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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 3  |  Page : 443-447
 

Efficacy and safety analysis of rituximab combined with chemotherapy in the treatment of B-cell lymphoma patients complicated with hepatitis B virus infection


Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of , Chengdu, Sichuan, China

Date of Web Publication24-Feb-2017

Correspondence Address:
Y Wang
Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.200679

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 » Abstract 

BACKGROUND: Lymphoma combined with hepatitis B infection occupies a relatively higher incidence in China than that of in Europe and America. AIMS: To observe the efficacy and safety of rituximab in combination with chemotherapy in patients with B-cell non-Hodgkin's lymphoma (NHL) and hepatitis B virus (HBV) infection. METHODS: Ninety-two B-cell lymphoma patients with HBV infection in Sichuan Cancer Hospital from January 2009 to October 2015 were divided into two groups. Patients in Group A (n = 33) were treated with rituximab combined with chemotherapy, while Group B (n = 59) accepted chemotherapy alone. RESULTS: The effective rate (complete response + partial response) was 69.7% in Group A and 44.1% in Group B with significantly statistical difference (P = 0.018). Some of the patients got different grades of hepatic function damage during the period of chemotherapy, but there was no statistically significant difference between these two groups (P = 0.071). CONCLUSIONS: For CD20-positive NHL patients complicated with HBV infection, rituximab combined with chemotherapy modality is effective. The promise efficacy of this regimen could be achieved relying on controllable safety based on antiviral treatment.


Keywords: Antiviral therapy, B-cell lymphoma, chemotherapy, hepatitis B virus, rituximab


How to cite this article:
Wang S, Zhang Z, Cai H, Wang Y. Efficacy and safety analysis of rituximab combined with chemotherapy in the treatment of B-cell lymphoma patients complicated with hepatitis B virus infection. Indian J Cancer 2016;53:443-7

How to cite this URL:
Wang S, Zhang Z, Cai H, Wang Y. Efficacy and safety analysis of rituximab combined with chemotherapy in the treatment of B-cell lymphoma patients complicated with hepatitis B virus infection. Indian J Cancer [serial online] 2016 [cited 2017 Oct 20];53:443-7. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/443/200679



 » Introduction Top


The incidence of non-Hodgkin lymphoma (NHL) has increased steadily during the last several decades. Currently, NHL is ranked as the 10th most common cancer worldwide and the 11th most common cancer in China.[1] NHL is mostly originated from B lymphocytes, and the CD20 expression is positive. In recent years, with the clinical application of targeted drug rituximab combined with chemotherapy, a greatly improved outcome for patients with NHL has been achieved. However, with the popularization and application of rituximab combined with chemotherapy, clinical findings have shown that in the treatment of lymphoma with hepatitis B virus (HBV) infection, it was easy to induce HBV reactivation, cause aggravation of hepatic damage, even result in liver failure. According to an investigation in 2006, the hepatitis B surface antigen (HBsAg)-positive rate was 7.2% among people aged from 1 to 60 years in China, approximately 1/3 of total global HBV infections.[2]

The proportion of patients with lymphoma combined with hepatitis B (HBsAg-positive) is high in China (12%–30%), much higher than the global average.[1],[3],[4],[5] Hence, rituximab application in the treatment of B-cell lymphoma complicated with HBV infection had been hampered in clinical practice for a certain period. Later, clinical practice showed that the preventive antivirus treatment can effectively prevent HBV reactivation; the application of rituximab was further expanded.

In our paper, we reviewed the treatment of 92 cases of B-cell lymphoma combined with HBV infection in our hospital in recent 5 years. The therapeutic effect, liver function, and clinical data were retrospectively analyzed and discussed.


 » Methods Top


Clinical data

Inclusion criteria: (a) B-cell NHL patients who were treated in the Department of Medical Oncology, Sichuan Cancer Hospital (Chengdu, China) from January 2009 to October 2015. (b) All patients were examined for HBV infection statuses. (c) All diagnoses were confirmed and staged by pathological biopsy and immunohistochemistry. (d) The diagnosis, classification, and staging were determined according to the World Health Organization (WHO) classification of tumors, pathology and genetics of tumors of hematopoietic and lymphoid tissues in 2001, and Ann Arbor staging criteria.

