Clinical Significance of Epstein-Barr Virus in Peripheral T-Cell Lymphoma, Not Otherwise Specified

Introduction: The prognostic implication of Epstein-Barr virus (EBV) in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is unclear. This study aimed to identify its clinical impact on survival outcomes in newly diagnosed patients with PTCL-NOS.

Methods: Between January 2007 and March 2020, 145 patients were newly diagnosed with PTCL-NOS at Asan Medical Center, Seoul, Korea. A total of 131 patients who underwent baseline blood real-time polymerase chain reaction (PCR) for EBV-DNA were included in this analysis. Real-time blood PCR for EBV-DNA was performed using whole blood (WB) or plasma samples prior to treatments. All patients were tested for WB EBV-DNA, of which 52 were also tested for plasma EBV-DNA. In addition, the presence of EBV was assessed by EBV-encoded small RNA (EBER) in situ hybridization (ISH) in tissue samples from 121 patients. Progression-free survival (PFS) was defined as time from the date of diagnosis to disease progression or death of any cause, and overall survival (OS) was defined as time from the date of diagnosis to death of any cause. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test.

Results: The median age at diagnosis was 60 years (range, 19-86 years), 84 patients (64.1%) were male, and 108 patients (82.4%) had advanced stage diseases (stage III or IV). A total of 55 patients (42.0%) were positive for WB EBV-DNA in the entire cohort (n=131), 9 patients (17.3%, 9/52) were positive for plasma EBV-DNA, and 59 patients (48.8%, 59/121) were positive for EBER ISH. Among 52 patients who were tested for both WB and plasma PCR, 16 patients (30.8%) showed discordant results, all of them with positive results for WB PCR but negative results for plasma PCR. There was no significant difference in baseline characteristics between EBV positive and negative groups according to WB EBV-DNA (n=131) and EBER ISH (n=121), while higher proportion of patients with positive plasma EBV-DNA had bone marrow involvement (77.8% vs. 23.3%, p = 0.003) and thrombocytopenia (37.5% vs. 7.5%, p = 0.050) compared to patients with negative plasma EBV-DNA. With a median follow-up duration of 80.5 months (95% confidence interval [CI], 63.8-130), the median PFS and OS of the entire cohort were 8.1 months (95% CI, 5.8-10.2) and 18.6 months (95% CI, 13.1-28.0), respectively. Patients with positive WB EBV-DNA showed worse PFS compared to those with negative WB EBV-DNA (median, 5.0 vs. 9.6 months, p = 0.046), although there was no significant difference in OS (positive vs. negative: median, 13.0 vs. 20.8 months, p = 0.337). There was no significant difference in survival outcomes according to positivity of EBER ISH (positive vs. negative: median PFS, 6.7 vs. 9.7 months, p = 0.389; median OS, 15.7 vs. 21.2 months, p = 0.565) or plasma EBV-DNA (positive vs. negative: median PFS, 5.4 vs. 9.3 months, p = 0.268; median OS, 13.3 vs. 30.5 months, p = 0.325). In the multivariate analysis, positive WB EBV-DNA showed a trend towards worse PFS with hazard ratio of 1.54 (95% CI, 0.99-2.38, p = 0.055), but there was no association with OS (p = 0.713).

Conclusion: Our study demonstrated that EBV positivity as measured by EBER-ISH, WB, or plasma PCR in PTCL-NOS was not significantly associated with survival. Nevertheless, there was a trend towards worse PFS in patients who were positive for WB EBV-DNA. Thus, further investigations are warranted in larger cohorts to determine its clinical implications.

Yoon:Takeda: Honoraria; BMS: Honoraria; Boryung: Honoraria, Research Funding; Amgen: Honoraria; Beigene: Research Funding; Novartis: Honoraria; Sanofi: Research Funding; GSK: Honoraria; GI Cell: Consultancy; Ab Clone: Consultancy; Pharos iBio: Consultancy; Samyang: Honoraria, Research Funding; Celltrion: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kirin: Honoraria, Research Funding; Roche: Honoraria.