognitive preservation. CAR T-cell therapy has introduced distinct inflammatory syndromes usually reversible, including immune effector cell-associated neurotoxicity syndrome (ICANS) characterized by stereotyped cognitive dysfunctions and tumor inflammation-associated neurotoxicity (TIAN), which can mimic focal progression. Bispecific antibodies' neurotoxicity profile resembles to that of CAR T-cell therapy with a lower rate of ICANS. Multimodal monitoring using neuropsychological testing, advanced neuroimaging, cerebrospinal fluid biomarkers, and circulating tumor DNA may improve diagnostic accuracy. SUMMARY: Future therapeutic progress in PCNSL should prioritize prediction, early detection, and prevention of neurotoxicity alongside disease control.