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Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 248-253

Diffuse large B-cell lymphoma with concurrent hepatitis B virus infection in the MabThera era: Unique clinical features and worse outcomes

1 Department of Hematology, Ningbo No.1 Hospital, Ningbo, China
2 Department of Psychosomatic Medicine, Ningbo No.1 Hospital, Ningbo, China
3 Department of Stem Cell Lab, Ningbo No.1 Hospital, Ningbo, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Guifang Ouyang
Floor 6, Building 3, Department of Hematology, Ningbo No.1 Hospital, No.59, Liuting Street, Haishu District, Ningbo, Zhejiang
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.187285

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 > Abstract 

Aim of Study: Hepatitis B virus (HBV) infection is a risk factor in diffuse large B-cell lymphoma (DLBCL); however, little is known other than the prevalence evidence. In addition, the impact of HBV infection to DLBCL remains controversial. The purpose of this study was to investigate the HBV infection status of 136 patients with DLBCL, analyze the clinical property of HBV-infected patients, and determine the effects of HBV infection to the outcomes of DLBCL patients.
Materials and Methods: A retrospective analysis was performed in our center from January 2007 to December 2014. A total of 136 DLBCL patients accepting three or more cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen were analyzed.
Results: Of the 136 patients, 55 were HBV-infected and their clinical features were different in several aspects such as young onset age (P = 0.027), frequent occurrence of B symptom (P = 0.009), and advanced disease stage (Stage III/IV, P = 0.037). Besides more HBV-infected patients exhibited lower levels of peripheral lymphocyte-to-monocyte ratio (≤2.0). In the survival assessment, HBV-infected patients were worse in both progression-free survival (PFS) (P = 0.001) and overall survival (OS) (P = 0.030) in MabThera treated group, but get a draw in CHOP regimen group (P = 0.658 in PFS and P = 0.798 in OS). Sort of surprisingly, HBV-infected patients treated with MabThera did not have a superior to the traditional regimen in both PFS (P = 0.969) and OS (P = 0.875).
Conclusion: DLBCL patients with HBV infection are subset with unique clinical characters and have worse outcomes. The benefit of MabThera to HBV-infected DLBCL patients was uncertain thus have to be weighed against the costs before application.

Keywords: Cyclophosphamide, doxorubicin, vincristine, and prednisolone, diffuse large B-cell lymphoma, hepatitis B virus, lymphocyte-to-monocyte ratio, MabThera, rituximab

How to cite this article:
Yan X, Zhou M, Lou Z, Mu Q, Sheng L, Zhang P, Wang Y, Ouyang G. Diffuse large B-cell lymphoma with concurrent hepatitis B virus infection in the MabThera era: Unique clinical features and worse outcomes. J Can Res Ther 2018;14, Suppl S1:248-53

How to cite this URL:
Yan X, Zhou M, Lou Z, Mu Q, Sheng L, Zhang P, Wang Y, Ouyang G. Diffuse large B-cell lymphoma with concurrent hepatitis B virus infection in the MabThera era: Unique clinical features and worse outcomes. J Can Res Ther [serial online] 2018 [cited 2021 Dec 4];14:248-53. Available from: https://www.cancerjournal.net/text.asp?2018/14/8/248/187285

 > Introduction Top

Hepatitis B virus (HBV) infection is a worldwide health problem with 2 billion individuals having been infected and 350–400 million chronic carriers of hepatitis B surface antigen (HBsAg).[1] As stated by the World Health Organization (WHO), hepatitis B is endemic in China. One-third of the HBV infectors worldwide resides in China.[2] Besides the harms of the viral infection itself to health, HBV is associated with pathophysiology of many tumors, and lymphoma is one of them.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) among adults. Moreover, a relatively higher prevalence of HBV infection in DLBCL (approximately 25–60%) was found when compared with other lymphomas such as T-cell lymphoma and follicular lymphoma.[3],[4],[5],[6] Compared with the consensus opinion that HBV-related with the onset of DLBCL, the specific role of HBV in DLBCL including the affection to its prognosis seems far more unclear.[7] Only a few studies provided limited information for the relationships of HBV with the outcomes of DLBCL, but the results seem quite inconsistent. Some retrospective analyses revealed that HBsAg is an independent unfavorable factor for the outcomes (both progression-free survival [PFS] and overall survival [OS]) in DLBCL patients, in spite of antiviral prophylaxis application.[8],[9],[10] Still some others reported that HBV infection did not appear to affect the prognosis of DLBCL patients given antiviral prophylaxis, based on cohort studies as well.[11],[12]

In the era of MabThera, the cure rate of DLBCL has been largely increased than treated with the traditional regimen. However, at the meantime of the benefit brought by rituximab, it did also increase the risk of viral reactivation and hepatic impairment in DLBCL patients with HBV infection in the duration of chemotherapies.[13] The management, nowadays, to such a subset of DLBCL patients has no difference with HBV-uninfected patients other than the additional antiviral prophylaxis because both the features of HBV-associated lymphoma and the possible roles of HBV in lymphoma remain largely unclear.[6]

Hence, the aim of this study was to evaluate the potential roles of HBV in DLBCL and to determine the significance of HBV to the prognosis of DLBCL.

