‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin’s lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.

Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

A significant association between hepatitis C virus(HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma(DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCVnegative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy(R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate.Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions(i.e., hepatitis B virus or immune immunodeficiency virus coinfected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase elevation, criteria for discontinuing or starting immuno-chemotherapy, as well as the exact role of monoclonal antibodies will be analyzed.

Hepatitis viruses and non-Hodgkin's lymphoma: A review

Non-Hodgkin's lymphoma(NHL) is among the haematological malignancies with high prevalence worldwide, causing estimated 355 900 new cases and 191 400 deaths in 2008. High prevalence of NHL is documented in economically more developed areas while low prevalence is observed in less developed areas of the globe. A wide array of environmental factors have been reported to be either directly involved or in modifying the risk of NHL development. In addition to these factors, a number of infectious agents, chiefly viruses have also been implicated in the development of NHL. This article reviews the available literature to discuss the role of hepatitis viruses in NHL development, possible mechanisms of lymphomagenesis and also identify the areas in which further research is required to better understand this disease. A brief discussion on the clinical aspects such as classification, staging, treatment approaches have also been included in this article.

Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma

The association of hepatitis C virus(HCV) and B-cell non-Hodgkin lymphomas(NHL) has been highlighted by several epidemiological and biological insights; however the most convincing evidence is represented by interventional studies demonstrating the capability of antiviral treatment(AT) with interferon(IFN) with or without ribavirin to induce the regression of indolent lymphomas, especially of marginal-zone origin. In the largest published retrospective study(100 patients) the overall response rate(ORR) after first-line IFN-based AT was 77%(44% complete responses) and responses were sustainable(median duration of response 33 mo). These results were confirmed by a recent metaanalysis on 254 patients, demonstrating an ORR of 73%. Moreover this analysis confirmed the highly significant correlation between the achievement of viral eradication sustained virological response(SVR) and hematological responses. Two large prospective studies demonstrated that AT is associated with improved survival and argue in favor of current guidelines' recommendation of AT as preferential first-line option in asymptomatic patients with HCV-associated indolent NHL. The recently approved direct-acting antiviral agents(DAAs) revolutionized the treatment of HCV infection, leading to SVR approaching 100% in all genotypes. Very preliminary data of IFN-free DAAs therapy in indolent HCV-positive NHL seem to confirm their activity in inducing lymphoma regression.

Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies

Over the last decade,epidemiological studies have discovered a link between hepatitis C virus(HCV)and hepatitis B virus(HBV)infection and non-Hodgkin lymphoma(NHL).The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases.HBV infection was found to significantly enhance the incidence of NHL,according to the epidemiological data.The exact mechanism of HCV leading to NHL has not been fully clarified,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HCV and cytokines;(2)Direct mechanisms:oncogenic effects mediated by intracellular HCV proteins;(3)hit-and-run mechanism:permanent genetic B lymphocytes damage by the transitional entry of HCV.The specific role of HBV in the occurrence of NHL is still unclear,and the research on its mechanism is less extensively explored than HCV,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HBV;(2)Direct mechanisms:oncogenic effects mediated by intracellular HBV DNA.In fact,it is reasonable to consider direct-acting antivirals(DAAs)as first-line therapy for indolent HCV-associated BNHL patients who do not require immediate chemotherapy.Chemotherapy for NHL is affected by HBV infection and replication.At the same time,chemotherapy can also activate HBV replication.Following recent guidelines,all patients with􀀫HBsAg positive/HBV DNA≥2,000IU/mL should be treated for HBV.The data on epidemiology,interventional studies,and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.

Hepatitis C infection and lymphoproliferative disease:Accidental comorbidities?

Chronic hepatitis C virus(HCV)infection has been associated with liver cancer and cirrhosis,autoimmune disorders such as thyroiditis and mixed cryoglobulinema,and alterations in immune function and chronic inflammation,both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma(NHL).HCV bound to B cell surface receptors can induce lymphoproliferation,leading to DNA mutations and/or lower antigen response thresholds.These findings and epidemiological reports suggest an association between HCV infection and NHL.We performed a systematic review of the literature to clarify this potential relationship.We searched the English-language literature utilizing Medline,Embase,Paper First,Web ofScience,Google Scholar,and the Cochrane Database of Systematic Reviews,with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases.References were screened to further identify relevant studies and literature in the basic sciences.A total of 62 reports discussing the relationship between HCV,NHL,and lymphoproliferative diseases were identified.Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV,particularly in areas with high HCV prevalence.Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size,short follow-up periods,and database limitations.The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases.Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear.Lymphomagenesis is a multifactorial process involving genetic,environmental,and infectious factors.HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted.

HCV infection, B-cell non-Hodgkin's lymphoma and immunochemotherapy: Evidence and open questions

There is plenty of data confirming that hepatitis C virus (HCV) infection is a predisposing factor for a B-cell non-Hodgkin's lymphoma (B-NHL) outbreak, while relatively few reports have addressed the role of HCV in affecting B-NHL patients' outcome. HCV infection may influence the short-term outcome of B-NHL because of the emergence of severe hepatic toxicity (HT) during immunochemotherapy. Furthermore, the long term outcome of HCV-related liver disease and patients' quality of life will possibly be affected by Rituximab maintenance, multiple-lines of toxicity during chemotherapy and hematopoietic stem cell transplantation. In this review, data dealing with aggressive and low-grade B-NHL were separately analyzed. The few retrospective papers reporting on aggressive B-NHL patients showed that HCV infection is a risk factor for the outbreak of severe HT during treatment. This adverse event not infrequently leads to the reduction of treatment density and intensity. Existing papers report that low-grade B-NHL patients with HCV infection may have a more widespread disease, more frequent relapses or a lower ORR compared to HCV-negative patients. Notwithstanding, there is no statistical evidence that the prognosis of HCV-positive patients is inferior to that of HCV-negative subjects. HCV-positive prospective studies and longer follow-up are necessary to ascertain if HCV-positive B-NHL patients have inferior outcomes and if there are long term sequels of immunochemotherapies on the progression of liver disease.

Hepatitis C Associated B-cell Non-Hodgkin Lymphoma:Clinical Features and the Role of Antiviral Therapy

The link between chronic hepatitis C virus (HCV) infection and a subset of B-cell non-Hodgkin lymphomas (B-NHL) is strongly supported by epidemiological studies.Evidence demonstrating complete regression of lymphoma after antiviral treatments suggests possible chronic antigenic stimulation for the origin of B-NHL and provides evidence for a virus-mediated lymphomagenesis.B-NHL is a heterogeneous group of lymphomas with varied clinical presentation and may be indolent or aggressive.The optimal management of HCV related B-NHL is not clear.Antiviral treatment may be sufficient for low-grade lymphomas,but chemotherapy is necessary in patients with high grade lymphomas.Interferon (IFN)-based antiviral treatment regimens for HCV infection are limited by poor tolerance and suboptimal antiviral response.Recently approved novel direct acting antiviral (DAA) drugs are highly effective and safe.This has opened a new era for the treatment of HCV related B-NHL alone or in conjunction with chemotherapy.Treatment of HCV associated B-NHL should be performed in an interdisciplinary approach in close consultation with hematologist and hepatologist.In this review,we summarize data regarding clinical features and epidemiology of B-NHL and discuss novel therapeutic approaches,including DAAs,that may prove to be effective in the treatment of HCV associated lymphomas.