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IMPACT OF CELL OF ORIGIN, GENE REARRANGEMENTS, FRONTLINE TREATMENT ON INCIDENCE OF CENTRAL NERVOUS SYSTEM LYMPHOMA RELAPSE IN NEWLY DIAGNOSED LARGE B‐CELL LYMPHOMA
Abstract   Peer reviewed

IMPACT OF CELL OF ORIGIN, GENE REARRANGEMENTS, FRONTLINE TREATMENT ON INCIDENCE OF CENTRAL NERVOUS SYSTEM LYMPHOMA RELAPSE IN NEWLY DIAGNOSED LARGE B‐CELL LYMPHOMA

A. S. Falade, R. Mwangi, P. J. Hampel, S. A. Mina, J. Paludo, S. S. Zanwar, E. Mou, X. Andrade-Gonzalez, G. Thanarajasingam, A. J. Novak, …
Hematological oncology, Vol.43(S3)
06/2025
DOI: 10.1002/hon.70094_307

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Abstract

Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2%–10% of patients 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 patients enrolled from 2002 to 2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Patients with primary CNS lymphoma or CNS involvement at DLBCL diagnosis, and patients treated with high-dose methotrexate containing regimens were excluded. COO was classified into GCB versus non-GCB subtypes 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 diagnosis using Cox proportional hazards. Results: A total of 1278 newly diagnosed DLBCL patients were included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) patients. Patients with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than patients without SCNSL (63.9%), p = 0.02., with a 3 yr SCNSL incidence of 0.016 (0.008–0.0033) in low CNS-IPI versus 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), higher BCL2 expression (39.1% vs. 25.4%, p = 0.02), advanced stage (76.1% vs. 59.9%, p = 0.03), and elevated LDH (73.7% vs. 56.0%, p = 0.02) 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 indicated that only 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. At a median follow-up of 12 yrs (IQR 9–15) from diagnosis, overall survival (OS) for the entire cohort was 52.1%; 17.4% for patients with SCNSL versus 53.4% for patients without SCNSL, p < 0.001. Conclusions: This large cohort study underscores the prognostic importance of COO in predicting SCNSL risk, alongside CNS-IPI. Non-GCB COO independently increases SCNSL risk even after adjusting for CNS-IPI. Despite advancements in treatment, pts with SCNSL have poor outcomes. Future strategies to mitigate CNS relapse in high-risk pts, including tailored surveillance and prevention, warrant further investigation.

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