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Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and Role of Antiviral Therapy

Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and... Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 638185, 10 pages doi:10.1155/2012/638185 Review Article Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and Role of Antiviral Therapy 1 2 3 1 Luca Arcaini, Michele Merli, Stefano Volpetti, Sara Rattotti, 1 3, 4 Manuel Gotti, and Francesco Zaja Department of Hematology Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy Division of Hematology, Department of Internal Medicine, Ospedale di Circolo, Fondazione Macchi, 21100 Varese, Italy Department of Hematology, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, 33100 Udine, Italy Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy Correspondence should be addressed to Francesco Zaja, zaja.francesco@aoud.sanita.fvg.it Received 16 May 2012; Revised 4 July 2012; Accepted 4 July 2012 Academic Editor: Jurg ¨ Schifferli Copyright © 2012 Luca Arcaini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin’s lymphomas (NHL) has been demonstrated by epidemiological studies, in particular in highly endemic geographical areas such as Italy, Japan, and southern parts of United States. In these countries, together with diffuse large B-cell lymphomas, marginal zone lymphomas are the histotypes most frequently associated with HCV infection; in Italy around 20–30% cases of marginal zone lymphomas are HCV positive. Recently, antiviral treatment with interferon with or without ribavirin has been proved to be effective in the treatment of HCV-positive patients affected by indolent lymphoma, prevalently of marginal zone origin. An increasing number of experiences confirmed the validity of this approach in marginal zone lymphomas and in other indolent NHL subtypes like lymphoplasmacytic lymphoma. Across different studies, overall response rate was approximately 75%. Hematological responses resulted significantly associated with the eradication of the virus. This is the strongest evidence of a causative link between HCV and lymphomas. The aim of this paper is to illustrate the relationship between HCV infection and different subtypes of indolent B-cell lymphomas and to systematically summarize the data from the therapeutic studies that reported the use of antiviral treatment as hematological therapy in patients with HCV-associated indolent lymphomas. 1. Introduction lymphoma and extranodal marginal zone lymphoma of mucosa-associated tissue (MALT), and lymphoplasmacytic In the last two decades, evidences from either epidemiolog- lymphoma. According to the currently more accepted patho- ical studies, biological insights, and also therapeutic genetic model, the role of HCV infection in lymphomage- approaches provided strong support to the association nesis may be related to the chronic antigenic stimulation of between hepatitis C virus (HCV) and B-cell non-Hodgkin’s B-cell immunologic response by the virus [3], similarly to lymphomas (NHL). HCV has been associated with B-cell the well-characterized induction of gastric MALT lymphoma indolent lymphomas, especially marginal zone lymphomas, development by Helicobacter pylori chronic infection [4]. In as well as with aggressive lymphomas, mainly diffuse large a similar way, chronic HCV infection may possibly sustain B-cell lymphomas. Indolent lymphomas are defined from a a multistep evolution from type II mixed cryoglobulinemia clinical point of view as scarcely symptomatic lymphomas, to overt low-grade NHL and eventually to high-grade NHL growing and spreading slowly [1] and encompass the follow- [3, 4]. The most convincing argument in favour of a causative ing histologic subtypes of low-grade lymphoma according link between HCV and lymphoproliferation is represented by to the WHO classification [2]: follicular lymphoma, small interventional studies demonstrating that in HCV-positive lymphocytic lymphoma, marginal zone lymphomas, splenic patients affected by indolent NHL eradication of HCV with marginal zone lymphoma, primary nodal marginal zone antiviral treatment (AT) could directly induce lymphoma 2 Clinical and Developmental Immunology regression [5]. Moreover, the upcoming novel antiviral anti- long-term followup. Type II mixed cryoglobulinemia is often HCV agents as boceprevir and telaprevir, whose addition to characterized by IgH or Bcl2 rearrangement and by t(14; standard treatment has already demonstrated an increased 18) translocation [12]. Treatment of HCV type II mixed rate of viral eradication also in more resistant genotypes (i.e., cryoglobulinemia with severe organ damage may target genotype 1b) [6, 7], will possibly further improve the efficacy either the viral trigger (HCV) or the downstream arm of B- of this treatment for HCV-positive indolent NHL in the near cell autoimmunity. AT with pegylated interferon + ribavirin future. has been shown to reverse bone marrow B-cell expansion in patients with HCV-MC, leading to a clinical and virologic response in up to 60% of cases [13]. Recent studies 2. Methods showed that the combination of AT (PEG-interferon + The aim of this paper is to systematically summarize the ribavirin) with the anti-CD20 monoclonal antibody ritux- available data indolent B-cell NHL associated with HCV imab is well tolerated and more effective than AT alone, by infection and the up-to-now reported experiences with the increasing the rate of complete clinical response, immuno- use of AT with interferon with or without ribavirin as hema- logic (cryoglobulin clearance) and molecular response tologic treatment in patients with HCV-positive indolent B- (eradication of B-cell clonal expansions), and shortening the cell NHL. time to achieve a complete clinical response [14, 15]. To thisaim,weperformed asystematicPubMedsearch (http://www.pubmed.gov/) using the keywords “indolent lymphoma,” “marginal zone lymphoma,” “MALT lympho- 3.2. Epidemiology of HCV and Its Association with Lym- ma,” “lymphoplasmacytic lymphoma,” “hepatitis C virus,” phomas. HCV infection is a global health problem, with up “interferon,” “ribavirin,” “antiviral therapy.” All relevant arti- to 170 million persons infected worldwide (3% of global cles were included, as well as the most significant abstracts population) [25]. However relevant regional differences in presented at American Society of Hematology (ASH) meet- the prevalence of infection are described. The lowest preva- ings and International Conference on Malignant Lym- lence rates are reported in Northern Europe and Scandinavia phomas (ICML) meetings since 2005. The articles were (0.01–0.1%) while in Italy, Egypt, Japan, and southern parts reviewed with reference to the features of HCV-associated of United States, prevalence estimates exceeds 2% [26]. indolent NHL and were assessed specifically concerning HCV infection is a leading cause of chronic hepatitis, cir- virological and hematological response in cases treated with rhosis, and hepatocellular carcinoma and has been associated AT. to extrahepatic manifestations, especially type II mixed cryoglobulinemia and a spectrum of B-cell NHL with or 3. HCV Infection, Cryoglobulinemia, without cryoglobulinemia [3]. Several epidemiological stud- ies have been performed beginning from the mid 1990s to and Lymphomas investigate the link between HCV and NHL. Early studies 3.1. HCV and Cryoglobulinemia. The initial finding that based on relatively small number of cases suggested a lead to the extensive investigation of the association significant increased risk of B-cell NHL in HCV-positive between HCV and NHL was the very high prevalence patients, especially in countries with high prevalence of (nearly 90–100%) of HCV infection in patients with type HCV infection as Italy [27], Japan, and southern regions II mixed cryoglobulinemia [8]. Cryoglobulins are serum of USA, while studies from areas with low HCV prevalence immunoglobulins that become insoluble and precipitate did not show any evident association [28]. In 2003, a at temperatures below 37 C. The antigenic component systematic review of studies evaluating prevalence of HCV of the immune complexes has been found to be highly infection in B-cell NHL [29] was published. In this report, 48 enriched in viral HCV core protein and HCV-RNA. Type studies (5,542 patients) were identified. Mean HCV infection II mixed cryoglobulinemia is characterized by a mixture prevalence was 13%. In 10 case-control studies examined, of monoclonal and polyclonal immunoglobulins. The HCV prevalence in B-cell NHL was 17% compared to 1.5% monoclonal component of type II mixed cryoglobulinemia in healthy controls (odds ratio, OR = 10.8). Therefore, it is an IgM/k with a rheumatoid-factor activity (i.e., anti-IgG was concluded that HCV prevalence in patients with B-cell cross-reactive binding) that reflects the expansion of a NHL is higher than that reported in general population (15% B-cell monoclonal population [9]. Overall, up to 50% of vs. 1.5%), suggesting a role of HCV in the aetiology of B- HCV-infected patients exhibit low levels of circulating mixed cell NHL. Subsequently, in 2006, an updated metaanalysis cryoglobulins, whereas overt cryoglobulinemic vasculitis of 15 case-control studies on the association between HCV develops in ≤5% of infected patients [10]. Symptoms vary infection and NHL demonstrated a pooled relative risk of from purpura and arthralgia to more severe manifestations lymphoma among HCV-positive subjects of 2–2.5 depending like peripheral