Exclusion criteria: (a) Patients who were treated with <3 courses of chemotherapy regimens were excluded in the investigation of chemotherapeutic outcome evaluation because it was difficult to judge the curative effect for the patients who were administered one to two courses of chemotherapy. (b) Patients who received chemotherapy regimens in other hospitals and whose clinical data cannot be obtained.

A total of 92 B-cell NHL patients who were treated in the Department of Medical Oncology, Sichuan Cancer Hospital (Chengdu, China) from January 2009 to October 2015 and whose HBV infection statuses were examined, were included in this study. All cases accepted HBsAg, hepatitis B surface antibody, hepatitis B e antigen (HBeAg), hepatitis B e antibody, and hepatitis B core antibody detection and part of the cases accepted HBV-DNA quantitative examination. CD20 was positive in all cases. Patients were divided into two groups according to whether rituximab was combined with chemotherapy regimen or not. Thirty-three patients in Group A accepted comprehensive treatment of rituximab and chemotherapy while 59 patients in Group B were treated with chemotherapy alone. The median age of patients in Group A was 58 years (aged from 18 to 78) and in Group B was 52 years (aged from 20 to 85). [Figure 1] shows the selection process of patients for this study. The baseline characteristics of the two groups are shown in [Table 1].
Figure 1: Selection process of patients

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Table 1: Baseline characteristics

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Chemotherapy regimen

All patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or modified CHOP regimen. The first-line chemotherapy regimen in Group A was mainly rituximab-CHOP (R-CHOP), and the second-line regimen included rituximab, etoposide, doxorubicin, vincristine, prednisone, and cyclophosphamide (R-EPOCH), rituximab, dexamethasone, ifosfamide, cisplatin, and etoposide (R-DICE), and rituximab, gemcitabine, and oxaliplatin (R-GemOX). The first-line chemotherapy regimen in Group B was mainly CHOP, and the second line chemotherapy regimen included EPOCH, DICE, and GemOX. Thirty-three patients were treated with rituximab (375 mg/m 2) combined with chemotherapy in Group A with median cycles of five (range from 2 to 16). A clinical efficacy evaluation was performed every two cycles. The chemotherapy regimen is shown in [Table 2].
Table 2: Chemotherapy regimen

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Therapeutic effect evaluation criterion

According to the Response Evaluation Criteria in Solid Tumor standard for efficacy evaluation, complete response (CR) was defined as the disappearance of all target lesions for at least 4 weeks. Any pathological lymph node (whether target or nontarget) must have a reduction in short axis to <10 mm. Partial response (PR) was defined as at least the 30% decrease in the sum diameters of target lesions, taking as reference the baseline of sum diameters. Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of study (this includes the baseline sum if that is the smallest on the study). Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The effective rate is CR + PR.

Adverse reaction of liver

Liver function damage was evaluated according to the WHO toxicity grading scale for determining the severity of adverse events, Grade 0: Alanine transaminase (ALT) ≤1.25 N, bilirubin (BIL) ≤1.25 × N, and alkaline phosphatase (AKP) ≤1.25 × N. Grade I: ALT 1.25–2.5 × N or BIL 1.25–2.5 × N or AKP 1.25–2.5 × N. Grade II: ALT 2.6–5 × N or BIL 2.5–5 × N or AKP 2.5–5 × N. Grade III: ALT 5.1–10 × N or BIL 5.1–10 × N or AKP 5.1–10 × N. Grade IV: ALT >10 × N or BIL >10 × N or AKP >10 × N. Referring to the views of Japanese experts in 2012, for HBsAg-positive patients, HBV reactivation was defined as HBV-DNA exceeded baseline levels by ten times or HBeAg-negative patients' serum HBeAg to turn positive. For those patients whose baseline HBV-DNA levels were below the detection limit, HBV reactivation was defined as HBV-DNA can be detected.

Anti-hepatitis B virus therapy

All of these 92 patients were confirmed with HBV infection by the detection of hepatitis B antigen and antibody before they received chemotherapy. The majority of patients were treated with anti-HBV drugs before chemotherapy in both Group A and Group B. Some of the patients did not use antiviral drugs throughout the course of chemotherapy. The rest of patients initiated antiviral treatment during the period of chemotherapy. The timing of initiation of anti-HBV treatment is shown in [Table 3].
Table 3: Timing of initiation of anti-hepatitis B virus treatment

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Statistical analysis

All the data were analyzed by SPSS version 19 (Chicago, IL, USA); Chi-square test was used to compare the rates or proportions among different subgroups.


