Hepatitis C virus – Associated marginal zone lymphoma

Best Practice & Research Clinical Haematology xxx (2017) 1e9

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Hepatitis C virus e Associated marginal zone lymphoma Marine Armand a, b, Caroline Besson c, d, Olivier Hermine e, f, g,
de
ric Davi a, b, * Fre ^pital Piti
Department of Hematology, Ho e-Salp^ etri ere, AP-HP, Paris, France UPMC Univ Paris 06, UMRS-1138, Paris, France c Hemato-Oncology Unit, Centre Hospitalier de Versailles, Le Chesnay, France d Universit
e Versailles Saint Quentin en Yvelines, Universit
e Paris-Saclay, France e ^pital Necker, APHP, Paris, France Department of Hematology, Ho f Inserm UMR1163, CNRS ERL 8254, Institut Imagine, Paris, France g Universit
e Sorbonne Paris Cit
e, Paris, France a

b

a b s t r a c t Keywords: Hepatitis C virus Marginal zone lymphoma Lymphomagenesis Treatment

The link between hepatitis C virus (HCV) infection and the development of B-cell nonHodgkin lymphoma is now well established and based on a number of epidemiological studies. It is further supported by the observation of lymphoma regression after HCV eradication by antiviral treatment. The far most frequent entities are marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). MZL usually emerge on a background of mixed cryoglobulinemia, a low-grade lymphoproliferation, and often transform into DLBCL, thereby following a multistep oncogenesis process. The role of HCV in lymphomagenesis is not yet fully understood but several mechanisms have been proposed including (i) chronic external stimulation through the B-cell receptor and other surface receptors, and (ii) direct transformation by intracellular viral proteins, the former being probably predominant in MZL. Regression of HCV-associated MZL can be achieved with antiviral therapy and the novel generation of direct-acting antiviral agents appears highly effective and safe for the treatment of these lymphoma. © 2017 Published by Elsevier Ltd.

Introduction The link between infectious agents and the development of marginal zone lymphoma (MZL) has been recognized for a long time. The prototypic example is that of Helicobacter pylori and gastric mucosa-associated lymphoid tissue (MALT)-type lymphoma, which involves a multistep pathogenesis process starting with clonal B cell expansion driven by chronic immune stimulation induced by the bacteria, followed by sequential acquisition of additional genetic abnormalities [1]. Importantly, in the early stages the lymphoma depend on the bacteria for their growth and tumor regression can be obtained with H. pylori eradication by antibiotics treatment, whereas this dependency is lost in later stages. Hepatitis C virus (HVC) infection is a worldwide public health problem affecting an estimated 180 million individuals, but with important geographic variations [2]. In 15%e35% of patients, persistent chronic infection leads to hepatic fibrosis and cirrhosis and may ultimately evolve into hepatocarcinoma. A number of extrahepatic manifestations have also been reported, among which lymphoproliferative disorders are the most documented [3]. ^pital Pitie
-Salpe ^trie re, 47-83 Bd de l'Ho ^pital, 7513, Paris, France. * Corresponding author. Department of Hematology, Ho E-mail address: [email protected] (F. Davi). http://dx.doi.org/10.1016/j.beha.2017.02.001 1521-6926/© 2017 Published by Elsevier Ltd.

Please cite this article in press as: Armand M, et al., Hepatitis C virus e Associated marginal zone lymphoma, Best Practice & Research Clinical Haematology (2017), http://dx.doi.org/10.1016/j.beha.2017.02.001

