Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.

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