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

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.

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.

Future therapeutic progress in PCNSL should prioritize prediction, early detection, and prevention of neurotoxicity alongside disease control.