neuropathy and glomerulonephritis. on study design. Relative risks resulted consistently increased Importantly, in HCV-infected patients with symptomatic for all major B-NHL subtypes. The study, indeed, confirmed cryoglobulinemia, the risk to develop an NHL is greatly that the risk to develop NHL in the context of HCV increased with respect to the general population (about 35 infection is most dramatically evident in populations with times according to a multicenter Italian study) [11]. As a high HCV prevalence and that consequently the fraction of result, approximately 8–10% of patients with type II mixed NHL attributable to HCV infection varies greatly by country, cryoglobulinemia ultimately progress to a frank NHL after reaching 10% in highly endemic areas. Clinical and Developmental Immunology 3 Table 1: Clinical pathological studies describing indolent NHL subtypes associated with HCV infection. N pts tested Cryoglobulinemia, Year Diagnosis N pts N HCV+ (%) Genotypes for HCV N (%) 1b (n = 10), 2b (n = 1), Arcaini et al. [16] 2006 SMZL 309 255 49 (19) 13 (10) 2a/2c (n = 4) 1(n = 7), 2 (n = 4), Saadoun et al. [17] 2005 SLVL 18 18 18 (100) 18 (100) 3(n = 1), 4 (n = 1) NMZL Arcaini et al. [18] 2007 47 38 9 (24) NA 2 (14) MALT-MZL 172 172 60 (35%) Skin 29 29 21 (43) 1a (n = 11), 1b (n = 1), Salivary glands Arcaini et al. [19] 2006 32 32 15 (47) NA 2a/2c (n = 10) Orbit 25 25 9 (36) Other sites 66 66 15 (22) MALT-MZL Ferreri et al. [20] 2006 55 55 7 (13) NA 2 (29) orbit Subcutaneous 2a/2c (n = 4), 2a (n = 2) Paulli et al. [21] 2009 13 13 13 (100) 3 (75) MALT- MZL 2b, (n = 1) Tedeschi et al. [22] 2009 WM 140 140 21 (15) NA 10 (48) WM 122 66 6(9) NA 0 Arcaini et al. [23] 2011 SMZL 98 92 25 (27) NA 3 Goldaniga et al. 2008 B-CLPD 156 113 6 (5) NA NA [24] SMZL: splenic marginal zone lymphoma; NMZL: nodal marginal zone lymphoma; SLVL: splenic lymphoma with villous lymphocytes; MZL: marginal zone lymphoma; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; SLL: small lymphocytic lymphoma; NHL: non- Hodgkin’s lymphoma; B-CLPD: B-cell chronic lymphoproliferative disorders. The numbers of cases analyzed in these series were too 4.1. Marginal Zone Lymphomas. Within specific indolent small to establish a correlation between HCV and specific NHL subtypes, the association with HCV infection has histotypes. In the Epilymph [30] case-control study, the sub- been best characterized in marginal zone lymphomas. In type most clearly associated with HCV infection was diffuse the 2008 edition of WHO classification three marginal zone large B-cell lymphoma, followed by marginal zone lym- lymphoma entities were listed [2]: splenic B-cell marginal phoma and lymphoplasmacytic lymphoma; however these zone lymphoma, nodal marginal zone lymphoma, and results were based on relatively few cases. To obtain a more extranodal marginal zone B-cell lymphoma of MALT type. robust estimate of the risk to develop specific NHL subtypes Marginal zone B-cells have been demonstrated to play role after HCV infection, the International Lymphoma Epidemi- in the immune response to T-cell-independent antigens and ology Consortium (InterLymph), based in Europe, North frequently display reactivity to self antigens. Marginal zone America, and Australia, performed a pooled case-control B-cells are involved in various infectious and autoimmune study including in the analysis data of 7 previous surveys conditions and marginal zone-related neoplasms often retain [31]. Overall, among 4,784 cases of NHL and 6,269 controls the features of these cells. Many infectious agents are involved matched by sex, age, and study centre, HCV infection was in the pathogenesis of specific types of marginal zone lym- detected in 172 NHL cases (3.6%) and in 169 (2.7%) phomas: Helicobacter pylori for gastric MALT lymphoma [4], controls. In subtype-specific analyses, HCV prevalence was Campylobacter jejuni for immunoproliferative small intestine associated with diffuse large B-cell lymphoma (OR 2.24), disease [35], Borrelia burgdorferi for MALT lymphoma of the marginal zone lymphoma (OR, 2.47), and lymphoplasma- skin [36], and Chlamydia psittaci for MALT lymphoma of the cytic lymphoma (OR 2.57) whereas risk estimates were not orbit [37, 38]. In all these cases, eradication of the antigen increased for follicular lymphomas (OR 1.02). Moreover, after antimicrobial therapy may lead to a regression of the also retrospective series reported a high HCV prevalence lymphoma. For example, eradication of Helicobacter pylori among patients with marginal zone lymphoma [4, 16–18, 20, leads to the complete regression of gastric MALT lymphoma 32], lymphoplasmacytic lymphoma, and diffuse large B-cell in most cases, and relapse of the lymphoma is anticipated by lymphoma [33, 34]. the reoccurrence of the infection [4]. Accordingly to this scenario, also chronic stimulation by HCV may play a role in development of a subgroup of 4. HCV and Indolent Lymphomas: Clinical and marginal zone lymphoma cases. The association between Pathological Studies HCV and marginal zone lymphomas is demonstrated by epi- As mentioned above, many well-characterized clinical-path- demiological studies, as previously summarized, and by clinical-pathological studies of well-characterized marginal ological studies investigated the association of HCV infection with specific indolent NHL subtypes (Table 1). zone lymphoma series. However, the major support to the 4 Clinical and Developmental Immunology potential causal role of HCV in marginal zone lymphoma- Sjog ¨ ren’s syndrome and HCV infection reported an elevated genesis is represented by the antilymphoma activity of AT occurrence of parotid involvement and a high proportion evidenced in a subset of HCV-positive MZL. of MALT lymphomas with primary extranodal involvement (exocrine glands, liver, and stomach) [53]. In 2006, Ferreri et al. found HCV seropositivity in 13% of ocular adnexa 4.2. Splenic Marginal Zone Lymphoma. Splenic marginal lymphoma of MALT type with a more aggressive behaviour zone lymphoma is a rare indolent lymphoma subtype which [20]. Taken together, these data indicate that the typical pre- accounts for less than 2% of all NHL [39]. In some cases sentation of HCV-related MALT lymphomas is constituted lymphocytes with villous projections are found in peripheral by some well-defined forms with a single and peculiar MALT blood, and the disease is termed splenic lymphoma with localization. At this regard, it has recently reported a series villous lymphocytes [40, 41]. This entity is considered as the of 12 HCV-positive patients presenting with subcutaneous leukemic counterpart of splenic marginal zone lymphoma nodules resembling “lipomas” and a typical histology of [42]. In almost all patients a symptomatic splenomegaly extranodal marginal zone lymphoma of MALT [21]. HCV- is the presenting feature. In a large series, HCV serology RNA was detectable in all 10 patients tested. From a clinical was positive in 49 out of 255 available patients (19%) [16]. point of view, it has to be underlined that the clinical benign Among 56 patients tested for HCV-RNA, 25 (45%) were appearance of these “lipoma-like” lesions and their indolent positive. Cryoglobulins were detected in 13 out of 130 clinical behaviour may result in diagnostic delay. patients tested (10%). In 2005, French authors reported a series of splenic lym- 4.5. Lymphoplasmacytic Lymphoma/Waldenstrom Macroglob- phomas with villous lymphocytes associated with type II ulinemia. Beside marginal zone lymphomas, one of the cryoglobulinemia and HCV infection [17]. All 18 patients other indolent B-cell NHL subtypes that has been frequently had type II mixed cryoglobulinemia, with symptoms of associated to HCV infection is lymphoplasmacytic lym- vasculitis in 13. Clinical symptoms of cryoglobulinemia pre- phoma, a neoplasm of small B lymphocytes, plasmocytoid ceded the diagnosis of lymphoma in 7 patients (at a mean lymphocytes, and plasma cells, usually involving bone mar- time of 3.5 years before lymphoma diagnosis) and were row and sometimes lymph nodes and spleen. Waldenstrom concurrent in the other 6 patients. The authors concluded macroglobulinemia is found in a significant proportion that splenic lymphoma with villous lymphocytes could be of patients with lymphoplasmacytic lymphomas and is integrated in the spectrum of cryoglobulin-associated B-cell defined as lymphoplasmacytic lymphoma with bone marrow proliferations, configuring a new clinical entity. involvement and the detection of a paraprotein of IgM type in the serum. Lymphoplasmacytic lymphoma and Walden- 4.3. Primary Nodal Marginal Zone Lymphoma. Primary strom macroglobulinemia have been associated with HCV nodal marginal zone lymphoma is listed in the WHO lym- infection and mixed cryoglobulinemia in some but not phoma classification as a rare but distinct clinical pathologic all series, perhaps related to geographic differences. For subtype characterized by exclusive primary lymph node example, while a US series did not find any HCV-positive localization in absence of prior or concurrent extranodal site cases among 100 untreated patients affected by Waldenstrom of involvement. Primary nodal marginal zone lymphoma is macroglobulinemia [54], an Italian multicentre study [22] a rare disease accounting for nearly 2% of lymphoid neo- reported 21 HCV-positive cases among 140 patients (15%). plasms and is frequently associated with HCV infection with HCV infection was associated to lower counts of platelets, preferential use of specific VH segments [43]. In a large series neutrophil granulocytes, and hemoglobin, and with the [18], HCV serology was positive in 9 out of 38 patients (24%) presence of cryoglobulins, splenomegaly, increased LDH, and HCV-RNA was detectable in 4/8 patients studied. and β -microglobulin levels. However, the analyses did not reveal any difference between HCV-positive and HCV- 4.4. MALT Lymphoma. MALT lymphomas represent 8% of negative patients in terms of “disease progression needing treatment,” “time from diagnosis to first therapy,” and overall all NHL [44–46], behave usually as indolent diseases, and develop more frequently in middle and advanced age, survival. Interestingly, a recent report specifically focused on with a female predominance [47–50]. Interestingly, some the comparison between Waldenstrom macroglobulinemia and splenic marginal zone lymphoma, found that, despite studies reported an increased prevalence of HCV infection in unselected patients with gastric lymphoma [51]. In an Italian some common features, splenic marginal zone lymphoma multicenter study, data on HCV serology were available in displayed a clearly higher association with HCV infection (25 all 172 cases of nongastric MALT lymphoma [32]. HCV HCV-positive patients out of 92, 27%) than Waldenstrom infection was documented in 60 patients (35%). A total of macroglobulinemia (6/66 patients, 9%) [55]. 