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HCV is a small encapsulated positive-stranded RNA virus of the Flaviviridae family. Its 9,6 kb genome is translated into a polyprotein of approximately 3000 aminoacids, which is further processed into 10 structural and non-structural proteins [4]. The former include the core capsid protein and two envelop proteins, E1 and E2. Most of the non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) are enzymes essential for HCV replication and constitute targets for new therapeutic agents. Six major serotypes, differing by their geographic distribution and responsiveness to antiviral treatment have been described. Epidemiology of HCV-associated lymphomas Early epidemiological studies reported conflicting results regarding the prevalence of HCV infection within patients with non-Hodgkin's lymphoma (NHL). High levels were found mainly in Italian cohorts (20%e40%) [5,6] and to a lesser extent in Japanese studies (8%e16%) [7,8]. In contrast, other European or Northern American studies failed to find any difference [9,10]. Discrepancies may have been explained, at least in part, by the relative small size of the cohorts, differences in methods used to detect the virus, HCV genotype distribution, as well as by environmental and/or genetic cofactors. Further epidemiological studies including large scale caseecontrol cohorts and meta-analyses of retrospective series allowed to obtain a better assessment of the prevalence of HCV in NHL patients. They confirmed an increased although moderate risk of developing NHL in HCV-infected patients compared to HCV-negative controls (relative risk ¼ 2e3) [11e13]. Thus, up to 10% of NHL can be associated with HCV in countries with high prevalence of the virus [11,14]. Pozzato et al. have recently conducted a metaanalysis on 19 case-controls and 4 cohort studies including in total about 9000 lymphoma cases (and over 12,000 controls) screened for the presence of HCV infection [15]. They found that HCV infection was associated with an overall 2.3 relative risk of developing NHL. There was however geographical heterogeneity linked to different prevalence of HCV infection within the population, with higher relative risk of NHL (>3) being observed in regions with high prevalence of infection such as the Mediterranean basin. Besides regional differences, the prevalence of HCV infection may also vary according to the lymphoma histological subtype. A large meta-analysis from the International Lymphoma Epidemiology Consortium (InterLymph) identified 172 HCV-positive cases among 4784 NHL [16]. HCV was found to be associated with MZL (odds ratio [OR], 2.47; 95% confidence interval [CI], 1.44e4.23), diffuse large B-cell lymphoma (DLBCL) (OR, 2.24; 95% CI, 1.68e2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14e5.79). In contrast, there was no increased risk for follicular lymphoma (OR, 1.02; 95% CI, 0.65e1.60). Other studies also ruled out an association of HCV with chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma or T-cell lymphoma [12]. Michot et al. recently reported the histological characteristics of 116 HCV positive B-cell NHL cases [17]. MZL and DLBCL were by far the two most frequent subtypes (39% each) confirming previous studies [12,15,16]. Interestingly in more than a third of cases, there was evidence that DLBCL originated from a low-grade NHL (mainly MZL) due to the presence of small neoplastic B cells infiltration in the tissue biopsies, confirming previous findings [18]. Altogether these data indicate that (i) MZL is probably the most frequent entity associated with HCV infection, and (ii) might be particularly prone to transform into aggressive DLBCL. Characteristics of HCV-associated MZL HCV-associated MZL develop following a long duration of infection with median time ranging from 15 to 25 years. A recent study including 45 MZL cases found that they frequently displayed bone marrow and/or blood (45%) and spleen (44%) involvement [17]. When compared to DLBCL, MZL presented more often with cryoglobulinemia (75% vs 44%) and rheumatoid factor (68% vs 35%). All 3 subtypes of MZL, i.e. MALT, nodal and splenic have been found to occur in HCV infected patients [6,17,19,20]. Although HCV-positive gastric MALT have been reported [6], HCV infection seems to occur more frequently in non-gastric MALT. Arcaini et al. reported a series of 60 non-gastric MALT in which the most frequent localizations were the skin (35%), salivary glands (25%) and orbit (15%) [19]. In addition, HCV-associated MZL may present with distinctive characteristics. Saadoun et al. described 18 cases of splenic lymphoma with villous lymphocytes (SLVL) and type II cryglobulinemia and proposed it could represent a new entity [21]. Most of these patients were women (78%) and had symptomatic cryglobulinemia (72%). Paulli et al. reported 12 cases with an unusual subtype of MALT-type MZL, consisting in a sub-cutaneous “lipoma-like” presentation, also occurring predominantly in women (83%) and associated with an indolent clinical course [22]. Linking HCV infection to B-cell clonal proliferations Mixed cryoglobulinemia: a pre-lymphoma stage Mixed cryoglobulinemia (MC) is the most frequent extra-hepatic manifestation of HCV infection. Cryoglobulins are serum immunoglobulins (Ig) which precipitate at temperature below 37  C. Depending on their composition they are classified as type I if only a single monoclonal Ig is present, or as MC which combine polyclonal IgG and either monoclonal (type II) or polyclonal (type III) IgM [23]. A very high prevalence of HCV infection (>90%) is found among patients with type II MC [24]. Conversely MC are detected in 30%e60% of patients of HCV-positive subjects, but with wide geographical heterogeneity [25,26]. In HCV-infected patients, they are usually present at low levels and symptomatic MC with clinical signs of vasculitis Please cite this article in press as: Armand M, et al., Hepatitis C virus e Associated marginal zone lymphoma, Best Practice & Research Clinical Haematology (2017), http://dx.doi.org/10.1016/j.beha.2017.02.001

