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ARTICLE IN PRESSNCH-1893; No. of Pages 11

Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx

Hepatitis C virus and lymphomaSemra Paydas ∗

Cukurova University, Faculty of Medicine, Dept of Oncology, 01330 Adana, Turkey

Accepted 14 October 2014

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. What is the most common extra-hepatic manifestation of HCV? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. What is risk of NHL in cases with HCV? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Which test is more useful to determine the prevalence of HCV in cases with lymphoma? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. What is the route of HCV transmission? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. What is the pathogenetic role of HCV in NHL? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. What is the clinical/pathological/genotypic properties of HCV related NHL? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Anti-viral treatment for HCV associated NHL: when and whom? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Management of DLBCL associated with HCV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000. Potential benefits/harms of rituximab and anti-viral using in cases with HCV associated NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

bstract

Hepatitis C virus (HCV) is a hepatotrophic and lymphotrophic virus and is a global health problem. Cirrhosis and hepatocellular cancerre the most common complications of HCV. Association between HCV and B cell non-Hodgkin lymphomas (B-NHL) has been shown inpidemiological studies in the last 20 years. High prevalence of HCV infection among patients with NHL has been reported in the early 1990sy Ferri in Italy and this association has been confirmed in later studies. Geographically, HCV related NHL is highly variable and chronicather than cleared HCV infection is required for lymphomagenesis. Although anti-HCV antibody test is the most commonly used techniquen epidemiological studies, HCV-RNA is more useful test to detect the association between HCV and NHL. The optimal management of HCVelated NHL is not clear. However, anti-viral treatment may be sufficient for cases with low grade and/or asymptomatic lymphomas, whilemmuno-chemotherapy is necessary, in spite of probable hepatic toxicity, in cases with high grade lymphomas.

2014 Elsevier Ireland Ltd. All rights reserved.

eywords: Lymphoma; HCV; Aggressive/indolent lymphoma; HCV prognostic score; Sustained viral response; Rituximab, Immuno-chemotherapy

a
. Introduction
Please cite this article in press as: Paydas S. Hepatitis C

http://dx.doi.org/10.1016/j.critrevonc.2014.10.008

Hepatitis C virus (HCV) is a hepatotrophic and lym-hotrophic virus [1,2] HCV is a global health problem

∗ Tel.: +90 322 3386060 3142; fax: +90 322 3387320.E-mail address: [email protected]

pceluH

ttp://dx.doi.org/10.1016/j.critrevonc.2014.10.008040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

ffecting 3% of the world population and 180 million peo-le are infected with HCV [3,4]. Cirrhosis and hepatocellularancer are the most common complications of HCV [5]. How-ver, HCV related health problems are not limited to the

virus and lymphoma. Crit Rev Oncol/Hematol (2014),

iver, hematological problems like type II mixed cryoglob-linemia (MC) or B-NHL may be seen in cases infected withCV. In the last 20 years epidemiological studies have shown

dx.doi.org/10.1016/j.critrevonc.2014.10.008


mailto:[email protected]


ARTICLE IN PRESSONCH-1893; No. of Pages 11

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S. Paydas / Critical Reviews in On

relationship between B-NHL and HCV. MC is the mostommonly documented extrahepatic disorder in cases withCV. Strong associations between HCV and MC have been

hown to exist using serological and molecular techniques6–8]. The biologic rational for an etiological relationshipetween HCV and B-NHL is based on epidemiological datand clinical observations [9]. High prevalence of HCV infec-ion among patients with NHL has been reported in thearly 1990s by Ferri et al. [10]. Geographically, HCV relatedHL is highly variable. In a systematic review, prevalence ofCV infection has been evaluated among over 6000 cases inurope, America and Asia. High HCV prevalence has been

ound especially in Southern and Eastern Europe, Japan andouthern United States. This is due to different HCV preva-

ence in these countries, ranging from 1–2% to more than 10%11]. It is clear that chronic rather than cleared HCV infections required for lymphomagenesis and chronic antigenic stim-lation driven by chronic infection leads to lymphoma [12].or this reason HCV-RNA is a more useful test to detect thessociation between HCV and NHL.

. What is the most common extra-hepaticanifestation of HCV?