22 out of 24 patients tested (92%) had viremia. Interestingly, three specific MALT lymphoma sites showed an elevated 4.6. B-Cell Chronic Lymphoproliferative Disorders. Follicular prevalence of HCV infection: salivary glands (47%), skin lymphoma and small lymphocytic lymphoma are low-grade (43%), and orbit (36%). These data, while confirming the lymphoma subtypes rarely associated with HCV-positive link between HCV infection and salivary glands lymphoma infection, as evidenced by the above mentioned epidemi- [52], reveal a possible relationship between HCV and two ological studies. Interestingly, these findings have been other MALT presentations of lymphoma: orbit and skin. confirmed by a single institution Bayesian analysis that was Interestingly, a study on B-cell lymphoma in patients with performed to estimate the prevalence of HCV infection Clinical and Developmental Immunology 5 across the different NHL histologies. This approach was HCV infection and NHL development. However, the most able to demonstrate the association of splenic marginal convincing evidence to support the causal role of HCV zone lymphoma and diffuse large B-cell lymphoma with in lymphomagenesis is the possible regression of indolent HCV infection, while did not find any correlation with lymphoma after eradication of HCV infection with AT. follicular lymphoma and small lymphocytic lymphoma [56], Beginning from the seminal work by Hermine et al. in splenic thus confirming previous findings of classic epidemiologic lymphomas with villous lymphocytes in 2002 [5], data from studies. Moreover, this study showed that another disease literature demonstrate that AT could be considered as first- entity could be associated with HCV, the so-called “B- line approach in HCV-associated indolent lymphomas when cell chronic lymphoproliferative disorders.” B-cell chronic there is not immediate need of conventional (immuno)- lymphoproliferative disorders are defined as the miscella- chemotherapy treatment. Among specific NHL subtypes, neous category of non-CLL leukemic lymphoproliferative this treatment modality has been more frequently exploited disorders with Royal Marsden Hospital scoring system ≤3 in marginal zone lymphomas; however other studies have [57, 58] and are often reported also as “low-grade B-NHL supported the validity of this approach for all indolent not otherwise specified.” Although one series reported a histologies when associated to HCV infection. In Table 2 we low rate of HCV positivity (5%) in CD5/CD10-negative summarized results of antilymphoma activity of AT with B-cell chronic lymphoproliferative disorders [24], further interferon with or without ribavirin in low-grade NHL. investigations are needed to elucidate this issue, given the Conversely, front-line AT is clearly insufficient in HCV- heterogeneity and the small numbers of studies focusing on positive aggressive lymphomas, in which an immediately this entity now available. active therapy is needed; in these cases AT may be a rationale recommendation after completion of conventional 5. Standard Treatment for HCV immunochemotherapy with the aim to clear a potential lymphoma trigger. Chronic Hepatitis The goal of AT in HCV-related chronic hepatitis is to prevent disease complications. This is best accomplished through 6.1. The First Experiences. In 2005, a systematic review con- virus eradication, defined as sustained virologic response cerning the efficacy of AT in lymphoproliferative disor- (SVR), that is, undetectable HCV-RNA by a sensitive ders was published [76]. Overall, 16 studies reporting the polymerase-chain-reaction- (PCR-) based assay 24 weeks employment of an antiviral regimen (interferon with or after discontinuation of treatment. Therapeutic options for without ribavirin) as primary hematologic treatment in HCV-related chronic hepatitis have improved significantly 65 HCV-infected patients diagnosed with a lymphopro- since the introduction of interferon monotherapy. The liferative disorder were identified. Complete remission of current standard of care is a combination of pegylated the lymphoproliferative disorder was achieved in 75% of interferon-α and weight-based ribavirin for 48 weeks for the cases. However, many of these series relied on case genotype 1 and 4 and for 24 weeks for genotype 2 and reports of few patients and included also patients with mixed 3. Patients with genotype 2 or 3 respond more favourably cryoglobulinemia with evidence of B-cell monoclonality to standard AT, obtaining a SVR in 75–90% of cases, [77]. whereas in genotype 1 and 4 the likelihood of achieving Among the studies included in the cited review, the SVR is considerably lower (45–52%) [59–61]. Recently, first experience of a relatively large cohort of patients with however, the introduction of the HCV NS3/4A protease NHL was performed by Hermine et al. in 2002 [5]. In this inhibitors boceprevir [6] and telaprevir [7], the first two report they described the outcome of 9 patients with splenic drugs belonging to a new and promising generation of lymphoma with villous lymphocytes and HCV infection direct-acting antiviral agents, has been demonstrated to treated with interferon-α2b (3 MU subcutaneously three dramatically improve SVR rates in genotype 1 patients. times a week for six months). Six patients had symptomatic In particular, in genotype 1 treatment-naive patients, the cryoglobulinemia. Complete hematological remission and addition of boceprevir or telaprevir to standard AT increased HCV negativity were observed in 7/9 (78%) patients. Two the rate of SVR to nearly 65–75%, whereas in relapsers or patients who did not respond were subsequently treated with nonresponders, the SVR rate improved to nearly 57–86%. interferon plus ribavirin (1,000 to 1,200 mg per day) and Other new potent protease inhibitors showing promising obtained the clearance of HCV-RNA as well as lymphoma activity are currently in late phases of development, as well response (one complete remission and one partial remis- as other new upcoming classes of direct-acting antiviral sion). On the contrary, none of 6 cases with SLVL without agents like polymerase inhibitors: their potential combina- HCV infection treated with interferon experienced any grade tion seems to herald for the near future the possibility to of lymphoma regression. obtain highly efficacious interferon-free regimens for HCV In 2005 a subsequent report from the same group therapy [62]. expanded these results in 18 patients with chronic HCV infection, mixed cryoglobulinemia, and splenic lymphoma 6. Antiviral Treatment of HCV-Positive with villous lymphocytes [17]. All patients were treated with Indolent Lymphomas interferon (+ribavirin in 10). Fourteen patients obtained a As previously discussed, case-control epidemiological studies complete hematologic remission after clearance of HCV- and clinical-pathological series evidenced the link between RNA. Two patients had a virologic partial response and 6 Clinical and Developmental Immunology Table 2: Antiviral treatment in patients with indolent B-cell lymphoma associated with HCV infection. Virologic NHL Year N pts Diagnosis Genotypes Cryoglobulinemia Antiviral treatment response response MZL of MALT (oral cavity) Bauduer [63] 1996 1 NA — α-IFN 1 1 PR Caramaschi et al. MZL of MALT (salivary glands) 1999 1 NA — α-IFN NA 1 CR [64] SMZL Moccia et al. [65] 1999 3 NA — α-IFN NA 2 CR LPL Patriarca et al. [66] 2001 1 2a/2c — α-IFN 1 1 CR SLVL Hermine et al. [5] 2002 9 NA 6 α-IFN 7 7 CR Decreased Leukemic MZL Casato et al. [67] 2002 1 NA 1 α-IFN 1CR HCV-RNA SMZL Pitini et al. [68] 2004 2 NA — α-IFN 2 2 CR MZL of MALT (stomach) Tursi et al. [69] 2004 16 NA — α-IFN-2b + RBV 11/16 16 CR SMZL (n = 4) Disseminated 3a (n = 1), 5a (n = 1) MZL (n = 1) Kelaidi et al. [70] 2004 8 8 α-IFN-2b + RBV 5 SVR, 2 PR 5 CR Leukemic MZL (n = 1) 1b MZL of MALT (n = 2) 4c/4d (1 duodenus; 1 ileus) 1b (n = 2),2b(n = 1) SMZL (n = 4) 2a/2c (n = 1), 1b (n = 1) NMZL (n = 2) 1b (n = 2) MZL of MALT (n = 2) Vallisa et al. [71] 2005 13 5 Peg-IFN +RBV 7SVR,1PR 7CR, 2PR 2a FL (n = 1) 2a/2c (n = 1), 1n (n = 1), LPL (n = 4) na (n = 2) MZL of MALT (salivary gland, Svoboda et al. [72] 2005 1 2b — Peg-IFN + RBV 1 CR liver) 1(n = 7) 2(n = 4) SLVL Saadoun et al. [17] 2005 18 18 α-IFN (+ RBV in 10) 14 CR, 4 PR 14 CR, 4 PR 3(n = 1) 4(n = 1) 2a/2c Subcutaneous MZL of MALT Paulli et al. [21] 2009 2 2Peg-IFN+RBV 2CR 1CR,1PR 2b B-NHL (liver) Oda et al. [73] 2010 1 2a — Peg-IFN + RBV SVR CR LPL Mauro et al. [74] 2012 1 1b 1 Peg-IFN + RBV (2nd line) SVR CR 1SLVL 1b (n = 11) α-IFN + RBV (n = 8) 1FL Mazzaro et al. [75] 2009 18 13 9SVR 9CR, 4PR 2a/2c (n = 7) Peg-IFN + RBV (n = 10) 16 LPL SMZL: splenic marginal zone lymphoma; NMZL: nodal marginal zone lymphoma; SLVL: splenic lymphoma with villous lymphocytes; MZL: marginal zone lymphoma; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; SLL: small lymphocytic lymphoma; NHL: non-Hodgkin’s lymphoma; NOS: not otherwise specified; IFN: interferon; RBV: ribavirin; CR: complete response; PR: partial response; SVR: sustained virologic response. Clinical and Developmental Immunology 7 obtained a complete hematologic response. Two virologic patients, 37%). Achievement of hematological response nonresponders achieved partial hematologic response. Nota- significantly related to the disappearance of HCV-RNA, as bly, viral genotype did not seem to correlate with the all patients who experienced SVR developed hematological response: in fact 4 out of 7 patients with HCV genotype 1, CR. In the previously cited study on subcutaneous “lipoma- that is usually associated with poor responses, achieved a like” extranodal marginal zone B-cell lymphoma of MALT complete lymphoma regression after interferon and rib- [78], one patient was treated with interferon and ribavirin as avirin. Interestingly, even for patients who exhibited a com- first- line treatment and obtained a rapid virological response plete hematological remission, no molecular response was and a partial lymphoma response. Interestingly, another evidenced, as monoclonal immunoglobulin gene rearrange- patient who relapsed 20 months after CHOP therapy plus ment was still detected in peripheral blood after treatment; radiotherapy was treated with interferon alone for 6 months however clinical relapses did not occur if viremia remained and achieved a complete regression of nodules after 1 month negative. Overall, these observations may suggest differences of therapy together with virological response. Eight months in oncogenic potential between HCV-driven B-cell clones in after stopping AT HCV-RNA returned positive and 3 months cryoglobulinemia with respect to splenic lymphoma and are later a subcutaneous lymphoma relapse occurred. in favour of a model in which a continuous viral stimulation In perspective, several lines of future clinical research can leads to cryoglobulinemia and, subsequently, in a subset of be pursued with the aim to further improve these results. patients, to indolent lymphoma. First, it has to be investigated if the combination of rituximab Another study reported first-line AT with interferon and and AT tested in symptomatic cryoglobulinemia by Saadoun ribavirin in 8 HCV-positive patients with different subtypes and colleagues (rituximab weekly for 4 doses followed by of marginal zone lymphoma (4 splenic marginal zone PEG-interferon weekly plus ribavirin daily for 48 weeks) lymphomas with or without villous lymphocytes, 1 dissem- [14] is able to obtain a better long-term control of disease inated marginal zone lymphoma, 1 leukemic marginal zone also in indolent B-cell NHL. Second, it has to be tested if lymphoma, and 2 intestinal MALT lymphomas); 5 out of 8 new antiviral combinations with new anti-HCV agents (i.e., patients (60%) obtained a response, which was correlated to PEG-interferon and ribavirin plus boceprevir or telaprevir), virological response in most cases [70]. that guarantee better rates of SVR in genotypes 1 hepatitis, Among most robust experiences, an Italian multicenter could allow to increase the rate of hematologic response study [71] reported results of AT in 13 indolent B-cell also in patients with more resistant genotypes. Finally, it NHL (4 splenic marginal zone lymphomas, 2 primary nodal has to be explored if future interferon-free regimens with marginal zone lymphomas, 2 extranodal lymphomas of direct antiviral agents only, could consent the access to AT MALT, 4 lymphoplasmacytic lymphomas, and 1 follicular also for HCV-positive NHL patients with contraindications lymphoma) carrying HCV infection. All patients underwent to interferon use, for example because of advanced age, AT alone with PEG-interferon and ribavirin, 10 as first line cytopenias, and/or comorbidities. and 3 as second or third line of therapy. Eleven patients completed planned treatment, while 2 discontinued it 6.3. Role of Antiviral Therapy in Aggressive B-Cell Lymphomas. becauseofsevereadverse effects. Among 12 assessable As previously mentioned, AT seems to be less efficacious than patients, 7 achieved complete response, 2 partial response standard immune-chemotherapy for HCV-positive aggres- (overall response rate 75%), 2 had stable disease, and one sive lymphomas (diffuse large B-cell lymphoma and mantle progressed during therapy. Hematologic responses resulted cell lymphoma) with respect to indolent ones. This is highly significantly associated to clearance or decrease in probably related to the lost of antigen dependence resulting serum HCV viral load, as 7 out of 9 achieved SVR, one had from acquisition of additional mutations that are possibly reduction in viremia, and 1 had no change in viral load. responsible of more aggressive behaviour, although anecdo- Virological response was more frequent in HCV genotype tal cases of diffuse large B-cell lymphoma [79] and mantle 2; however, hematologic response did not correlate with the cell lymphoma [80] treated with AT and obtaining remission viral genotype. One of the greatest accomplishment of this have been reported. Nevertheless, many researchers have study was the demonstration of the efficacy of AT in a wide explored the option to integrate AT in the context of range of HCV-positive low-grade NHL subtypes other than immune-chemotherapy programs in HCV-positive diffuse splenic marginal zone lymphoma, as complete responses large B-cell lymphomas. Although some rare cases of concur- were actually observed without significant differences in all rent delivery of AT and immune-chemotherapy with the aim indolent NHL histologies. to prevent or to treat hepatitis flares have been reported [81], treatment with interferon or PEG-interferon with or without 6.2. Recent Studies and Future Perspectives. Recently Mazzaro ribavirin is usually not feasible because of hematologic et al. [75] reported a comparison of PEG-interferon and toxicity,asshowedbyapilot studybyMusto andcoworkers standard interferon (plus ribavirin) as first-line treatment in 4 patients with diffuse large B-cell lymphoma [82]. The in 18 patients with HCV-positive low-grade B-cell NHL (1 same authors explored the option to perform sequential follicular lymphoma, 1 splenic lymphoma with villous lym- AT with PEG-interferon and ribavirin for 3 months in phocytes, and 16 lymphoplasmacytic lymphomas). Com- responding HCV-positive patients with diffuse large B-cell plete responses as well as SVR were higher in the group lymphomas after 6–8 cycles of R-CHOP. They found that treated with PEG-interferon (6/10 patients, 60%) with this strategy was effective, better tolerated and resulted in respect to the group treated with standard interferon (3/8 high rate of virus clearance in the first 12 patients treated. 8 Clinical and Developmental Immunology These preliminary data have been indirectly supported by [7] C. Hez ´ ode, N. Forestier, G. 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Moreover AT resulted associated association of hepatitis C virus infection with monoclonal with better disease-free survival in multivariate analyses. rheumatoid factors bearing the WA cross-idiotype: implica- These preliminary experiences confirmed that AT is not tions for the etiopathogenesis and therapy of mixed cryoglob- feasible in concomitance with immune-chemotherapy in ulinemia,” Clinical and Experimental Rheumatology, vol. 13, HCV-positive DLBCL because of an excess of hematologic supplement 13, pp. S-101–S-104, 1995. [10] C. Ferri, A. L. Zignego, and S. A. Pileri, “Cryoglobulins,” Jour- toxicity. On the other hand they suggest that a course of AT in nal of Clinical Pathology, vol. 55, no. 1, pp. 4–13, 2002. patients in remission after immune-chemotherapy appears [11] G. Monti, P. Pioltelli, F. Saccardo et al., “Incidence and to be an attractive option with the aim to prevent hepatitis characteristics of non-Hodgkin lymphomas in a multicenter reactivation in view of long-term control of the lymphoma. case file of patients with hepatitis C virus-related symptomatic However these data have to be confirmed in larger series and mixed cryoglobulinemias,” Archives of Internal Medicine, vol. preferentially in prospective manner. 165, no. 1, pp. 101–105, 2005. [12] A. L. Zignego, F. Giannelli, M. E. Marrocchi et al., “Frequency 7. Conclusions of bcl-2 rearrangement in patients with mixed cryoglobuline- mia and HCV-positive liver diseases,” Clinical and Experimen- In conclusion, anti-HCV treatment with interferon and rib- tal Rheumatology, vol. 15, no. 6, pp. 711–712, 1997. avirin seems to be indicated for indolent B-cell NHL sub- [13] C. 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Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and Role of Antiviral Therapy

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Copyright © 2012 Luca Arcaini et al.