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occur only in less than 10% of cases [25e27]. Longitudinal studies have shown that about 8%e10% of the type II MC transform into frank lymphoma [28]. However, for HCV-infected patients with symptomatic MC the risk of developing NHL can be 35 times higher than in the general population according to an Italian study [29]. The monoclonal component of the type II MC is an IgM directed against the IgG and thus displays a rheumatoid factor activity, often expressing the Wa cross-reactive idiotype [30]. These immune complexes also contain viral RNAs [24,31]. Analyses of liver biopsies from HCV patients with MC have revealed the presence of lymphoid cell infiltrates containing clonal or polyclonal B cells in respectively type II or type III MC [32,33]. Monoclonal B cells have also been detected in the blood and bone marrow of patients with type II MC [33,34]. Sequencing the immunoglobulin variable region (IGV) genes from these clonal B-cell expansions revealed a restricted IGV gene repertoire usage with similarities to that of HCVassociated NHL (see below). MC is therefore considered as a benign low-grade lymphoproliferation capable of evolving into overt lymphoma. Effect of antiviral therapy The most compelling evidence for a role of the HCV in the development of NHL comes from their response to treatment with antiviral therapy alone. Hermine et al. reported hematological remission in 9 patients with SLVL treated with alfainterferon (IFN) alone or in combination with ribavirin [35]. In contrast, 6 patients with HCV-negative SLVL failed to respond, demonstrating the specificity of the treatment. These results were confirmed by several studies showing that antiviral therapy leads to a global response rate of 60%e75% in HCV-associated low-grade lymphoma [36,37]. A similar rate of hematological response was recently observed in a series of 46 HCV-positive indolent NHL, the majority being MZL, treated by direct-acting antiviral agents (DAA), further demonstrating the role of the virus in sustaining these lymphoproliferations [38]. This situation is reminiscent of H. pylori-associated gastric MALT lymphoma where remission can be obtained with antibiotic treatment [39]. Pathogenesis of HCV-associated B-cell proliferations Several mechanisms have been proposed to explain the genesis of B-cell lymphoma in HVC-infected individuals. Chronic “external” stimulation A strong argument in favor of an antigenic stimulation in the development of HCV-associated NHL comes from the finding of a biased repertoire in their expressed IGV genes. A number of molecular studies have reported preferential usage of certain IGV genes, particularly in MZL, with IGHV1-69, IGHV3-7, IGHV4-59 for the heavy chains and IGK3-20, IGKV3-15 for the light chains being the most representative [40e43]. A similar IGV repertoire has also been found to be preferentially used in clonal B-cell populations of type II MC [41,44,45]. Quinn et al. showed that recombinant soluble Ig made from NHL Bcell receptor (BcR) could bind the HCV-E2 envelop protein of several genotypes [46]. Similar findings were made regarding the HCV-NS3 protein [47]. The E2 protein has been shown to be an important target of the antibody response following viral infection [48,49]. Interestingly, monoclonal antibodies derived from non-malignant cells of infected individuals responding to the E2 viral antigen were found to use preferentially the IGHV1-69 gene [43]. All these findings lead to the hypothesis that NHL could originate from B lymphocytes expressing a BcR specific for viral epitopes and clonally expanded by chronic antigenic stimulation. This scenario would imply a multistep transformation process whereby chronic BcR stimulation by viral proteins such as E2 or NS3 would lead to expansion of first polyclonal and then oligoclonal anti-HCV B cells, culminating in the final outgrowth of a monoclonal neoplastic population [41,50]. The anti-virus reactivity of the lymphomatous cells has been challenged however in a recent report by Ng et al. who expressed either in a soluble or membrane-bound form various lymphoma BcR including those with recurrent IGHV and IGKV sequences. None of these recombinant Ig proved capable of binding a panel of viral proteins nor the assembled HCV virion particules [51]. An alternative hypothesis implies a molecular mimicry between some viral epitopes, such as those from the hypervariable region 1 of E2 or NS3 proteins, and structurally similar Ig motifs recognized by RF [47,52]. Along this line, BcR with quasi-identical IGV amino-acid sequences to those of HCV-associated NHL and type II MC, including the highly variable complementary determining region 3, have been described in HCV-negative B-cell malignancies, often associated with RF, such as splenic MZL, MALT lymphoma and CLL [53e55]. These “stereotyped” receptors could also be detected in nonmalignant B cells with RF activity as well as normal splenic marginal zone B cells [56]. These findings suggest that HCV-associated NHL, and particularly MZL, originate from precursors with auto-immune properties rather than B cells targeting directly the virus itself. Besides the BcR, additional stimulation might come from other receptors on the surface of B lymphocytes chronically activated by the virus, and contribute to the emergence of clonal populations. The best documented example is CD81, a cellsurface tetraspanin which associates with CD19 and CD21 to form a costimulatory complex, lowering the threshold necessary for BcR-mediated B-cell activation [57]. CD81 has been shown to be a receptor for HCV binding to its envelop E2 protein, and necessary for entry of the virus in human cells [58,59]. Engagement of CD81 by the HCV-E2 protein was found to promote proliferation of B cells through activation of the c-Jun N-terminal kinases pathway [60]. Within this costimulatory complex, CD21, the complement receptor 2, is also necessary for binding of the virus to B cells [61]. Thus, sustained activation of B cells Please cite this article in press as: Armand M, et al., Hepatitis C virus e Associated marginal zone lymphoma, Best Practice & Research Clinical Haematology (2017), http://dx.doi.org/10.1016/j.beha.2017.02.001