The associatıon between HCV and NHL has beenescribed firstly by Pozzatto and Ferri [13,14]. Large numberf studies reported by Mele, Duberg and Anderson confirmedhe Italian studies [15–17]. Very high prevalence of (as highs 100%) HCV has been found in type II MC [18]. Althoughnly a minority of the HCV (+) patients show symptomaticC, for example vasculitis, the circulating cryoglobulin

each up to 50% of the infected patients [19]. Epidemiologictudies on HCV-MC show large differences in the geographicistribution: higher prevalence in Southern Europe comparedith Northern Europe or USA. It is clear that the presence ofixed cryoglobulin in HCV (+) patients may increase the risk

or NHL. A thirty-five fold increased risk for NHL has beenhown in HCV (+) patients with symptomatic MC in a mul-icenter Italian study [20]. Approximately 8–10% of patientsith HCV-MC progress to overt NHL. Even after HCV erad-

cation, HCV-MC patients may remain at increased risk toevelop B-NHL [21].

. What is risk of NHL in cases with HCV?

In the last 20 years etiologic association between HCVnd NHL has been reported in many studies. At the begin-ing in epidemiologic studies, it has been found a strongssociation between HCV and indolent lymphoma, but latertudies have shown also increased risk for aggressive lym-



homa. The most common association between HCV andHL has been reported from Italy. In two of these stud-

es, a three fold increased risk of low grade lymphoma haseen reported [15,22]. Four fold increased risk of follicular

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/Hematology xxx (2014) xxx–xxx

ymphoma has been reported from US [23]. Goldman fromgypt reported 4.4 and 3.3 fold increased risk for marginalone lymphoma and follicular lymphoma, respectively [24].nterestingly, a 5.2 fold increased risk of lymphoplasmacyticymphoma has been reported from Denmark [25]. Addition-lly, DANVIR cohort study from Denmark showed 29.97old increased risk of NHL during first year of follow up26]. Although the HCV related NHLs seem to be lower inountries with lower HCV prevalence, long-term cohort stud-es showed again higher prevalence of HCV related NHL inome countries.

Striking geographic variation about HCV and NHL sug-ests that genetic and/or environmental factors are involvedn the pathogenesis. For these reasons large scale studiesnd meta analyses have been performed and reported. How-ver, studies showing strong associations between HCV andHL have been included in these meta-analyses for example

taly, Egypt and Japan [24,27,28]. On the other hand theres a strict difference for HCV prevalence between North-rn and Southern countries of Europe; HCV prevalence is.1–1%, 0.2–1.2% and 2–5% in Northern, Central and South-rn Europe, respectively [9,29]. Some theories have beenroposed to explain the geographic differences in the associ-tion of HCV with B-NHL:

1) Differences in the HCV carrier population with NorthernEuropean countries in which transmission is via intra-venous drug use. Transmission, however, is mixed inSouthern Europe: intravenous drug abuse in younger andiatrogenic transmission is more frequent in olders.

2) Long lasting infection in Southern sites may be a causefor the development of NHL.

3) There is controversy about the NHL occurrence and cer-tain genotypes have not been included in low prevalencecountries.

4) Most importantly patients with low grade lymphomacases had longer duration of viral infection while patientswith diffuse large B cell lymphoma (DLBCL) had ashorter duration of infection [3,30].

There are three meta-analyses about HCV associatedHL. First, analysis has been published in 2003 and HCV-C, 43 studies and 5542 cases have been included in this

eport. OR has been found to be 10.8. It has been found anssociation between lymphoplasmacytic lymphoma subtypend mean HCV prevalence has been found to be 13% in casesith NHL [18]. In this analysis, in 10 case-control studies,CV prevalence has been found to be 17% and 1.5% in casesith NHL and healthy controls, respectively [31,20]. Sec-nd, meta-analysis has been published by Matsuo [32]. Inhis analysis 23 studies and 4049 cases and 1.813.480 con-rols have been included and OR has been found as 5.7. Inhis meta-analysis lymphoma cell type and HCV relationship


as been evaluated and it has not been found an associ-tion between HCV and lymphoma subtype [32]. Third,eta-analysis has been published by Dal Maso [33]. Fifteen

ase-control and three prospective studies and 4678 cases



S. Paydas / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx 3

Table 1Meta-analyses and International extranodal lymphoma consortium results about NHL risk in patients with HCV.