 > Materials and Methods Top

Patients and treatment

A total of 136 patients diagnosed with DLBCL treated in Ningbo First Hospital between January 2007 and December 2014 were reviewed in this study. All the patients were confirmed by the biopsy pathology according to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008).[14] Baseline information including gender, age, stages of DLBCL, B symptoms, rituximab, international prognostic index (IPI) score, immunohistochemistry subtypes, lactate dehydrogenase (LDH) level, lymphocyte-to-monocyte ratio (LMR), bone marrow involvement, and extranodal disease were recorded. All the cases were clinically staged based on the Ann Arbor staging criteria.[15] Patients all underwent serological examination before chemotherapy to exclude combined hepatitis A, hepatitis C, and human immunodeficiency virus infection. MabThera was recommended as the preferred therapy. Forty patients eventually abandoned rituximab and chose the traditional cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, most because of limited family economics. All the registered patients received at least three cycles of first-line CHOP or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimens. All the cases were followed up by outpatient service or telephone for at least 6 months after diagnosis, and the deadline of follow-up in this cohort was June 30, 2015.

Hepatitis B virus-related management

Routine screening for HBV-related markers was performed by chemiluminescence immunoassay (Freedom EVO-2/BEPIII System) immediately after the diagnosis of DLBCL, including HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe), and hepatitis B core antibody (anti-HBc). Real-time quantitative polymerase chain reaction (ABI-7300) was used to determine the HBV DNA copy number before chemotherapy if HBsAg or anti-HBc was positive. Patients were classified into two groups depending on the viral serological results: (1) HBV-infected group defined as one or more positive parameters in HBsAg, anti-HBe, HBeAg, or high dose of anti-HBc, presenting different periods in HBV infection, (2) HBV-uninfected group defined as none positive index or anti-HBs positive with or without low dose of anti-HBc, presenting the state of never infected by HBV or past immunization history by vaccination or personal resistance.

As recommended by most main guidelines.[16],[17],[18] Antiviral prophylaxis with lamivudine or entecavir was performed in HBsAg-positive patients, started at least 1 week before the beginning of chemotherapy and withdraw by 6 months after the termination of chemotherapy. For patients with negative HBsAg and undetectable HBV-DNA but positive anti-HBc, prophylactic measures were not routinely administered. Blood biochemistry and HBV-DNA copies were monitored before every cycle of chemotherapy and each month in principle to evaluate the injury of liver function.

Response criteria

Curative effects were evaluated using physical examination, imaging studies and bone marrow biopsy according to The 2007 Response Criteria for Malignant Lymphoma standard.[19] Complete remission (CR) was defined as disappearance of all disease evidence. Partial remission (PR) was defined as ≥50% of tumor regression and no changes in the nonmeasurable lesions. Stable disease (SD) was defined as regression of <50% of measurable disease or no new lesions and no growth of existing lesion sites. Progressive disease was defined as an increase in the size of the existing lesion by more than 25% or new lesion appearance.

Statistical analysis

Either Chi-square test or Fisher's exact test was used for categorical variables. Two-independent sample analyses were performed using nonparametric test. OS and PFS were measured from the date of diagnosis of DLBCL until the death of any cause or disease progression. Survival curves were constructed using Kaplan–Meier survival analysis and the differences between two groups were compared by log-rank test. All P values were two-sided, and P < 0.05 was considered statistically significant.

