Anatomical Localization–Based Analysis of Relapsed Secondary Central Nervous System Aggressive B‐Cell Lymphoma (R‐SCNSL)

162 patients with relapsed secondary central nervous system lymphoma (R-SCNSL) (median age, 65 years; male, 59.9%) including central nervous system (CNS)-only (n = 120) and concomitant CNS/systemic relapse (n = 42) were retrospectively analyzed. Overall, 21.9% of patients were classified as high risk according to the CNS International Prognostic Index (CNS-IPI). Several biological and clinical features were significantly associated with leptomeningeal involvement, including double- or triple-hit (DHL/THL) status, MYC rearrangement, negative BCL6 expression by IHC, bone marrow involvement, and concomitant R-SCNSL. Multivariable analysis showed that leptomeningeal involvement independently predicted inferior OS and was associated with a 98% increase in the hazard of death compared with parenchymal relapse (HR = 1.98, 95% CI: 1.20-3.26, p = 0.008). Based on anatomical localization, R-SCNSL was classified into four subtypes: parenchymal-only involvement (parenchymal-CNS [P-CNS], 68/42%) and parenchymal involvement plus systemic relapse (parenchymal-concomitant [P-concomitant], 17/10.5%); and leptomeningeal with or without parenchymal involvement (leptomeningeal-CNS [LM-CNS], 52/32.1%) and leptomeningeal with systemic relapse (leptomeningeal-concomitant [LM-concomitant], 25/15.4%). This anatomical classification significantly impacted OS and PFS (p < 0.001). Two-year OS and PFS were 58.2% and 29.1% for P-CNS, 32.4% and 17.7% for P-concomitant, 22% and 13.9% for LM-CNS, and 7.1% and 0% for LM-concomitant, respectively. ASCT showed a trend toward improved survival among patients with a response (CR/PR) in a 4-month landmark analysis. These findings support the clinical application of the anatomical classification in the management of R-SCNSL.