Impact of cell of origin, gene rearrangements, and frontline treatment on incidence of secondary central nervous system lymphoma in newly diagnosed diffuse large B-cell lymphoma.

7052 Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2-10% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). The CNS-International Prognostic Index (CNS-IPI) is a validated tool used to assess the risk of CNS relapse. However, with advancements in molecular profiling and treatments, the predictors of SCNSL, including the predictive ability of CNS-IPI combined with other molecular markers and treatment regimens, have become uncertain. This study evaluates new prognostic markers for CNS relapse in DLBCL, focusing on cell-of-origin (COO), gene rearrangements, and treatment types. Methods: DLBCL pts enrolled from 2002-2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Pts with primary CNS lymphoma or CNS involvement at diagnosis, and pts treated with high-dose methotrexate containing regimens were excluded. COO classification (GCB vs non-GCB) was determined using Hans algorithm and/or NanoString data. Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of SCNSL. Survival analysis was performed from time of DLBCL diagnosis using Cox proportional hazards model. Results: Among 1278 newly diagnosed DLBCL pts included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) pts. Pts with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than pts without SCNSL (63.9%, p=0.02). The 3 yr SCNSL incidence was 0.016 (0.008-0.0033) in low CNS-IPI vs 0.043 (0.031-0.0060) in high CNS-IPI. Those with SCNSL were significantly more likely at baseline to have non-GCB COO (56.3% vs. 36.5%, p=0.02), and advanced stage (76.1% vs. 59.9%, p=0.03) compared to those without SCNSL. The incidence of SCNSL was not influenced by MYC, BCL2, or BCL6 rearrangements, nor by treatment with R-CHOP, R-EPOCH, or other immunochemotherapy regimens. MVA showed that intermediate CNS-IPI (HR 2.32, 95% CI 1.09-4.92, p=0.029), high CNS-IPI (HR 3.59, 95% CI 1.49-8.62, p=0.004), and non-GCB COO (HR 2.19, 95% CI 1.08-4.42, p=0.0029) were independently associated with increased SCNSL risk. After a median follow-up of 12 years (IQR 9–15), overall survival (OS) was 52.1% for the cohort, with OS significantly worse for SCNSL pts (17.4% vs. 53.4%, p&lt;0.001). Conclusions: This large cohort with extensive follow-up highlights the role of COO as an additional prognostic factor for SCNSL while reinforcing CNS-IPI’s prognostic value. Non-GCB COO pts had a higher risk of SCNSL even when adjusted by CNS-IPI risk. Despite advancements in management, SCNSL pts continue to have poor outcomes. Strategies to reduce the incidence of CNS relapse in high-risk pts require further investigation. MER CNS relapse hazard ratios (95% CI). Characteristics Hazard Ratio 95% CI P-Value CNS-IPI Group 0-1 Low Ref Ref Ref 2-3 Intermediate 2.32 1.09 - 4.92 0.029 4+ High 3.59 1.49 - 8.62 0.004 Cell of Origin* GCB Ref Ref Ref non-GCB 2.19 1.08 - 4.42 0.029 Double Hit* non-DHL Ref Ref Ref DHL 1.08 0.14 - 8.3 0.941 Not Done/Missing 1.38 0.76 - 2.51 0.297 Double Expressor* Negative Ref Ref Ref Positive 2.36 0.71 - 7.85 0.162 Not Done/Missing 1.91 0.89 - 4.08 0.097 IC Group* R-CHOP R-EPOCH Ref 1.63 Ref 0.71 - 3.74 <jats:td colspan="1" rowspan="1"