 > Results Top

Patient characteristics

The final cohort included 136 patients, aged 24–87 years, with a median age of 57 years. Patients with HBV infection had a younger onset age (47 years, range 18–78) comparing with HBV-free patients (61 years, range 22–87). Overall, 74 patients were male, 62 were female, and the ratio of male to female was 1.19:1 [Table 1]. The HBV infection rate in the entire sample of DLBCL was 40.4% (55/136). Among them, 33 cases were HBsAg-positive. About 70.9% of the HBV-infected patients showed more advanced stages (III–IV) of the disease. The proportion was much higher than that of HBV-uninfected patients (53.1%) (P < 0.05). More HBV-infected patients had a complaint of B symptoms (63.6% vs. 40.7%, P < 0.01). Based on the immunohistochemical algorithms, the proportion of patients classified into GCB type was similar in both groups, 56.3% in the HBV-infected group and 46.9% in the HBV-uninfected group. There was no difference in LDH level, IPI scores, bone marrow involvement, extra nodule involvement, and response to primary chemotherapy between the patients with or without HBV infection. Moreover, the proportion of patients given MabThera regimen was similar in the two groups. The median courses of regimen were 6 (range from 3 to 8). There were no significant differences in the number of cycles of chemotherapy-treated between HBV-infected and HBV-uninfected groups (P = 0.233). The baseline clinical characteristics were showed in [Table 1].
Table 1: General information and clinical characteristics of hepatitis B virus-infected and uninfected patients

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Lymphocyte-to-monocyte ratio

Recently, peripheral LMR was proved to be a novel potential marker to predict survival and identify high-risk patients in DLBCL.[20],[21],[22] It appeals to people with its cheap, readily available, and reproducible properties. However, none of the existing reports have assessed this data in DLBCL patients with HBV infection yet. We collected the peripheral LMR level of patients at diagnosis and found that more HBV-infected patients had an LMR value below 2.0 (47% vs. 28%, P < 0.05) [Table 2].
Table 2: Lymphocyte-to-monocyte ratio levels in hepatitis B virus-infected and uninfected patients

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Curative effect

The disease condition was assessed after first-line treatment. In 55 HBV-infected patients, 39 achieved CR (71%), 6 reached PR (11%), 2 exhibited SD (4%), and 8 experienced PD (14%). In 81 HBV-uninfected patients, 51 achieved CR (63%), 7 reached PR (8%), 12 exhibited SD (12%), and 13 experienced PD (16%). There was no statistical difference in curative effect between the two groups. HBV-infected patients and HBV-uninfected patients got a similar CR rate (P = 0.362) after first-line therapy [Table 3]. Interestingly, among the patients who achieved CR at the first cycle of treatment, 16 in 39 HBV-infected patients (41.0%) changed regimen afterward, while only 10 in 51 HBV-uninfected patients (19.6%) used more than one lines of chemotherapy (P = 0.026).
Table 3: Response to the first-line MabThera treatment

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Overall, the median PFS was 35.3 months, and the median OS was 80.5 months. In the CHOP regimen group [Figure 1], HBV-infected patients and HBV-uninfected patients did not have a significant difference in PFS (P = 0.658) and OS (P = 0.798), with a median PFS of 20.2 months and 31.7 months, respectively, and a median OS of 36.3 months and 43.0 months, respectively. This result was consistent with the former published studies.[23],[24],[25]
Figure 1: Survival analysis according to HBV infection status: (a) Progression-free survival of HBV-infected patients and HBV-free patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen. (b) Overall survival of HBV-infected patients and HBV-free patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen. (c) Progression-free survival of HBV-infected patients and HBV-free patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen. (d) Overall survival of HBV-infected patients and HBV-free patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen

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In the R-CHOP group, the HBV-uninfected patients had advantages over the HBV-infected patients in both PFS(P = 0.001) and OS (P = 0.030) shown in [Figure 1]. With a median follow-up of 32.2 months, the median PFS was 65 months and median OS were not reached in the HBV-uninfected patients. In the HBV-infected patients, the median PFS and OS were estimated to be 25.9 and 45.0 months, respectively.

Surprisingly, in our results, MabThera did not bring benefit to the PFS (P = 0.969) and OS (P = 0.875) in HBV-infected patients. In the HBV-uninfected patients, MabThera improved both PFS (P = 0.041) and OS (P = 0.012) as expected.

 > Discussion Top

It has been widely acknowledged that high incidence of HBV infection is associated with B-cell NHL, especially DLBCL.[3] In our analysis, the HBsAg-positive rate and HBV infection rate in DLBCL patients were 24.3% and 40.4%, respectively higher than the previously published HBsAg carrier rate (7.2%) and HBV infection rate (30–35%) from sero-epidemiological survey in China.[26],[27] Moreover, our prevalence data are within the range of other studies.[4],[5],[28] The high incidence of HBV infection in the DLBCL population indicate certain effects of HBV to the pathogenesis of DLBCL.[29],[30] In our observation, the subset of HBV-infected patients differed in several aspects with HBV-free patients. The HBV-infected ones had a relatively younger onset age, more frequently occurrence of B symptoms, and more advanced disease stages.

