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Hepatitis B Surface Antigen Positivity Is an Independent Unfavorable Prognostic Factor for Overall Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with Standard Chemoimmunotherapy


 Introduction
 Hepatitis B virus (HBV) is one of the most common viral infections in humans. Global prevalence of chronic HBV infection is heterogeneous, with 2-20% of a given population being infected with HBV. In some parts of Africa, Asia and South America, HBV infection is endemic and remains to be a significant public health issue.Previous studies have shown a positive association between hepatitis B surface antigen (HBsAg)-positive HBV infection and B-cell non-Hodgkin lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL), the most common subtype of B-cell NHL. Nevertheless, the clinical characteristics of HBsAg positivity and negativity, as well as their prognostic implications in DLBCL patients treated with frontline standard chemoimmunotherapy remain to be clarified.
 Methods
 We conducted a single-institution retrospective study in a tertiary referral hospital in Taiwan, an HBV prevalent country in Asia. From January 2001 to December 2015, patients aged ≥20 years with newly diagnosed DLBCL treated with standard rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were selected. Retrospective chart review was performed to collect data on clinical features, laboratory profiles, serum markers for HBV infection such as HBsAg and HBV-DNA loads before chemotherapy, as well as data on treatment response and outcome. The cohort was followed up until the cutoff date of June 30, 2018.
 Results
 A total of 393 DLBCL patients were analyzed in this study, with a median age of 60.5 years (range, 23.5 years to 90.9 years) and the sex ratio of 1.38 to 1.The 5-year overall survival (OS) rates were 65.2% after a median follow-up time of 68.8 months. In this cohort, 100 patients (25.4%) were found to have HBsAg positivity before treatment.Eighty-two of them had received prophylactic antiviral therapy, including 28 with lamivudine, 44 with entecavir and 10 with others. Besides, forty-five of HBsAg-positive patients had data of serum HBV-DNA loads before treatment, and 44 of them had received prophylactic anti-HBV therapy. Compared to HBsAg-negative patients, HBsAg-positive patients had a younger median onset age (55.9 years vs. 61.4 years, P=0.004), a trend of more advanced stage (stage III/IV: 62% vs. 51.2%, P=0.064), higher serum LDH levels at diagnosis (62% vs. 50.2%, P=0.048), and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (high-intermediate/high: 50% vs. 41.6%, P=0.162).
 Regarding to treatment response and outcome, HBsAg-positive patients, compared to HBsAg-negative patients, had a trend of lower overall response rates (78% vs. 84.3%, P=0.169) and complete remission rates (73% vs. 79.9%, P=0.163). Furthermore, compared to HBsAg-negative patients, HBsAg-positive patientshad a poorer median OS (median OS, not reached vs. 95.8 months, P=0.001, Figure 1) and a shorter median progression-free survival (PFS) (median PFS, not reached vs. 34.3 months, P=0.031), respectively. By multivariate analysis, HBsAg positivity is an independent poor prognostic factor for OS irrespective of NCCN-IPI score, serum albumin levels and B symptoms.
 No significant difference was found in outcome between patients with high HBV-DNA loads (> 2000 IU/mL, n=21) and those with low HBV-DNA loads (≤2000 IU/mL, n=24). With respect to prophylactic anti-HBV treatment, patients without prophylactic therapy (n=18), compared to those with prophylactic therapy (n=82), had a trend of shorter median OS (27.9 months vs. 96.2 months, P=0.346). Moreover, no significant difference was found in median OS between HBsAg-positive patients when administrated with anti-HBV lamivudine and those when administrated with anti-HBV entecavir.
 Conclusions
 This study demonstrated that HBsAg positivity has unique clinical relevance to patients with DLBCL, as well as its impact in the efficacy of treatment. HBsAg positivity may serve as a relevant biomarker to predict clinical outcome in DLBCL patients treated with R-CHOP. Prophylactic anti-HBV therapy may be of great importance in HBsAg-positive DLBCL patients. Further studies to explore the etiopathogenesis of HBV infection in DLBCL may help to discovery new treatment targets to improve the outcome of this group of patients.
 Figure 1. Figure 1.
 
 
 No relevant conflicts of interest to declare.