 » Results Top


Curative effect comparison

The effective rate of Group A was 69.7% and Group B was 44.1%. This difference had statistical significance (P = 0.018). The CR rate of Group A was 33.3% and Group B was 11.9%, the difference also showed statistical significance (P = 0.012). Combined with actual data, the efficiency and CR rate of the rituximab plus chemotherapy group were higher than pure chemotherapy group. The evaluations of curative effect in the two groups are shown in [Table 4].
Table 4: Curative effect

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Liver function impairment

During the period of chemotherapy, 15 patients and 14 patients of Group A adopted lamivudine and entecavir treatment, respectively, against HBV, 4 patients did not adopt any antiviral therapy. In Group B, 17 patients adopted entecavir treatment against HBV, 36 patients adopted lamivudine, and 6 patients did not adopt any antiviral therapy. Some of the patients of these two groups got different grades of liver damage during the period of chemotherapy, thereinto, the number of patients with normal liver function in Group A was 18, the number of patients appeared Grade I–II liver damage was 14 and Grade III–IV was 1 [Table 1]. In Group B, there are 25 patients with normal liver function, and 22 patients appeared Grade I–II of liver damage, and 12 patients appeared Grade III–IV of liver damage [Table 1]. Chi-square test showed no statistically significant difference (P = 0.071) of liver function damage between these two groups. Twenty-seven patients in Group A and 42 in Group B were tested for HBV-DNA. During the period of chemotherapy [Table 1], the HBV reactivation was observed in 6 cases in Group A and 16 cases in Group B with the HBV reactivation rate of 22.2% and 38.1%, respectively. HBV reactivation rate between these two groups showed no statistically significant difference (P = 0.167) with Chi-square test.

Survival analysis curve

Through methods of outpatient visit, telephone follow-up, and so on, the follow-up data of 92 patients were collected [Table 5]. Taking 1 month as the interval period, life table process was adopted to estimate survival rate of these two groups, as well as to compare the survival rates between two groups. The median survival time of Groups A and B was 64 months and 30 months, respectively, with a significant difference between these two groups (P = 0.047), which prompted the longer survival time of Group A. Survival function is shown in [Figure 2].
Table 5: Follow-up data

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Figure 2: Overall survival curves for patients. Group A (n = 33): Patients were treated with rituximab combined with chemotherapy; Group B (n = 59): Patients accepted chemotherapy alone

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 » Discussion Top


Rituximab is a monoclonal antibody with the target antigen of CD20 on the surface of B-cell. The combination of rituximab and conventional chemotherapy can significantly improve the overall survival time and total effective rate of follicular lymphoma, mantle cell lymphoma, diffused large B-cell lymphoma patients.[6],[7],[8],[9] The clinical efficacy data analysis in our hospital confirmed the above conclusion (P = 0.018). At present, the chemotherapy regimens containing rituximab have been widely used as a first-line treatment for many types of NHL; however, NHL patients with HBV infection had a high risk for the HBV-DNA reactivation, which is associated with rituximab therapy. Thus, we aimed to compare and further evaluate the effect of chemotherapy with and without rituximab in NHL patients with HBV infection.

The results of Tsutsumi et al.[10] suggested that rituximab remarkably reduced the antibody titer for HBV in NHL patients. Rituximab, which may cause the significant decrease of B lymphocytes, may finally induce the decrease of plasma cells which can produce HBV antibody. As a result, the immunological balance against HBV infection will be broken and thus provides an opportunity for the reactivation of HBV. In addition, the immune suppression and bone marrow suppression caused by chemotherapy can also induce a large number of HBV proliferation, which leads to the reactivation of HBV. HBV reactivation will increase the incidence of hepatitis and related mortality. Moreover, it may cause interruption of the effective treatment of lymphoma, which affects the survival and prognosis of patients. Therefore, rituximab application in the treatment of patients with B-cell lymphoma complicated with HBV infection has been hampered in clinical practice for a certain period.