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Abstract

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 638185, 10 pages doi:10.1155/2012/638185 Review Article Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and Role of Antiviral Therapy 1 2 3 1 Luca Arcaini, Michele Merli, Stefano Volpetti, Sara Rattotti, 1 3, 4 Manuel Gotti, and Francesco Zaja Department of Hematology Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy Division of Hematology, Department of Internal Medicine, Ospedale di Circolo, Fondazione Macchi, 21100 Varese, Italy Department of Hematology, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, 33100 Udine, Italy Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy Correspondence should be addressed to Francesco Zaja, zaja.francesco@aoud.sanita.fvg.it Received 16 May 2012; Revised 4 July 2012; Accepted 4 July 2012 Academic Editor: Jurg ¨ Schifferli Copyright © 2012 Luca Arcaini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin’s lymphomas (NHL) has been demonstrated by epidemiological studies, in particular in highly endemic geographical areas such as Italy, Japan, and southern parts of United States. In these countries, together with diffuse large B-cell lymphomas, marginal zone lymphomas are the histotypes most frequently associated with HCV infection; in Italy around 20–30% cases of marginal zone lymphomas are HCV positive. Recently, antiviral treatment with interferon with or without ribavirin has been proved to be effective in the treatment of HCV-positive patients affected by indolent lymphoma, prevalently of marginal zone origin. An increasing number of experiences confirmed the validity of this approach in marginal zone lymphomas and in other indolent NHL subtypes like lymphoplasmacytic lymphoma. Across different studies, overall response rate was approximately 75%. Hematological responses resulted significantly associated with the eradication of the virus. This is the strongest evidence of a causative link between HCV and lymphomas. The aim of this paper is to illustrate the relationship between HCV infection and different subtypes of indolent B-cell lymphomas and to systematically summarize the data from the therapeutic studies that reported the use of antiviral treatment as hematological therapy in patients with HCV-associated indolent lymphomas. 1. Introduction lymphoma and extranodal marginal zone lymphoma of mucosa-associated tissue (MALT), and lymphoplasmacytic In the last two decades, evidences from either epidemiolog- lymphoma. According to the currently more accepted patho- ical studies, biological insights, and also therapeutic genetic model, the role of HCV infection in lymphomage- approaches provided strong support to the association nesis may be related to the chronic antigenic stimulation of between hepatitis C virus (HCV) and B-cell non-Hodgkin’s B-cell immunologic response by the virus [3], similarly to lymphomas (NHL). HCV has been associated with B-cell the well-characterized induction of gastric MALT lymphoma indolent lymphomas, especially marginal zone lymphomas, development by Helicobacter pylori chronic infection [4]. In as well as with aggressive lymphomas, mainly diffuse large a similar way, chronic HCV infection may possibly sustain B-cell lymphomas. Indolent lymphomas are defined from a a multistep evolution from type II mixed cryoglobulinemia clinical point of view as scarcely symptomatic lymphomas, to overt low-grade NHL and eventually to high-grade NHL growing and spreading slowly [1] and encompass the follow- [3, 4]. The most convincing argument in favour of a causative ing histologic subtypes of low-grade lymphoma according link between HCV and lymphoproliferation is represented by to the WHO classification [2]: follicular lymphoma, small interventional studies demonstrating that in HCV-positive lymphocytic lymphoma, marginal zone lymphomas, splenic patients affected by indolent NHL eradication of HCV with marginal zone lymphoma, primary nodal marginal zone antiviral treatment (AT) could directly induce lymphoma 2 Clinical and Developmental Immunology regression [5]. Moreover, the upcoming novel antiviral anti- long-term followup. Type II mixed cryoglobulinemia is often HCV agents as boceprevir and telaprevir, whose addition to characterized by IgH or Bcl2 rearrangement and by t(14; standard treatment has already demonstrated an increased 18) translocation [12]. Treatment of HCV type II mixed rate of viral eradication also in more resistant genotypes (i.e., cryoglobulinemia with severe organ damage may target genotype 1b) [6, 7], will possibly further improve the efficacy either the viral trigger (HCV) or the downstream arm of B- of this treatment for HCV-positive indolent NHL in the near cell autoimmunity. AT with pegylated interferon + ribavirin future. has been shown to reverse bone marrow B-cell expansion in patients with HCV-MC, leading to a clinical and virologic response in up to 60% of cases [13]. Recent studies 2. Methods showed that the combination of AT (PEG-interferon + The aim of this paper is to systematically summarize the ribavirin) with the anti-CD20 monoclonal antibody ritux- available data indolent B-cell NHL associated with HCV imab is well tolerated and more effective than AT alone, by infection and the up-to-now reported experiences with the increasing the rate of complete clinical response, immuno- use of AT with interferon with or without ribavirin as hema- logic (cryoglobulin clearance) and molecular response tologic treatment in patients with HCV-positive indolent B- (eradication of B-cell clonal expansions), and shortening the cell NHL. time to achieve a complete clinical response [14, 15]. To thisaim,weperformed asystematicPubMedsearch (http://www.pubmed.gov/) using the keywords “indolent lymphoma,” “marginal zone lymphoma,” “MALT lympho- 3.2. Epidemiology of HCV and Its Association with Lym- ma,” “lymphoplasmacytic lymphoma,” “hepatitis C virus,” phomas. HCV infection is a global health problem, with up “interferon,” “ribavirin,” “antiviral therapy.” All relevant arti- to 170 million persons infected worldwide (3% of global cles were included, as well as the most significant abstracts population) [25]. However relevant regional differences in presented at American Society of Hematology (ASH) meet- the prevalence of infection are described. The lowest preva- ings and International Conference on Malignant Lym- lence rates are reported in Northern Europe and Scandinavia phomas (ICML) meetings since 2005. The articles were (0.01–0.1%) while in Italy, Egypt, Japan, and southern parts reviewed with reference to the features of HCV-associated of United States, prevalence estimates exceeds 2% [26]. indolent NHL and were assessed specifically concerning HCV infection is a leading cause of chronic hepatitis, cir- virological and hematological response in cases treated with rhosis, and hepatocellular carcinoma and has been associated AT. to extrahepatic manifestations, especially type II mixed cryoglobulinemia and a spectrum of B-cell NHL with or 3. HCV Infection, Cryoglobulinemia, without cryoglobulinemia [3]. Several epidemiological stud- ies have been performed beginning from the mid 1990s to and Lymphomas investigate the link between HCV and NHL. Early studies 3.1. HCV and Cryoglobulinemia. The initial finding that based on relatively small number of cases suggested a lead to the extensive investigation of the association significant increased risk of B-cell NHL in HCV-positive between HCV and NHL was the very high prevalence patients, especially in countries with high prevalence of (nearly 90–100%) of HCV infection in patients with type HCV infection as Italy [27], Japan, and southern regions II mixed cryoglobulinemia [8]. Cryoglobulins are serum of USA, while studies from areas with low HCV prevalence immunoglobulins that become insoluble and precipitate did not show any evident association [28]. In 2003, a at temperatures below 37 C. The antigenic component systematic review of studies evaluating prevalence of HCV of the immune complexes has been found to be highly infection in B-cell NHL [29] was published. In this report, 48 enriched in viral HCV core protein and HCV-RNA. Type studies (5,542 patients) were identified. Mean HCV infection II mixed cryoglobulinemia is characterized by a mixture prevalence was 13%. In 10 case-control studies examined, of monoclonal and polyclonal immunoglobulins. The HCV prevalence in B-cell NHL was 17% compared to 1.5% monoclonal component of type II mixed cryoglobulinemia in healthy controls (odds ratio, OR = 10.8). Therefore, it is an IgM/k with a rheumatoid-factor activity (i.e., anti-IgG was concluded that HCV prevalence in patients with B-cell cross-reactive binding) that reflects the expansion of a NHL is higher than that reported in general population (15% B-cell monoclonal population [9]. Overall, up to 50% of vs. 1.5%), suggesting a role of HCV in the aetiology of B- HCV-infected patients exhibit low levels of circulating mixed cell NHL. Subsequently, in 2006, an updated