Moreover, our result revealed that LMR in peripheral blood was statistically lower in HBV-infected patients, which to our knowledge was not reported before. Lymphocyte and monocyte are both immunologically relevant markers. Recently, the number and type of lymphocytes and monocytes detectable in the peripheral blood of patients with DLBCL were investigated and indicated that LMR, assessed at diagnosis using a simple automatic blood count, might predict the prognosis of DLBCL patients.[20] As HBV and other virus might participate in the lymphomagenesis by its immunosuppression after infection, the value of LMR just reflected the severity of the immunosuppression condition to some extent. Our result was confirmed to this inference. Meanwhile, the lower LMR in HBV-infected patients indicated poor OSs among these patients.

Although HBV is closely related to DLBCL and is supposed to be an unfavorable factor, the actual roles that HBV played in the outcomes of DLBCL still lack enough concerns. And, even the limited published data are not in accordance with each other. The widespread use of the revolutionary regimen of MabThera made measurements become more complicated. In our cohort, survival rate was analyzed separately based on the application of rituximab. The results showed both worse PFS and OS in HBV-infected patients receiving R-CHOP regimen comparing with HBV-uninfected patients. However, in patients receiving traditional CHOP regimen, the outcome was not influenced by the state of HBV infection.

We further analyzed the detail curative effects of MabThera to the two subsets of patients. It revealed that the two groups exhibited similar CR rate after the first-line treatment. However, in the general information, we found more HBV-infected CR patients took the second-line regimen or more as time went on. This indicated that despite the initial similar response to the chemotherapy, HBV-infected patients were less likely to maintain the no progression state. Consistent with this, no significant surviving advantages including PFS and OS were found in HBV-infected patients treated with MabThera. In HBV-free patients, application of rituximab regimen improved both PFS and OS as expected.

As far as we know, the appearance of rituximab thoroughly altered the fate of DLBCL patients, with longer remission time and better-surviving data.[31],[32],[33],[34] It is also confirmed that DLBCL patients with resolved HBV infection had a higher risk of viral reactivation compared with uninfected patients after rituximab-containing chemotherapy.[35],[36] However, the resolution to the known problems caused by rituximab is just prophylactic antiviral treatments at the present period. HBV-infected patients were not actually concerned as a unique population in DLBCL. The exact benefit of MabThera to the HBV-infected DLBCL patients was lack of enough concern. In our cohort study, HBV patients treated with R-CHOP-like regimen did not win out in the OS rate. With positive antiviral prophylaxis and proper supportive treatment, only a few HBV-infected patients (5.2%) in our study had HBV reactivation and hepatic lesion rates in the two groups were similar (data not listed), which were not likely to influent the OS. As chronic HBV stimulation leads to malfunction of immune system which possibly plays an important role in the pathogenesis of B-cell lymphoma, and the usage of rituximab caused B-cell depletion and aggravated the immune suppression, HBV-infected patients may suffer an earlier relapse or disease progression than HBV-free patients, thus affects the outcome of DLBCL. It may explain that despite good response to the MabThera, patients with HBV infection did not get much profit in the long-term survival from MabThera. Taking the financial burden and viral reactivation risks of rituximab into consideration, treatment strategies option toward HBV-infected patients needs to be evaluated more carefully. Additional multicenter research is required to clarify the exact survival benefit of MabThera to HBV-infected patients.

Limitation of our report mainly comes from the selection bias and the number of sample. Patients accepted <3 circles of regimens were excluded from our research thus rejected a part of patients with more severe disease condition or worse personal economy, which may include more HBV-infected patients. As this is single-institution experience, meta-analysis or multicenter research is needed for more convincing statistic results.

 > Conclusion Top

HBV-infected patients are a unique subset of DLBCL patients with an earlier onset, more appearance of B symptoms, and later disease stages, rather than simple concurrent virus infection status. Besides, the peripheral LMR level was lower in HBV-infected patients which associated with adverse outcomes. In the MabThera era, even with proper antiviral prophylaxis, HBV-infection still impacts the outcome of the DLBCL patients with both worse PFS and OS than the HBV-free patients. In our cohort, although HBV-patients had a similar response to MabThera with the rest of patients, this revolutionary treatment did not bring significant benefit to the final survival by the ends of follow-up. Consider the profound immune suppression of MabThera to the HBV-infected patients that could increase the risk of complications and the additional economic cost of rituximab; we have to think twice in the treatment option decision in HBV-infected patients.

Financial support and sponsorship

Natural Science Foundation of Ningbo, China, grant number 2014A610217.

Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]

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