Later, with the development of clinical practice, domestic and foreign researches revealed that in patients with B-cell lymphoma combined with HBV infection, prophylactic antivirus therapy can effectively prevent HBV reactivation during the treatment of chemotherapy combined with rituximab.[11],[12],[13] Accordingly, it is important to screen patients with HBV infection before chemotherapy and rituximab administration. Moreover, the corresponding strategy to prevent HBV reactivation during chemotherapy should be made according to the different status of HBV virus. Currently, the international guidelines recommended HbsAg-positive patients to take prophylactic antiviral therapy before chemotherapy as early as possible, and after the completion of chemotherapy or immunotherapy, antiviral therapy should be maintained for at least 6–12 months.[4],[14],[15]

As the HBV-DNA test has been carried out in our institution since 2012, partial of patients hospitalized before 2012 could only complete their HBV-DNA detection by relying on the facilities of other hospitals. As a result, 6 patients in Group A and 17 in Group B did not accept this detection. The HBV reactivation rate of Groups A and B was 22.2% and 38.1%, respectively, which was consistent with the literature.

The rate of HBV reactivation in the rituximab group was slightly lower than that of the simple chemotherapy group (P = 0.167). This study also showed that only 1 case of Group A got Grade III–IV liver function damage during the treatment, while 12 cases were observed in Group B (P = 0.071). This result is unlikely to be consistent with the consensus that rituximab increases the risk of HBV reactivation; the main reasons may be attributed to that clinical use of rituximab in patients had more stringent requirements with liver function, the baseline liver function of patients in Group A was better than that of Group B; Furthermore, most of the patients in Group A accepted anti-HBV treatment before chemotherapy (Group A - 78.8% vs. Group B - 61%, P = 0.081), and anti-HBV drugs were inclined to be given after liver damage occurred during chemotherapy in Group B. It was further demonstrated that the use of rituximab combined with chemotherapy was relatively safe and effective based on preventive anti-HBV treatment.


 » Conclusions Top


In a word, regardless of our retrospective analysis in small sample size, definite efficacy and controllable safety were observed in the treatment of CD20-positive B-cell NHL patients complicated with HBV infection. By means of monitoring indicators such as HBV-DNA quantity and liver function, plus full course of antiviral therapy, rituximab combined with chemotherapy could achieve the optimal efficacy for lymphoma patients with HBV infection and to achieve the prevention and management of HBV reactivation; meanwhile, the side effects could be reduced to a minimum extent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Wang F, Xu RH, Han B, Shi YX, Luo HY, Jiang WQ, et al. High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers. Cancer 2007;109:1360-4.  Back to cited text no. 1
    
2.
Hang X, Bi S, Yang W Epidemiological setosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination. Vaccine 2009;27:6550-7.  Back to cited text no. 2
    
3.
Chen MH, Hsiao LT, Chiou TJ, Liu JH, Gau JP, Teng HW, et al. High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin's lymphoma. Ann Hematol 2008;87:475-80.  Back to cited text no. 3
    
4.
Ikeda M. Reactivation of hepatitis B virus in patients receiving chemotherapy. Jpn J Clin Oncol 2013;43:8-16.  Back to cited text no. 4
    
5.
Wang YH, Fan L, Wang L, Zhang R, Xu J, Fang C, et al. Efficacy of prophylactic lamivudine to prevent hepatitis B virus reactivation in B-cell lymphoma treated with rituximab-containing chemotherapy. Support Care Cancer 2013;21:1265-71.  Back to cited text no. 5
    
6.
Schulz H, Bohlius JF, Trelle S, Skoetz N, Reiser M, Kober T, et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst 2007;99:706-14.  Back to cited text no. 6
    
7.
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725-32.  Back to cited text no. 7
    
8.
Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 2001;97:101-6.  Back to cited text no. 8
    
9.
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-42.  Back to cited text no. 9
    
10.
Tsutsumi Y, Tanaka J, Kawamura T, Miura T, Kanamori H, Obara S, et al. Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin's lymphoma. Ann Hematol 2004;83:58-60.  Back to cited text no. 10
    
11.
Lim LL, Wai CT, Lee YM, Kong HL, Lim R, Koay E, et al. Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Aliment Pharmacol Ther 2002;16:1939-44.  Back to cited text no. 11
    
12.
Wu XY, Li X, Chen ZH, Wen JY, Lin Q, Xing YF, et al. An optimized antiviral modification strategy for prevention of hepatitis B reactivation in patients undergoing prophylactic lamivudine and chemotherapy: A pilot study. Tumour Biol 2013;34:909-18.  Back to cited text no. 12
    
13.
Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009;27:605-11.  Back to cited text no. 13
    
14.
Liaw YF, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu CJ, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol Int 2012;6:531-61.  Back to cited text no. 14
    
15.
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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