A Real-World (RW) Analysis of the Relationship between Epstein-Barr Virus (EBV) Positivity and Baseline Characteristics, Treatment Patterns and Clinical Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL)

Background: EBV-positive DLBCL (EBV+ DLBCL) constitutes < 5% of all large B-cell lymphomas (LBCL) in the United States (US). Multiple retrospective studies regarding characteristics and outcomes of EBV+ DLBCL in the US have shown inconsistent results, due to limited number of patients (pts). The aim of this study is to conduct a comprehensive comparative analysis of clinical and socioeconomic characteristics, treatment patterns and clinical outcomes between newly diagnosed and relapsed/refractory (R/R) EBV+ DLBCL and DLBCL not otherwise specified (NOS) by leveraging the nationwide Flatiron Health electronic record-derived de-identified database.

Methods: EBV+ DLBCL was defined by positive EBER staining of malignant lymphocytes confirmed via abstraction. Adult pts with DLBCL NOS or EBV+ DLBCL diagnosed between 01/2011 and 05/2024, ≥ 2 EHR-documented visits, ≥1 line of systemic therapy and ≥ 12 months of potential follow-up were included in the analysis. Pts were excluded if they had HIV infection, BCL2 and MYC rearrangements, history of indolent lymphoma, other LBCL types, or transplant prior to systemic therapy. Demographic and clinical characteristics were compared at the first line (1L) initiation, including age, sex, race/ethnicity, insurance, socioeconomic status index, ECOG performance status, group stage at diagnosis, involvement of extranodal sites, radiotherapy, CNS involvement, and lactate dehydrogenase level. The Kaplan-Meier method and log-rank tests were used to estimate median real-world overall survival (rwOS) and time to next treatment (rwTTNT) by disease types in both 1L and 2L. For each line of therapy (1L, 2L), multivariable Cox proportional hazards models were used to assess the association between disease types and outcomes, adjusting for the demographic and clinical characteristics described above and transplant as a time-varying covariate.

Results: Of 5,919 pts included in the analysis, 202 pts had EBV+ DLBCL and 5,717 pts had DLBCL NOS. Demographics and most of clinical characteristics were similar between disease groups at 1L. Pts with EBV+ DLBCL were more likely to have CD30 positivity (37% vs 8.4%) and be treated at academic centers (32% vs 20%), but less likely to have early stage disease (21% vs 31%) and receive radiotherapy as part of initial treatment (16% vs 22%).

The most common systemic treatment at 1L among both EBV+ DLBCL and DLBCL NOS pts was chemotherapy and anti-CD20 combination therapy (CIT) (82% and 92%, respectively) followed by anti-CD20 monotherapy (7.9% and 3.1%, respectively). Only 35% of EBV+ DLBCL pts and 27% of DLBCL NOS pts received 2L therapy, and 12% in both groups received 3L therapy. CIT remained the most common treatment strategy in R/R pts with EBV+ DLBCL and DLBCL NOS (50% vs 56% at 2L and 24% vs 31% at 3L, respectively). In R/R EBV+ DLBCL, utilization of anti-CD30 based therapy was limited (<3%). Proportions of R/R pts who received chimeric antigen receptor therapy or transplant remained less than 10% in both groups at 2L and 3L.

The median follow up for the entire cohort was 34 months (IQR; 12-68 months). The median rwTTNT from 1L initiation was 29.7 months (95% CI: 18.6 - 47.7) in EBV+DLBCL, compared to 62.1 months (95% CI: 56.6 - 66.6) in DLBCL NOS. The association remained significant after adjusting for other covariates (adjusted HR [aHR]: 1.41; 95% CI: 1.18 - 1.69; p<0.001). Similarly, pts with EBV+ DLBCL had a median rwOS of 69.5 months at 1L (95% CI: 53.5 - 95.3), compared to 96.8 months among those with DLBCL NOS (95% CI: 91.6 - 100.5). EBV+ DLBCL had higher hazards of death, compared to DLBCL NOS in the adjusted analysis (aHR: 1.43; 95% CI: 1.16 - 1.76; p<0.001). From 2L initiation, EBV+ DLBCL had a median rwTTNT of 5.3 months (95% CI: 4.1 - 23.5) and a median rwOS of 17.9 months (95% CI: 12.5 - NA), compared to 8.8 months (95% CI: 8.0 - 9.7) and 30.2 months (95% CI: 24.8 - 35.5) respectively for DLBCL NOS. However, these differences were not statistically significant between the disease groups (aHR for rwTTNT: 1.05; 95% CI: 0.78-1.41; aHR for rwOS: 1.12; 95% CI: 0.87 -1.69).

Conclusion: In this large cohort of pts with DLBCL, baseline characteristics were comparable between pts with EBV+ DLBCL and DLBCL NOS. Newly diagnosed pts with EBV+ DLBCL were treated in similar ways as pts with DLBCL NOS but had significantly worse survival outcomes. These findings highlight the need for better therapeutic strategies to improve survival in EBV+ DLBCL.