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by the virus might result from the bridging and simultaneous engagement of at least 2 types of cell-surface receptors including (i) the BcR binding either the virus directly or immune complexes containing viral particules, and (ii) the CD19CD21-CD81 costimulatory complex. Of note, CD81 engagement by itself might be sufficient to promote B cell activation without BcR participation [60]. Direct transformation by viral proteins Lacking reverse transcriptase allowing integration into the host genome and well-recognized oncogenes, HCV cannot be considered as a “classical” oncogenic virus. That notwithstanding, there is experimental data suggesting that HCV proteins can contribute to transform target cells. Indeed, the core and non-structural NS3 proteins have been shown to induce cell transformation upon transfection in murine (or rat) fibroblasts [62,63]. More relevant to lymphomagenesis, several transgenic models in mice point out an oncogenic role for HCV proteins. Thus, mice expressing the virus core protein developed follicular center-cell type lymphoma with high frequency (80%) after a long period of latency (20 months) [64]. Another model involving the inducible and persistent expression of structural proteins in IFN regulatory factor-1-null mice (irf-1/CN2 mice) resulted in very high incidence of lymphoma and/or lymphoproliferative disorders [65]. In a third model, conditional expression of the full HCV genome in B lymphocytes led to the occurrence of DLBCL in 25% of mice [66]. However, a main issue is whether these artificial models are relevant to the situation in humans. As discussed above, CD81, expressed on various cell types including B cells, serves as receptor for the virus [58]. Very recently, the co-stimulatory receptor B7.2 (CD86) has been shown to constitute a co-receptor for lymphotropic HCV strains derived from an HCV-positive B-cell lymphoma, enabling the virus to infect memory B cells [67]. Furthermore, active in vitro infection has been demonstrated with the establishment of an HCV-positive cell line (SB cells) producing virions in culture capable of infecting primary human hepatocytes, peripheral blood mononuclear cells (PBMC), as well as an another B-cell line (Raji) [68]. It has been much more difficult to establish that lymphocyte infection also occurs in vivo. Demonstration of negativestrand RNA, the viral replicative intermediates, has served for many years as a proof of active in vivo replication of HCV within human lymphocytes, but results have been controversial, in part due to possible technical artifacts [69,70]. More convincing evidence has come from the detection of viral proteins (NS3, core) expressed in the PBMC of infected individuals [71e73]. Very recently, Canioni et al. demonstrated the expression of HCV NS3 protein in primary B cells of HCV-associated lymphoma [74]. Interestingly, NS3-positive cases were found much more frequently within DLBCL (12/14 cases) than MZL (4/ 14 cases, with 2/4 NS3þ cases being enriched in large cells) suggesting that oncogenic viral proteins play a role mainly in the development of DLBCL. The “hit and run” model Machida et al. found a 5- to 10-fold increased mutation frequency in IGH, BCL6, TP53 and CTNNB1 (b-catenin) genes, in in vitro infected B cell lines as well as HCV-associated PBMCs and lymphoma [75]. They could relate this “mutator” phenotype to the ability of the virus to cause double strand DNA breaks and to induce activation-induced cytidine deaminase (AID) and error-prone polymerases. The authors proposed that this could represent a “hit and run” mechanism for HCV lymphomagenesis, explaining the finding of genetic damages in absence of detectable HCV replicative form in the B cells. However these results were not confirmed by subsequent studies performed on peripheral or intrahepatic B cells from HCV-infected patients [76,77]. Molecular pathways involved in B-cell transformation How lymphocyte infection by the virus leads to transformation still remains uncertain although a few mechanisms seem to emerge. Transfection of human B lymphocytes with HCV core protein resulted in significant inhibition of apoptosis with downregulation of caspase-1 and caspase-4 gene expression [78]. Altered expression profile was also observed in B-cell lymphoma arising in transgenic mice harboring the full-length HCV genome, with in particular overerexpression of the gene coding for the NF-KB activator lymphotoxin-beta receptor, and underexpression of the gene coding for A20, a negative regulator of NF-KB with tumor suppressor characteristics, resulting in an NF-KB activation in lymphomatous cells [79]. Gene expression alterations also involved the microRNAs (miRNAs) network. Thus, reduced expression of miR-26b, a miRNA with tumor suppressor properties, was found in HCV-positive SMZL compared to HCV-negative SMZL [80]. Similar findings were obtained in the murine transgenic model mentioned above [79]. Very recently, the HCV non-structural protein NS3/4A was shown to interact with checkpoint kinase 2 (CHK2), a protein playing a critical role in the DNA damage response, and to down-regulate its activity in lymphoma cells. This in turn modulated activity of HuR, a RNA-binding protein regulating gene expression, resulting in upregulation of mRNAs involved in the BcR signaling pathway [73]. Induction of DNA damages might also result from HCV stimulation of nitric oxid and reactive oxygen species production, which were shown to be the primary inducers of double strands breaks along with mitochondrial damages in infected cells [75,81]. 