Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity

Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphomas (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 FL patients for HBV infection status, clinical features and gene mutational profile. Anti-HBc was detectable in sixteen patients (13.2%), although all had undetectable HBV DNA. Anti-HBc+ cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs. 57.2 years, P=0.007) and higher β2-microglobulin (56.3% vs. 28.9%, P=0.04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV-hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year PFS (12.9% vs 58.3%; P<0.0001) and OS (22.0% vs. 86.2%, P<0.0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, two key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

Download Full-text

Prospective Analysis of Hepatitis B Virus Reactivation In Patients with Diffuse Large B Cell Lymphoma After Rituximab Combination Chemotherapy

Blood ◽

10.1182/blood.v116.21.3950.3950 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3950-3950

Author(s):

Nozomi Niitsu ◽

Yuki Hagiwara ◽

Ken Tanae ◽

Mika Kohri ◽

Miyuki Hayama ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hbv Dna ◽

Hbv Reactivation ◽

Large B Cell Lymphoma ◽

B Virus ◽

Large B Cell

Abstract Abstract 3950 Reactivation of hepatitis B virus (HBV) was reported in patients who were being treated with rituximab-combination chemotherapy (R-chemotherapy). HBV reactivation was a well-known complication in lymphoma patients who were positive for hepatitis B surface antigen (HBsAg) in the pre-rituximab era. Recently, it was reported that HBV reactivation can occur in HBsAg-negative patients with past infection of HBV, upon administering R-chemotherapy for B-cell lymphoma. The association between rituximab and HBV reactivation is still unknown. There have been cases of HBV reactivation in patients with past HBV infection during the course of chemotherapy and/or immunotherapy, sometimes proving fatal. Nevertheless, it remains uncertain whether diffuse large B-cell lymphoma (DLBCL) patients with past HBV infection are at substantial risk for reactivation of latent HBV. We prospectively studied the frequency of and risk factors for HBV reactivation in DLBCL patients who received R-chemotherapy. A total of 356 HBsAg-negative patients with DLBCL were treated with R-chemotherapy. Anti-HBs and anti-HBc tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. The serum HBV-DNA load was determined by quantitative RT-PCR [COBAS® AmpliPrep/COBAS® TaqMan® HBV-Test, Roche Diagnostics K.K. Tokyo, Japan]. A total of 356 HBsAg-negative patients with DLBCL were enrolled in this study. Among the 51 (16.2%) HBV carriers, 6 patients developed HBV reactivation and 45 patients did not develop HBV reactivation during the study period. Exploratory analysis was conducted on potential factors associated with the development of HBV reactivation. Male gender and having a low anti-HBs titer before R-chemotherapy were significantly associated with HBV reactivation. Age, clinical stage, B symptoms, lactate dehydrogenase (LDH), performance status, international prognostic index, and chemotherapy regimen were not associated with HBV reactivation. Among the 51 HBV carriers, 8 patients (15.7%) were positive for only anti-HBs, 27 (53%) were positive for both anti-HBs and anti-HBc, and 16 (31.3%) were positive for only anti-HBc. HBV reactivation occurred during or after R-chemotherapy in the 6 patients (12%); two patients developed reactivation after three or seven cycles of R-CHOP, respectively, whereas four patients developed reactivation after completion of R-CHOP therapy at a median interval of 90 days (range, 20 to 143 days). All 6 patients who developed HBV reactivation were positive for anti-HBc, and 3 of them were also positive for anti-HBs. The pretreatment anti-HBs titer of the 6 patients was low (range, <2.0 to 40.2 mIU/ml). When HBV-DNA became detectable in the serum, entecavir administration was started and the serum HBV-DNA became negative within 13 weeks. Elevation of ALT and AST was not observed in any of the 6 patients. The serum HBV-DNA level did not increase after entecavir administration was started in any patient. When HBV reactivation occurred, the liver function did not become elevated and HBsAg remained negative in all six patients. After serum HBV-DNA became undetectable, R-chemotherapy was resumed. None of the 6 patients developed hepatitis B. In the 6 patients who developed HBV reactivation, the anti-HBs titer before R-chemotherapy and the anti-HBs titer at the time of HBV reactivation did not significantly differ. In the 45 patients who did not develop HBV reactivation, the anti-HBs titer before R-chemotherapy ranged from 11.6 to <1,000 mIU/ml. After the end of R-chemotherapy, the anti-HBs titer was lower in 42 of the 45 patients. The posttreatment anti-HBs titer of the 42 patients was 10.2–542 mIU/ml. The anti-HBs titer returned to the value before the start of R-chemotherapy 6–18 months after the end of R-chemotherapy. HBV reactivation occurred in some patients who had been anti-HBs-negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of R-chemotherapy, but R-chemotherapy could be resumed after entecavir administration reduced the serum HBV-DNA level. Entecavir prophylaxis was not performed when R-chemotherapy was started, and it was thought that entecavir could be started when the serum HBV-DNA increased. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Genetic landscape of hepatitis B virus–associated diffuse large B-cell lymphoma

Blood ◽

10.1182/blood-2017-11-817601 ◽

2018 ◽

Vol 131 (24) ◽

pp. 2670-2681 ◽

Cited By ~ 16

Author(s):

Weicheng Ren ◽

Xiaofei Ye ◽

Hong Su ◽

Wei Li ◽

Dongbing Liu ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hbv Infection ◽

Disease Stage ◽

Large B Cell Lymphoma ◽

B Virus ◽

Large B Cell

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

Download Full-text

Prevalence and Prognostic Molecular Profiles in Hepatitis B Virus Infected Patients with Diffuse Large B Cell Lymphoma: A Retrospective Study From Chinese Population