metaanalysis cryoglobulins, whereas overt cryoglobulinemic vasculitis of 15 case-control studies on the association between HCV develops in ≤5% of infected patients [10]. Symptoms vary infection and NHL demonstrated a pooled relative risk of from purpura and arthralgia to more severe manifestations lymphoma among HCV-positive subjects of 2–2.5 depending like peripheral neuropathy and glomerulonephritis. on study design. Relative risks resulted consistently increased Importantly, in HCV-infected patients with symptomatic for all major B-NHL subtypes. The study, indeed, confirmed cryoglobulinemia, the risk to develop an NHL is greatly that the risk to develop NHL in the context of HCV increased with respect to the general population (about 35 infection is most dramatically evident in populations with times according to a multicenter Italian study) [11]. As a high HCV prevalence and that consequently the fraction of result, approximately 8–10% of patients with type II mixed NHL attributable to HCV infection varies greatly by country, cryoglobulinemia ultimately progress to a frank NHL after reaching 10% in highly endemic areas. Clinical and Developmental Immunology 3 Table 1: Clinical pathological studies describing indolent NHL subtypes associated with HCV infection. N pts tested Cryoglobulinemia, Year Diagnosis N pts N HCV+ (%) Genotypes for HCV N (%) 1b (n = 10), 2b (n = 1), Arcaini et al. [16] 2006 SMZL 309 255 49 (19) 13 (10) 2a/2c (n = 4) 1(n = 7), 2 (n = 4), Saadoun et al. [17] 2005 SLVL 18 18 18 (100) 18 (100) 3(n = 1), 4 (n = 1) NMZL Arcaini et al. [18] 2007 47 38 9 (24) NA 2 (14) MALT-MZL 172 172 60 (35%) Skin 29 29 21 (43) 1a (n = 11), 1b (n = 1), Salivary glands Arcaini et al. [19] 2006 32 32 15 (47) NA 2a/2c (n = 10) Orbit 25 25 9 (36) Other sites 66 66 15 (22) MALT-MZL Ferreri et al. [20] 2006 55 55 7 (13) NA 2 (29) orbit Subcutaneous 2a/2c (n = 4), 2a (n = 2) Paulli et al. [21] 2009 13 13 13 (100) 3 (75) MALT- MZL 2b, (n = 1) Tedeschi et al. [22] 2009 WM 140 140 21 (15) NA 10 (48) WM 122 66 6(9) NA 0 Arcaini et al. [23] 2011 SMZL 98 92 25 (27) NA 3 Goldaniga et al. 2008 B-CLPD 156 113 6 (5) NA NA [24] SMZL: splenic marginal zone lymphoma; NMZL: nodal marginal zone lymphoma; SLVL: splenic lymphoma with villous lymphocytes; MZL: marginal zone lymphoma; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; SLL: small lymphocytic lymphoma; NHL: non- Hodgkin’s lymphoma; B-CLPD: B-cell chronic lymphoproliferative disorders. The numbers of cases analyzed in these series were too 4.1. Marginal Zone Lymphomas. Within specific indolent small to establish a correlation between HCV and specific NHL subtypes, the association with HCV infection has histotypes. In the Epilymph [30] case-control study, the sub- been best characterized in marginal zone lymphomas. In type most clearly associated with HCV infection was diffuse the 2008 edition of WHO classification three marginal zone large B-cell lymphoma, followed by marginal zone lym- lymphoma entities were listed [2]: splenic B-cell marginal phoma and lymphoplasmacytic lymphoma; however these zone lymphoma, nodal marginal zone lymphoma, and results were based on relatively few cases. To obtain a more extranodal marginal zone B-cell lymphoma of MALT type. robust estimate of the risk to develop specific NHL subtypes Marginal zone B-cells have been demonstrated to play role after HCV infection, the International Lymphoma Epidemi- in the immune response to T-cell-independent antigens and ology Consortium (InterLymph), based in Europe, North frequently display reactivity to self antigens. Marginal zone America, and Australia, performed a pooled case-control B-cells are involved in various infectious and autoimmune study including in the analysis data of 7 previous surveys conditions and marginal zone-related neoplasms often retain [31]. Overall, among 4,784 cases of NHL and 6,269 controls the features of these cells. Many infectious agents are involved matched by sex, age, and study centre, HCV infection was in the pathogenesis of specific types of marginal zone lym- detected in 172 NHL cases (3.6%) and in 169 (2.7%) phomas: Helicobacter pylori for gastric MALT lymphoma [4], controls. In subtype-specific analyses, HCV prevalence was Campylobacter jejuni for immunoproliferative small intestine associated with diffuse large B-cell lymphoma (OR 2.24), disease [35], Borrelia burgdorferi for MALT lymphoma of the marginal zone lymphoma (OR, 2.47), and lymphoplasma- skin [36], and Chlamydia psittaci for MALT lymphoma of the cytic lymphoma (OR 2.57) whereas risk estimates were not orbit [37, 38]. In all these cases, eradication of the antigen increased for follicular lymphomas (OR 1.02). Moreover, after antimicrobial therapy may lead to a regression of the also retrospective series reported a high HCV prevalence lymphoma. For example, eradication of Helicobacter pylori among patients with marginal zone lymphoma [4, 16–18, 20, leads to the complete regression of gastric MALT lymphoma 32], lymphoplasmacytic lymphoma, and diffuse large B-cell in most cases, and relapse of the lymphoma is anticipated by lymphoma [33, 34]. the reoccurrence of the infection [4]. Accordingly to this scenario, also chronic stimulation by HCV may play a role in development of a subgroup of 4. HCV and Indolent Lymphomas: Clinical and marginal zone lymphoma cases. The association between Pathological Studies HCV and marginal zone lymphomas is demonstrated by epi- As mentioned above, many well-characterized clinical-path- demiological studies, as previously summarized, and by clinical-pathological studies of well-characterized marginal ological studies investigated the association of HCV infection with specific indolent NHL subtypes (Table 1). zone lymphoma series. However, the major support to the 4 Clinical and Developmental Immunology potential causal role of HCV in marginal zone lymphoma- Sjog ¨ ren’s syndrome and HCV infection reported an elevated genesis is represented by the antilymphoma activity of AT occurrence of parotid involvement and a high proportion evidenced in a subset of HCV-positive MZL. of MALT lymphomas with primary extranodal involvement (exocrine glands, liver, and stomach) [53]. In 2006, Ferreri et al. found HCV seropositivity in 13% of ocular adnexa 4.2. Splenic Marginal Zone Lymphoma. Splenic marginal lymphoma of MALT type with a more aggressive behaviour zone lymphoma is a rare indolent lymphoma subtype which [20]. Taken together, these data indicate that the typical pre- accounts for less than 2% of all NHL [39]. In some cases sentation of HCV-related MALT lymphomas is constituted lymphocytes with villous projections are found in peripheral by some well-defined forms with a single and peculiar MALT blood, and the disease is termed splenic lymphoma with localization. At this regard, it has recently reported a series villous lymphocytes [40, 41]. This entity is considered as the of 12 HCV-positive patients presenting with subcutaneous leukemic counterpart of splenic marginal zone lymphoma nodules resembling “lipomas” and a typical histology of [42]. In almost all patients a symptomatic splenomegaly extranodal marginal zone lymphoma of MALT [21]. HCV- is the presenting feature. In a large series, HCV serology RNA was detectable in all 10 patients tested. From a clinical was positive in 49 out of 255 available patients (19%) [16]. point of view, it has to be underlined that the clinical benign Among 56 patients tested for HCV-RNA, 25 (45%) were appearance of these “lipoma-like” lesions and their indolent positive. Cryoglobulins were detected in 13 out of 130 clinical behaviour may result in diagnostic delay. patients tested (10%). In 2005, French authors reported a series of splenic lym- 4.5. Lymphoplasmacytic Lymphoma/Waldenstrom Macroglob- phomas with villous lymphocytes associated with type II ulinemia. Beside marginal zone lymphomas, one of the cryoglobulinemia and HCV infection [17]. All 18 patients other indolent B-cell NHL subtypes that has been frequently had type II mixed cryoglobulinemia, with symptoms of associated to HCV infection is lymphoplasmacytic lym- vasculitis in 13. Clinical symptoms of cryoglobulinemia pre- phoma, a neoplasm of small B lymphocytes, plasmocytoid ceded the diagnosis of lymphoma in 7 patients (at a mean lymphocytes, and plasma cells, usually involving bone mar- time of 3.5 years before lymphoma diagnosis) and were row and sometimes lymph nodes and spleen. Waldenstrom concurrent in the other 6 patients. The authors concluded macroglobulinemia is found in a significant proportion that splenic lymphoma with villous lymphocytes could be of patients with lymphoplasmacytic lymphomas and is integrated in the spectrum of cryoglobulin-associated B-cell defined as lymphoplasmacytic lymphoma with bone marrow proliferations, configuring a new clinical entity. involvement and the detection of a paraprotein of IgM type in the serum. Lymphoplasmacytic lymphoma and Walden- 4.3. Primary Nodal Marginal Zone Lymphoma. Primary strom macroglobulinemia have been associated with HCV