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Genomics alterations in HCV-associated lymphoma Similar to H. pylori-induced gastric MALT lymphoma, HCV-associated lymphomagenesis is a multistep process which might require sequential acquisition of genetic abnormalities. Increased prevalence of t(14; 18) translocation, evidenced by IGH-BCL2 rearrangements, has been reported in the PBMC of patients chronically infected by HCV, those with MC showing the highest frequency (up to 71%) [82e84]. However in patients with HCV-associated lymphoma, the translocation has rarely or not been detected in the tumor biopsies, while it was found in their PBMC at similar rate to those of HCV-negative lymphoma patients [85,86]. Furthermore follicular lymphoma is a not a common subtype among HCV-associated lymphoma [12,15,16]. As IGH-BCL2 rearrangements can be detected at low frequency in healthy individuals [84,87], one hypothesis is that in patients with HCV infection, chronic inflammation creates a favorable microenvironment allowing expansion of bystander t(14; 18)-positive B-cell clones unrelated to the lymphomatous population [88]. Only very limited number of studies have explored the molecular and cytogenetics features of HCV-associated lymphoma. Matteucci et al. have shown that low- and high-grade lymphoma display distinct genomic imbalances [86]. Gain of chromosome 3q was seen essentially in indolent SMZL (4/6 cases) as well as in one case of type II MC without lymphoma. Conversely, 2q loss spanning a 850 kb region at 2q22.3 was detected only in aggressive DLBCL (4/5 cases). Mutations in the NOTCH pathway, which occur frequently in HCV-negative MZL, have been recently identified in about a quarter of HCV-positive DLBCL, with NOTCH2 being the main target (20% of cases) [89]. These mutations were associated with a poor outcome and observed in cases displaying low-grade component in the diagnostic biopsy, strongly suggesting that these NOTCH-mutated DLBCL may represent transformed MZL. Treatment of HCV-associated marginal zone lymphoma Classical IFN-based antiviral therapy (AVT) can lead to regression of HCV-associated MZL [35,90,91]. AVT has been shown to have a beneficial impact on overall survival of patients with HCV-associated NHL [17,92]. Remarkably, the correlation between hematological and virologic responses supports a direct impact of HCV infection on lymphomagenesis [35]. However, the contribution of a direct anti-lymphoma activity of IFN could not be ruled out until the recent demonstration of the efficacy of IFN-free DAA in patients with HCV-associated indolent lymphomas [38]. Inteferon-based therapy The favorable impact of IFN-based antiviral therapy on the outcome of patients with HCV associated MZL has been consistently reported in the Fondazione Italiana Linfomi study [92] and in the French ANRS HC-13 Lympho-C study [17]. The ANRS LymphoC study reported a series of 116 patients with the two main histological types being MZL and DLBCL. A sustained virological response (SVR) was achieved in 61% of patients receiving antiviral treatment. Among the 14 patients who received AVT alone as first-line MZL treatment, 11 achieved hematological response, among which 8 patients had a complete response. These 11 hematological responder patients were also in SVR after AVT. Conversely, the 3 patients who did not achieve hematological response were virologic non-responders. Overall, patients with MZL had a 2-year progression-free survival (PFS) and overall survival (OS) of 78% and 83%, respectively, which significantly correlated with the use of AVT (p ¼ 0.05 and 0.03, respectively). Altogether, these results emphasize that AVT is the cornerstone of treatment for HCV-related MZL. Direct antiviral therapy The therapy of HCV infection is undergoing major transformation. After nearly 25 years of IFN-based therapies, a new generation of DAA has entered clinical practice [93]. Recently, several DAAs were approved as part of different IFN-free combination therapies. These include second-generation NS3/4A inhibitors (simeprevir, ritonavir-boosted paritaprevir, grazoprevir), NS5A inhibitors (daclatasvir, ledipasvir, ombitasvir, elbasvir), a nucleotide polymerase inhibitor (sofosbuvir), and a non-nucleoside polymerase inhibitor (dasabuvir). In term of efficacy, DAA therapy can induce viral eradication in >90% of all patients across different genotypes and fibrosis stages with the exception of some patient subgroups (e.g. patients with decompensated cirrhosis). Furthermore, DAAs regimens are associated with a strikingly better tolerability profile than IFN treatment and thus represent an attractive alternative to treat HCV-associated NHL. We recently evaluated virologic and hematological response rates and toxicity of DAAs in an international series of patients with indolent NHL treated by DAAs in the absence of immunochemotherapy [38]. Main histological subtypes were MZL (n ¼ 37) and CLL/small lymphocytic lymphoma (SLL) (n ¼ 4). Median duration of DAA therapy was 12 weeks (range 6e24 weeks). DAA treatment led to a virological response in all patients except one who had decompensated cirrhosis. The hematological response reached 73% among patients with MZL while no response was observed in CLL/SLL patients. This proportion of hematological responses is similar to the one reported in a meta-analysis of HCV-related NHL patients receiving IFN-based treatment [94]. After a median follow-up of 8 months, 1-year PFS and OS were 75% and 98%, respectively. Toxicity of treatment was negligible. Overall, this international retrospective study demonstrates that as described in HCV infection without lymphoma, SVR can be obtained in nearly all patients (98%) with chronic HCV infection, and that frequent hematological responses can be achieved in HCV-associated MZL treated with IFN-free DAA. Please cite this article in press as: Armand M, et al., Hepatitis C virus e Associated marginal zone lymphoma, Best Practice & Research Clinical Haematology (2017), http://dx.doi.org/10.1016/j.beha.2017.02.001

