Higher Titer of Epstein-Barr Virus Nuclear Antigen Might be a Marker of Poorer Prognosis in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified
Authors: Kusano Yoshiharu , Terui Yasuhito , Ueda Kyoko , Yokoyama Masahiro , Nishimura Noriko , Mishima Yuko , Gunji Tadahiro , Nitta Hideaki , Takahasi Anna , Inoue Norihito , Hatake Kiyohiko 
Published: November 2019

Abstract
[Background] The therapeutic outcomes in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) are correlated with positivity of Epstein-Barr virus (EBV) -encoded small RNA in situ hybridization. EBV nuclear antigen 1 (EBNA), the only viral protein consistently expressed by EBV, itself positivity has been the mainstay evidence to diagnose the latent EBV infection to date. However, it has been unknown whether the difference value of EBNA titer has another clinical implication, to say nothing of hematological malignancies field.
[Methods] This is an observational trial in single cancer institute. EBNA has routinely measured before the treatment in patients with PTCL, NOS, who were diagnosed or treated in our hospital from July 2001 to December 2014. Then, we analyzed that whether patients with PTCL, NOS attributed their therapeutic outcomes to the each value of their pretreatment EBNA titer. Primary objective was to evaluate a prognostic value of EBNA titer for one-year overall survival (OS). Secondary objective was response rate.
[Results] In total of 30 cases, 24 showed EBNA positive (titer ≥ 10). Baseline patients characteristics run as follows; median age was 63 (26-83), 22 were men, 18 were advance stage, 11 were IPI ≥ 3, 9 showed elevated LDH. All patients were given six cycles of CHOP except one patient (CHOEP). Overall response rate (ORR) was 40% and complete response rate (CRR) was 27%. 40% showed progression disease. The median OS was 51.4 months. At the median follow-up of 12 months, the pretreatment EBNA level demonstrated significant correlation with prognosis. OS was 52.7% (95% confidential index [CI]: 30-71) and 100% (95%CI: 100-100) in cases that EBNA positive and EBNA negative, respectively (Figure 1, p value of log-rank test 0.013). Furthermore, we compared outcomes in the three groups: EBNA < 10, 10 ≤ EBNA ≤ 60, and EBNA > 60. Each group has same proportion of age > 60 (p value of fisher exact test 0.26), sex (p = 0.51), IPI ≥ 3 (p = 0.85), advance stage (p = 0.09), and elevated LDH (p = 0.64). ORR was 33% vs. 44% vs. 33% and CRR was 33% vs. 28% vs. 17% in cases that EBNA < 10, 10 ≤ EBNA ≤ 60, and EBNA > 60. In terms of OS, 100%, 63%, and 20% in cases that EBNA < 10, 10 ≤ EBNA ≤ 60, and EBNA > 60, respectively (Figure 2, p value of log-rank test < 0.01).
[Conclusion] As these results demonstrated, in this study, patients with high-level titer of EBNA demonstrated shorter OS. Especially, EBNA titer > 60 cases showed the worst outcome. By contrast, EBNA negativity demonstrated significantly longer OS. Higher EBNA might be an independent marker that associated with poorer outcomes in patients with PTCL, NOS.

Disclosures
Yokoyama: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.