Translating advances in primary central nervous system lymphoma: from prognostic stratification to treatment innovation.

Primary central nervous system lymphoma (PCNSL) is a rare but aggressive diffuse large B-cell lymphoma confined to the CNS, characterized by unique clinical behavior and therapeutic challenges. Outcomes have improved with high-dose methotrexate (HD-MTX)-based regimens, but relapse, treatment toxicity, and age-related frailty remain major barriers. This review synthesizes advances in prognostic stratification and treatment of PCNSL. We highlight two validated clinical models (IELSG and MSKCC) and emerging genomic biomarkers that refine risk assessment. HD-MTX-based induction (MTR, R-MPV, MATRix, R-MBVP) is the standard first-line approach for fit patients, including many older adults. Consolidation with thiotepa-based high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) yields durable disease control in eligible patients, whereas non-myeloablative cytarabine-based chemotherapy or reduced-dose whole-brain radiotherapy remains an option for those unfit for transplant. In relapsed disease, methotrexate rechallenge benefits prior responders, while BTK- or IMiD-based regimens, CAR-T therapy, and focal or whole-brain radiotherapy are under active investigation. Maintenance with HD-MTX or targeted agents shows promise but requires validation. Although therapeutic outcomes have steadily improved, particularly with HD-MTX-based induction and HDC-ASCT consolidation, long-term survival for elderly and relapsed patients remains unsatisfactory. The integration of molecular biomarkers, neurotoxicity-sparing consolidation, and novel immunotherapies may further individualize treatment and improve the durability of remission.