nodal marginal zone lymphoma is listed in the WHO lym- infection and mixed cryoglobulinemia in some but not phoma classification as a rare but distinct clinical pathologic all series, perhaps related to geographic differences. For subtype characterized by exclusive primary lymph node example, while a US series did not find any HCV-positive localization in absence of prior or concurrent extranodal site cases among 100 untreated patients affected by Waldenstrom of involvement. Primary nodal marginal zone lymphoma is macroglobulinemia [54], an Italian multicentre study [22] a rare disease accounting for nearly 2% of lymphoid neo- reported 21 HCV-positive cases among 140 patients (15%). plasms and is frequently associated with HCV infection with HCV infection was associated to lower counts of platelets, preferential use of specific VH segments [43]. In a large series neutrophil granulocytes, and hemoglobin, and with the [18], HCV serology was positive in 9 out of 38 patients (24%) presence of cryoglobulins, splenomegaly, increased LDH, and HCV-RNA was detectable in 4/8 patients studied. and β -microglobulin levels. However, the analyses did not reveal any difference between HCV-positive and HCV- 4.4. MALT Lymphoma. MALT lymphomas represent 8% of negative patients in terms of “disease progression needing treatment,” “time from diagnosis to first therapy,” and overall all NHL [44–46], behave usually as indolent diseases, and develop more frequently in middle and advanced age, survival. Interestingly, a recent report specifically focused on with a female predominance [47–50]. Interestingly, some the comparison between Waldenstrom macroglobulinemia and splenic marginal zone lymphoma, found that, despite studies reported an increased prevalence of HCV infection in unselected patients with gastric lymphoma [51]. In an Italian some common features, splenic marginal zone lymphoma multicenter study, data on HCV serology were available in displayed a clearly higher association with HCV infection (25 all 172 cases of nongastric MALT lymphoma [32]. HCV HCV-positive patients out of 92, 27%) than Waldenstrom infection was documented in 60 patients (35%). A total of macroglobulinemia (6/66 patients, 9%) [55]. 22 out of 24 patients tested (92%) had viremia. Interestingly, three specific MALT lymphoma sites showed an elevated 4.6. B-Cell Chronic Lymphoproliferative Disorders. Follicular prevalence of HCV infection: salivary glands (47%), skin lymphoma and small lymphocytic lymphoma are low-grade (43%), and orbit (36%). These data, while confirming the lymphoma subtypes rarely associated with HCV-positive link between HCV infection and salivary glands lymphoma infection, as evidenced by the above mentioned epidemi- [52], reveal a possible relationship between HCV and two ological studies. Interestingly, these findings have been other MALT presentations of lymphoma: orbit and skin. confirmed by a single institution Bayesian analysis that was Interestingly, a study on B-cell lymphoma in patients with performed to estimate the prevalence of HCV infection Clinical and Developmental Immunology 5 across the different NHL histologies. This approach was HCV infection and NHL development. However, the most able to demonstrate the association of splenic marginal convincing evidence to support the causal role of HCV zone lymphoma and diffuse large B-cell lymphoma with in lymphomagenesis is the possible regression of indolent HCV infection, while did not find any correlation with lymphoma after eradication of HCV infection with AT. follicular lymphoma and small lymphocytic lymphoma [56], Beginning from the seminal work by Hermine et al. in splenic thus confirming previous findings of classic epidemiologic lymphomas with villous lymphocytes in 2002 [5], data from studies. Moreover, this study showed that another disease literature demonstrate that AT could be considered as first- entity could be associated with HCV, the so-called “B- line approach in HCV-associated indolent lymphomas when cell chronic lymphoproliferative disorders.” B-cell chronic there is not immediate need of conventional (immuno)- lymphoproliferative disorders are defined as the miscella- chemotherapy treatment. Among specific NHL subtypes, neous category of non-CLL leukemic lymphoproliferative this treatment modality has been more frequently exploited disorders with Royal Marsden Hospital scoring system ≤3 in marginal zone lymphomas; however other studies have [57, 58] and are often reported also as “low-grade B-NHL supported the validity of this approach for all indolent not otherwise specified.” Although one series reported a histologies when associated to HCV infection. In Table 2 we low rate of HCV positivity (5%) in CD5/CD10-negative summarized results of antilymphoma activity of AT with B-cell chronic lymphoproliferative disorders [24], further interferon with or without ribavirin in low-grade NHL. investigations are needed to elucidate this issue, given the Conversely, front-line AT is clearly insufficient in HCV- heterogeneity and the small numbers of studies focusing on positive aggressive lymphomas, in which an immediately this entity now available. active therapy is needed; in these cases AT may be a rationale recommendation after completion of conventional 5. Standard Treatment for HCV immunochemotherapy with the aim to clear a potential lymphoma trigger. Chronic Hepatitis The goal of AT in HCV-related chronic hepatitis is to prevent disease complications. This is best accomplished through 6.1. The First Experiences. In 2005, a systematic review con- virus eradication, defined as sustained virologic response cerning the efficacy of AT in lymphoproliferative disor- (SVR), that is, undetectable HCV-RNA by a sensitive ders was published [76]. Overall, 16 studies reporting the polymerase-chain-reaction- (PCR-) based assay 24 weeks employment of an antiviral regimen (interferon with or after discontinuation of treatment. Therapeutic options for without ribavirin) as primary hematologic treatment in HCV-related chronic hepatitis have improved significantly 65 HCV-infected patients diagnosed with a lymphopro- since the introduction of interferon monotherapy. The liferative disorder were identified. Complete remission of current standard of care is a combination of pegylated the lymphoproliferative disorder was achieved in 75% of interferon-α and weight-based ribavirin for 48 weeks for the cases. However, many of these series relied on case genotype 1 and 4 and for 24 weeks for genotype 2 and reports of few patients and included also patients with mixed 3. Patients with genotype 2 or 3 respond more favourably cryoglobulinemia with evidence of B-cell monoclonality to standard AT, obtaining a SVR in 75–90% of cases, [77]. whereas in genotype 1 and 4 the likelihood of achieving Among the studies included in the cited review, the SVR is considerably lower (45–52%) [59–61]. Recently, first experience of a relatively large cohort of patients with however, the introduction of the HCV NS3/4A protease NHL was performed by Hermine et al. in 2002 [5]. In this inhibitors boceprevir [6] and telaprevir [7], the first two report they described the outcome of 9 patients with splenic drugs belonging to a new and promising generation of lymphoma with villous lymphocytes and HCV infection direct-acting antiviral agents, has been demonstrated to treated with interferon-α2b (3 MU subcutaneously three dramatically improve SVR rates in genotype 1 patients. times a week for six months). Six patients had symptomatic In particular, in genotype 1 treatment-naive patients, the cryoglobulinemia. Complete hematological remission and addition of boceprevir or telaprevir to standard AT increased HCV negativity were observed in 7/9 (78%) patients. Two the rate of SVR to nearly 65–75%, whereas in relapsers or patients who did not respond were subsequently treated with nonresponders, the SVR rate improved to nearly 57–86%. interferon plus ribavirin (1,000 to 1,200 mg per day) and Other new potent protease inhibitors showing promising obtained the clearance of HCV-RNA as well as lymphoma activity are currently in late phases of development, as well response (one complete remission and one partial remis- as other new upcoming classes of direct-acting antiviral sion). On the contrary, none of 6 cases with SLVL without agents like polymerase inhibitors: their potential combina- HCV infection treated with interferon experienced any grade tion seems to herald for the near future the possibility to of lymphoma regression. obtain highly efficacious interferon-free regimens for HCV In 2005 a subsequent report from the same group therapy [62]. expanded these results in 18 patients with chronic HCV infection, mixed cryoglobulinemia, and splenic lymphoma 6. Antiviral Treatment of HCV-Positive with villous lymphocytes [17]. All patients were treated with Indolent Lymphomas interferon (+ribavirin in 10). Fourteen patients obtained a As previously discussed, case-control epidemiological studies complete hematologic remission after