Clinical Outcomes of EBV-Positive Compared to EBV-Negative Diffuse Large B Cell Lymphoma in the Modern Era

Background

Epstein-Barr Virus (EBV) is an oncogenic virus associated with lymphoid malignancies including diffuse large B-cell lymphoma (DLBCL). EBV positive DLBCL has been associated with a worse prognosis compared to EBV negative DLBCL when chemotherapy alone was the mainstay of treatment (Park et al, Blood 2007; Okamoto et al, Hematological Oncology 2017). In the modern era with the availability of novel drugs and non-chemotherapy based approaches in the relapsed/refractory setting, it is unknown whether the prognosis of EBV positive DLBCL is still worse than that of EBV negative DLBCL.

Methods

We retrospectively analyzed patient and disease characteristics, treatment patterns, and clinical outcomes in adults diagnosed with DLBCL who received treatment between 1/1/2017 and 4/15/2023. This time period reflects the FDA approvals of chimeric antigen receptor (CAR) T- cell therapy, tafasitamab, loncastuximab, and polatuzumab vedotin. Bruton tyrosine kinase inhibitors were also routinely available. Only patients with known Epstein-Barr encoding region in situ hybridization (EBER ISH) results on pathology were included. Primary outcomes included progression free survival (PFS) and overall survival (OS). Demographic and disease characteristics were compared by EBER status. Overall (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups. A Cox proportional hazards model was used to estimate the association of EBER status and response with survival.

Results

213 DLBCL patients were included in the study, of whom 52 patients (24.4%) had EBV positive DLBCL based on EBER ISH positivity. There were no significant differences in patient characteristics (age, race, ethnicity, sex) or ECOG performance status between those with EBV positive and negative DLBCL. Patients with EBER positivity more often had solid organ transplant (SOT) or autoimmune disorders compared to those with EBER negativity (both p<0.05). Of the 138 patients with known DLBCL molecular subtype, 65 of EBV negative cases and 5 of EBV positive cases were germinal center B cell-like (p=0.002).

149/161 (92.5%) EBV negative DLBCL patients had chemotherapy in first line, compared to 40/52 (76.9%) in the EBV positive group (p=0.009). EBER negative patients appeared to have higher rates of complete (72.7% vs. 63.5%) and partial response (18% vs 15.4%), and lower rates of progressive disease (3.7% vs. 5.8%), however these differences did not reach statistical significance (p=0.12). 62/213 (29.1%) patients received a novel therapy at some point during treatment course and there were no differences in the rate of receipt of novel therapy as first line treatment (p=0.75) or subsequent lines of treatments (p=0.84) for EBER positive vs negative patients.

With median follow up of 54.5 months, unadjusted OS and PFS were similar between EBER groups (5-year OS: EBER-positive 47.6% vs. EBER-negative 59.8%, log-rank p=0.23; 5-year PFS: EBER-positive 43% vs. EBER-negative 49.9%, log-rank p=0.28). After adjustment for response to first-line treatment, EBER status is not associated with overall survival (p=0.45). After adjustment for EBER status, response to first line treatment is associated with overall survival (p<0.001). Progressive disease and partial response are associated with an increased risk of death compared to complete response (HR= 11.127, 95% CI 2.130-9.453, HR=3.832, 95% CI 2.285-6.427, respectively). Additionally, the EBER*response interaction was not significant (p=0.92), indicating that the association of response with OS does not vary based on EBER status.

Conclusions

While EBV positive DLBCL has historically been associated with worse outcomes compared to EBV negative DLBCL, our findings show that PFS and OS are similar in EBER positive and negative patients in the modern era. Although novel agents and CAR T therapy are a welcome addition to the armamentarium in the treatment of relapsed refractory DLBCL, these data suggest that response to first line treatment remains a key factor in determining survival outcomes. Additionally, EBV positivity itself does not represent an additional risk factor despite its association with history of SOT and autoimmune disease. Future studies are needed to examine the prognostic impact of EBV in DLBCL in specific patient populations such as the elderly, transplant recipients and those with autoimmune disease.