Concurrent viral infection as an adverse prognostic factor in diffuse large B-cell lymphoma, not otherwise specified

Abstract Background and Objectives Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, exhibits high clinical prognostic heterogeneity. Patients receiving first-line standard R-CHOP immunochemotherapy show significant prognostic variability: 50%–60% achieve cure, while 40%–50% present with relapsed/refractory disease or die from early progression. Adverse factors associated with DLBCL prognosis mainly include the following categories: Clinical factors: high-risk International Prognostic Index, involvement of special sites such as the central nervous system, and primary refractory to first-line therapy. Molecular subtype factors: subtypes such as MCD, N1, C3, and C5, which are adverse prognostic factors independent of clinical characteristics. Viral infection factors: most notably Epstein-Barr virus (EBV) infection. The 2022 WHO classification of lymphomas has defined DLBCL with positive expression of EBV-encoded small RNA in pathological cells as an independent subtype, “EBV-positive DLBCL (EBV+DLBCL)”. This subtype responds poorly to standard chemotherapy, with a significantly reduced 5-year overall survival rate (65.3% vs. 82.6%). Currently, research on the prognosis of DLBCL patients with concurrent viral infection remains limited. Based on this, this study retrospectively analyzed the clinical data of newly diagnosed DLBCL patients treated at our center over the past 5 years. Methods This retrospective study included newly diagnosed patients with DLBCL NOS, who were treated in the Department of Hematology, The First Hospital of Jilin University, from January 2018 to December 2023. The inclusion criteria were as follows: age ≥ 18 years (no gender restriction); pathologically confirmed DLBCL NOS; no prior history of anti-tumor therapy. Exclusion criteria included: diagnosis of EBV+DLBCL, primary mediastinal large B-cell lymphoma, or DLBCL involving immunoprivileged sites; fewer than 2 completed treatment courses; concurrent hepatitis infection with progression to hepatitis-induced cirrhosis; history of other malignant tumors or solid organ transplantation. Results This study analyzed the clinical characteristics of 727 newly diagnosed patients with DLBCL NOS, among whom 161 (22.1%) had concurrent viral infections. Specifically, the infections included: 66 cases of HBV infection, 50 cases of EBV infection, 29 cases of HCV infection, 4 cases of HIV infection, 3 cases of CMV infection, and 5 cases of co-infection with two or more viruses. Comparison of clinical characteristics showed that in patients with concurrent viral infections, the proportions of Ann Arbor stage Ⅲ–Ⅳ (69.6% vs. 57.4%, P=0.005), elevated lactate dehydrogenase (53.4% vs. 44%, P=0.034), and elevated β2-microglobulin (52.2% vs. 42.9%, P=0.038) were significantly higher. These findings suggest that such patients have higher tumor burden and may have a poorer prognosis. After screening based on the aforementioned inclusion and exclusion criteria, 607 patients were included in survival and prognostic analyses, with 474 patients without concurrent viral infections and 133 with concurrent viral infections (including 57 cases of HBV infection, 43 cases of EBV infection, 22 cases of HCV infection, 3 cases of CMV infection, 2 cases of HIV infection, and 6 cases of co-infection with two or more viruses). At a median follow-up of 29.4 months, the median progression-free survival (PFS) was not reached in the non-viral infection group versus 59.4 months in the viral infection group (P=0.0006), and median overall survival (OS) was not reached in either group (P<0.0001). The 3-year PFS rates were 66.2% and 56.4% in the two groups, respectively, and the 3-year OS rates were 76.7% and 69.1%, respectively. Multivariate Cox regression analysis showed that concurrent viral infection was an independent adverse prognostic factor affecting PFS (HR=1.823, 95% CI: 1.308–2.539, P<0.001) and OS (HR=2.127, 95% CI: 1.405–3.213, P<0.001) in DLBCL NOS patients. Conclusion DLBCL NOS patients with concurrent viral infections exhibit clinical characteristics of advanced disease stage and high tumor burden, with significantly poorer prognosis. Concurrent viral infection is one of the important independent adverse prognostic indicators in DLBCL NOS patients. Such patients should receive high attention from clinicians, and novel therapeutic strategies urgently need to be explored to improve their prognostic outcomes.