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Chemotherapy or immunotherapy These studies led to the conclusion that DAA should be used as the first option for HCV-associated MZL when cytoreductive treatment is not immediately necessary [95]. Moreover, data from patients treated with IFN-based AVT or with DAA also support the use of antivirals in patients in progression or relapse after chemotherapy-based first line therapy when cytoreductive treatment is not immediately necessary. In case of high tumor burden and/or symptomatic hematological disease, it is plausible that DAA alone would not be the most appropriate therapeutic strategy since 25% of patients do not respond to this therapy. Previous studies from the pre-DAA era reported that chemotherapy can lead to high rates of liver toxicity in HCVassociated B-NHL and that infection is a leading cause of death in these patients, suggesting that rituximab-based regimen should be preferred to chemotherapy whenever it is possible [18,96]. In the Lympho-C study, all the patients (n ¼ 8) treated with IFN-based antivirals combined with rituximab had a hematological response. This association has also been shown to be efficient in HCV-related MC [91]. There are some early reports of the combination of DAA and rituximab or chemotherapy [97]. In this study, 9 patients including 6 with MZL and 3 with DLBCL were treated by DAA and rituximab alone (n ¼ 3) or rituximab in combination with other drugs (n ¼ 6). SVR was achieved in all but one patient. The patients in SVR had a complete hematological response while the only patient with a partial hematological response had a virologic response failure. The safety profile of therapy with DAAs was very good. Overall, the AVT-R combination may constitute a preferential option in patients with MZL and symptomatic disease or high tumor burden.