Blood ◽

10.1182/blood.v118.21.5211.5211 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5211-5211

Author(s):

Huijie Wang ◽

Junning Cao ◽

Xiaonan Hong

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hbv Infection ◽

Positive Group ◽

Large B Cell Lymphoma ◽

Positive Expression ◽

B Virus ◽

Mantle Cell ◽

Positive Rate

Abstract Abstract 5211 Introduction: Meta-analysis demonstrated that B cell lymphoma appears to be at high risk of infection by Hepatitis B Virus (HBV). Recently, cohort study showed HBV infection is associated with the increasing risk of B cell type lymphoma. Retrospective studies demonstrated high prevalence of HBV infection in Chinese lymphoma patients, with HBsAg-positive rates ranging from 23.5% to 30.5%. HBsAg-positive Diffuse Large B Cell Lymphoma (DLBCL) patients are associated with younger age and more advanced stage. However, the relation between HBV infection and poor prognosis in DLBCL remains uncertain. Molecular markers based on Immunohistochemical (IHC) expression were widely used as prognostic markers in DLBCL. Our study aimed to investigate the prevalence of HBVinfection in the different subtypes of lymphoma, and the molecular prognostic profiles in HBsAg-positive DLBCL. Patient and Methods: From Jan 2008 to Dec 2010, a total of 672 patients diagnosed as lymphoma were tested for HBsAg. Of these, 399 were male and 273 were female; 426 were B-NHL, 216 were T-NHL and 30 were HL. The expressions of BCL-2, BCL-6, CD10, MUM-1 were tested in patients diagnosed with DLBCL. Results: We found the overall HBsAg-positive rate was 15.9% (107/672) in total lymphoma patients. The positive rate of HBsAg was higher in B-NHL patients (20%,85/426) than T-NHL(9.7%,21/216) and HL (3.3%,1/30) (P<0.001).The lower prevalence were observed several subtypes of lymphoma including mantle cell lymphoma (0/20, 0%), Burkett's lymphoma (0/13, 0%), HL (1/29, 3.3%) and PTCL (4/53, 7.5%).The rate of HBV infection was higher in DLBCL patients (20.9%, 68/326). Among prognostic molecular profiles in DLBCL, the positive expression rates of BCL-2, BCL-6, CD10 and MUM-1 were 65.4% (134/205), 51.3% (116/226), 17% (39/230) and 61.5% (139/226), respectively. The non-GCB subtype accounted of 68.7% of DLBCL. Between HBsAg negative and positive group of DLBCL, the positive expression rates of BCL-2 were 64.1% vs 69.2% (P=0.498), CD 10 were 16.6% v 18.2%(P=0.781), MUM-1 were 60.5% vs 64.8%(P=0.567). However, the BCL-6 positive rate was slight higher in HBsAg negative group compared with positive group (55% vs40%, P=0.053). Finally, non-GCB subtype rates were 67.7% vs 68.7% in HBsAg negative and positive group DLBCL. Conclusion: Our date demonstrated that the infection rate of HBV was higher in DLBCL, whereas lower in the subtypes of mantle cell lymphoma, burkitt's lymphoma and HL. Based on IHC analysis, non-GCB subtype accounted of two-third of DLBCL in our series. Patients with HBsAg-positive DLBCL had lower positive rate of BCL-6. However, the expression of Bcl-2, CD10, MUM-1 seems no significant difference between patients with HBsAg-positive and negative DLBCL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.7531 ◽

2010 ◽

Vol 28 (34) ◽

pp. 5097-5100 ◽

Cited By ~ 61

Author(s):

Nozomi Niitsu ◽

Yuki Hagiwara ◽

Ken Tanae ◽

Mika Kohri ◽

Naoki Takahashi

Keyword(s):

Hepatitis B ◽

B Cell ◽

Cell Lymphoma ◽

Hepatitis B Surface Antigen ◽

B Cell Lymphoma ◽

Hbv Dna ◽

Hbv Reactivation ◽

Large B Cell Lymphoma ◽

B Virus ◽

Large B Cell

Purpose Recently, there have been reports of hepatitis B virus (HBV) reactivation after rituximab combination chemotherapy in hepatitis B surface antigen (HBsAg) –negative patients with B-cell lymphoma. In this prospective study, the frequency of and risk factors for HBV reactivation in patients who were receiving rituximab chemotherapy were examined. Patients and Methods A total of 314 HBsAg-negative patients with diffuse large B-cell lymphoma were treated with rituximab chemotherapy. Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. Results Of the 314 patients, 51 (16.2%) were HBV carriers. HBV reactivation occurred during or after rituximab chemotherapy in six patients (12%). All six patients who developed HBV reactivation were anti-HBc positive, and three of them were also anti-HBs positive. In these six patients, the pretreatment anti-HBs titer was low. Entecavir administration was started when serum HBV DNA became positive, and serum HBV-DNA became negative within 1 to 3 weeks. Rituximab chemotherapy was then continued. Risk factors for HBV reactivation were being male and having a low anti-HBs titer. Conclusion HBV reactivation occurred in some patients who had been anti-HBs negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of rituximab chemotherapy, but rituximab chemotherapy could be continued after entecavir administration reduced the serum HBV-DNA level. Entecavir (BMS 200495) prophylaxis was not performed when rituximab chemotherapy was started, and it was thought that entecavir could be started when serum HBV-DNA increased.

Download Full-text