clearance of HCV- and clinical-pathological series evidenced the link between RNA. Two patients had a virologic partial response and 6 Clinical and Developmental Immunology Table 2: Antiviral treatment in patients with indolent B-cell lymphoma associated with HCV infection. Virologic NHL Year N pts Diagnosis Genotypes Cryoglobulinemia Antiviral treatment response response MZL of MALT (oral cavity) Bauduer [63] 1996 1 NA — α-IFN 1 1 PR Caramaschi et al. MZL of MALT (salivary glands) 1999 1 NA — α-IFN NA 1 CR [64] SMZL Moccia et al. [65] 1999 3 NA — α-IFN NA 2 CR LPL Patriarca et al. [66] 2001 1 2a/2c — α-IFN 1 1 CR SLVL Hermine et al. [5] 2002 9 NA 6 α-IFN 7 7 CR Decreased Leukemic MZL Casato et al. [67] 2002 1 NA 1 α-IFN 1CR HCV-RNA SMZL Pitini et al. [68] 2004 2 NA — α-IFN 2 2 CR MZL of MALT (stomach) Tursi et al. [69] 2004 16 NA — α-IFN-2b + RBV 11/16 16 CR SMZL (n = 4) Disseminated 3a (n = 1), 5a (n = 1) MZL (n = 1) Kelaidi et al. [70] 2004 8 8 α-IFN-2b + RBV 5 SVR, 2 PR 5 CR Leukemic MZL (n = 1) 1b MZL of MALT (n = 2) 4c/4d (1 duodenus; 1 ileus) 1b (n = 2),2b(n = 1) SMZL (n = 4) 2a/2c (n = 1), 1b (n = 1) NMZL (n = 2) 1b (n = 2) MZL of MALT (n = 2) Vallisa et al. [71] 2005 13 5 Peg-IFN +RBV 7SVR,1PR 7CR, 2PR 2a FL (n = 1) 2a/2c (n = 1), 1n (n = 1), LPL (n = 4) na (n = 2) MZL of MALT (salivary gland, Svoboda et al. [72] 2005 1 2b — Peg-IFN + RBV 1 CR liver) 1(n = 7) 2(n = 4) SLVL Saadoun et al. [17] 2005 18 18 α-IFN (+ RBV in 10) 14 CR, 4 PR 14 CR, 4 PR 3(n = 1) 4(n = 1) 2a/2c Subcutaneous MZL of MALT Paulli et al. [21] 2009 2 2Peg-IFN+RBV 2CR 1CR,1PR 2b B-NHL (liver) Oda et al. [73] 2010 1 2a — Peg-IFN + RBV SVR CR LPL Mauro et al. [74] 2012 1 1b 1 Peg-IFN + RBV (2nd line) SVR CR 1SLVL 1b (n = 11) α-IFN + RBV (n = 8) 1FL Mazzaro et al. [75] 2009 18 13 9SVR 9CR, 4PR 2a/2c (n = 7) Peg-IFN + RBV (n = 10) 16 LPL SMZL: splenic marginal zone lymphoma; NMZL: nodal marginal zone lymphoma; SLVL: splenic lymphoma with villous lymphocytes; MZL: marginal zone lymphoma; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; SLL: small lymphocytic lymphoma; NHL: non-Hodgkin’s lymphoma; NOS: not otherwise specified; IFN: interferon; RBV: ribavirin; CR: complete response; PR: partial response; SVR: sustained virologic response. Clinical and Developmental Immunology 7 obtained a complete hematologic response. Two virologic patients, 37%). Achievement of hematological response nonresponders achieved partial hematologic response. Nota- significantly related to the disappearance of HCV-RNA, as bly, viral genotype did not seem to correlate with the all patients who experienced SVR developed hematological response: in fact 4 out of 7 patients with HCV genotype 1, CR. In the previously cited study on subcutaneous “lipoma- that is usually associated with poor responses, achieved a like” extranodal marginal zone B-cell lymphoma of MALT complete lymphoma regression after interferon and rib- [78], one patient was treated with interferon and ribavirin as avirin. Interestingly, even for patients who exhibited a com- first- line treatment and obtained a rapid virological response plete hematological remission, no molecular response was and a partial lymphoma response. Interestingly, another evidenced, as monoclonal immunoglobulin gene rearrange- patient who relapsed 20 months after CHOP therapy plus ment was still detected in peripheral blood after treatment; radiotherapy was treated with interferon alone for 6 months however clinical relapses did not occur if viremia remained and achieved a complete regression of nodules after 1 month negative. Overall, these observations may suggest differences of therapy together with virological response. Eight months in oncogenic potential between HCV-driven B-cell clones in after stopping AT HCV-RNA returned positive and 3 months cryoglobulinemia with respect to splenic lymphoma and are later a subcutaneous lymphoma relapse occurred. in favour of a model in which a continuous viral stimulation In perspective, several lines of future clinical research can leads to cryoglobulinemia and, subsequently, in a subset of be pursued with the aim to further improve these results. patients, to indolent lymphoma. First, it has to be investigated if the combination of rituximab Another study reported first-line AT with interferon and and AT tested in symptomatic cryoglobulinemia by Saadoun ribavirin in 8 HCV-positive patients with different subtypes and colleagues (rituximab weekly for 4 doses followed by of marginal zone lymphoma (4 splenic marginal zone PEG-interferon weekly plus ribavirin daily for 48 weeks) lymphomas with or without villous lymphocytes, 1 dissem- [14] is able to obtain a better long-term control of disease inated marginal zone lymphoma, 1 leukemic marginal zone also in indolent B-cell NHL. Second, it has to be tested if lymphoma, and 2 intestinal MALT lymphomas); 5 out of 8 new antiviral combinations with new anti-HCV agents (i.e., patients (60%) obtained a response, which was correlated to PEG-interferon and ribavirin plus boceprevir or telaprevir), virological response in most cases [70]. that guarantee better rates of SVR in genotypes 1 hepatitis, Among most robust experiences, an Italian multicenter could allow to increase the rate of hematologic response study [71] reported results of AT in 13 indolent B-cell also in patients with more resistant genotypes. Finally, it NHL (4 splenic marginal zone lymphomas, 2 primary nodal has to be explored if future interferon-free regimens with marginal zone lymphomas, 2 extranodal lymphomas of direct antiviral agents only, could consent the access to AT MALT, 4 lymphoplasmacytic lymphomas, and 1 follicular also for HCV-positive NHL patients with contraindications lymphoma) carrying HCV infection. All patients underwent to interferon use, for example because of advanced age, AT alone with PEG-interferon and ribavirin, 10 as first line cytopenias, and/or comorbidities. and 3 as second or third line of therapy. Eleven patients completed planned treatment, while 2 discontinued it 6.3. Role of Antiviral Therapy in Aggressive B-Cell Lymphomas. becauseofsevereadverse effects. Among 12 assessable As previously mentioned, AT seems to be less efficacious than patients, 7 achieved complete response, 2 partial response standard immune-chemotherapy for HCV-positive aggres- (overall response rate 75%), 2 had stable disease, and one sive lymphomas (diffuse large B-cell lymphoma and mantle progressed during therapy. Hematologic responses resulted cell lymphoma) with respect to indolent ones. This is highly significantly associated to clearance or decrease in probably related to the lost of antigen dependence resulting serum HCV viral load, as 7 out of 9 achieved SVR, one had from acquisition of additional mutations that are possibly reduction in viremia, and 1 had no change in viral load. responsible of more aggressive behaviour, although anecdo- Virological response was more frequent in HCV genotype tal cases of diffuse large B-cell lymphoma [79] and mantle 2; however, hematologic response did not correlate with the cell lymphoma [80] treated with AT and obtaining remission viral genotype. One of the greatest accomplishment of this have been reported. Nevertheless, many researchers have study was the demonstration of the efficacy of AT in a wide explored the option to integrate AT in the context of range of HCV-positive low-grade NHL subtypes other than immune-chemotherapy programs in HCV-positive diffuse splenic marginal zone lymphoma, as complete responses large B-cell lymphomas. Although some rare cases of concur- were actually observed without significant differences in all rent delivery of AT and immune-chemotherapy with the aim indolent NHL histologies. to prevent or to treat hepatitis flares have been reported [81], treatment with interferon or PEG-interferon with or without 6.2. Recent Studies and Future Perspectives. Recently Mazzaro ribavirin is usually not feasible because of hematologic et al. [75] reported a comparison of PEG-interferon and toxicity,asshowedbyapilot studybyMusto andcoworkers standard interferon (plus ribavirin) as first-line treatment in 4 patients with diffuse large B-cell lymphoma [82]. The in 18 patients with HCV-positive low-grade B-cell NHL (1 same authors explored the option to perform sequential follicular lymphoma, 1 splenic lymphoma with villous lym- AT with PEG-interferon and ribavirin for 3 months in phocytes, and 16 lymphoplasmacytic lymphomas). Com- responding HCV-positive patients with diffuse large B-cell plete responses as well as SVR were higher in the group lymphomas after 6–8 cycles of R-CHOP. They found that treated with PEG-interferon (6/10 patients, 60%) with this strategy was effective, better tolerated and resulted in respect to the group treated with standard interferon (3/8 high rate of virus clearance in the first 12 patients treated. 8 Clinical and Developmental Immunology These preliminary data have been indirectly supported by [7] C. Hez ´ ode, N. Forestier, G. 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