Conclusions There is now good evidence linking HCV infection and MZL. Clinical and pathological data support a stepwise model from MC to transformed DLBC. HCV lymphomagenesis is not fully understood yet, and may involve several mechanisms including chronic “external” stimulation in the early stages and direct transformation by viral proteins in later stages. Both IFN-based therapy and DAA have demonstrated efficacy in HCV-associated MZL. Because of its safety, rapidity and efficacy to obtain SVR, DAA therapy should be preferred to IFN-based antiviral treatment. Further studies are warranted to evaluate the place of this combination in the treatment of patients with advanced, rapidly progressive and/or symptomatic disease.

Conflicts of interest The authors have no conflict of interest to disclose.

Practice Points Based on a large number of epidemiologic studies, HCV infection confers a 2e3 relative risk of developing NHL. MZL and DLBCL, either de novo or transformed, are the predominant histologic subtypes, accounting each for roughly 40% of HCV-associated lymphoma. Chronic external stimulation may constitute the main driving mechanism in MZL, while direct transformation by viral proteins may be a feature predominantly seen in DLBCL. MZL appear responsive to antiviral therapy and the new generation of DAA seem particularly promising considering their efficacy and low toxicity, although longer follow-up is required to evaluate their long-term therapeutic benefit.

Research Agenda The mutational landscape of HCV-associated MZL should be characterized, including the identification of genetic lesions associated with progression of MC to MZL, and MZL to DLBCL. Prospective trials with DAA are warranted to fully evaluate their therapeutic impact in the treatment of HCV-associated MZL.

Acknowledgements
patites virales) grant (ANRS This work is supported in part by an ANRS (Agence Nationale de Recherches sur le Sida et les he HC 13 Lympho-C). Please cite this article in press as: Armand M, et al., Hepatitis C virus e Associated marginal zone lymphoma, Best Practice & Research Clinical Haematology (2017), http://dx.doi.org/10.1016/j.beha.2017.02.001

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