Author Publicationyear

Number ofstudies

Number ofcases

OR for NHL OR for NHLsubtype

Reference

Gispert 2003 43 5542 10.8 LPL [18]Matsua 2004 23 4049 5.7 No association [32]Dal Maso 2006 18 4678 2.5 No association [33]International

extranodallymphomaconsortium

2008 7 4784 1.78 LPL: 2.99MZL:2.47DLBCL:2.24 [34]

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ave been included in these analysis. Relative risk has beenound as 2.5 and again no difference was found between lym-homa subtypes in this report [33]. Pooled analysis of datarom the International Lymphoma Epidemiology Consortiumovered 7 studies and 4784 cases and indicated a 1.78 foldncreased risk of NHL. HCV infection has been detected in72 NHL cases (3.6%) and 169 controls (2.7%) and OR haseen found as 2.99 for lymphoplasmacytic lymphoma, 2.47or marginal zone lymphoma, and 2.24 for DLBCL [34].able 1 shows the results of the three meta-analyses and extra-odal lymphoma epidemiology consortium for NHL risk inases with HCV.

In a report, subgroups of NHL have been evaluated ando clear association has been found between HCV and B-HL subtypes either indolent or aggressive [35]. However,

ome case-control studies showed higher risk of aggres-ive lymphomas compared to indolent lymphomas. Mortont al. recently published an interesting analysis. They inves-igated HBV, HCV and risk of NHL in solid organ transplanteceivers and they found that hepatitis viral infection statust the time of transplantation was not related with NHL risk36].

. Which test is more useful to determine therevalence of HCV in cases with lymphoma?

An important point for different results for the associa-ion between HCV and NHL is the method used to determinehe HCV infection. The detection of HCV antibodies withoutCV-RNA analysis may underestimate the true rate of HCV

nfection in patients with NHL. This is due to the abnormalCV antibody response both quantitatively and qualitatively

n cases with NHL [37]. We performed three studies to detecthe prevalence of HCV in Turkey. In our first study, anti-HCVntibody prevalence was evaluated in 228 cases with lym-hoproliferative disorders. Nine of 98 cases with NHL hadnti-HCV antibody and prevalence was found to be 10% [38].n our second study, anti-HCV antibody was studied in 223



ases and we found anti-HCV positivity in 18 cases (8.1%).his prevalence was compared with donor population andR and corrected OR were found to be 34.56 and 19.07,

espectively. Additionally, HCV-RNA was studied in 67 of

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acytic lymphoma; MZL, marginal zone lymphoma; DLBCL, diffuse large

hese 223 samples. In this study HCV-RNA was detectedn 21 of these cases (31.3%). This and some other studiesuggested that HCV-RNA is more beneficial for the detec-ion of HCV infection in these immune-suppressed cases39–43]. In our third study, RT-PCR was used to detect theCV-RNA both in serum and tissue samples. HCV-RNA wasetected in 11 of 30 tissue samples (37%) while HCV-RNAnd anti-HCV antibody were detected in only 7 (23.3%) and

(10%) serum samples of these 30 cases, respectively [44].n another study considering HCV-RNA, HCV prevalenceas found to be associated with diffuse large B cell lym-homa (OR: 2.19) and HCV-RNA was found to be morerequently associated with NHL than anti-HCV antibodies.his finding is related with impaired antibody production in

hese cases [12]. In a population based study from US, HCV-NA was found in 3.9 and 2.1% of the patients and controls,

espectively and it has been found 2.46 fold increased risk forollicular lymphoma, 3.99 fold increased risk for marginalone lymphoma and 2.04 fold increased risk for MALT lym-homa [45]. No relationship was found between anti-HCVntibodies and increased risk of NHL (OR: 2.2) in a case-ontrol study from a Danish–Swedish population. Analysisestricted to HCV-RNA indicated that OR was 1.7 in thisopulation [25]. In another Swedish study increased risk ofHL was found to be restricted to only HCV-RNA positive

ases [26]. Serum samples from eight European countries,etween 1998 and 2004, HCV-RNA positivity was found toe related with 1.42 fold increased risk of NHL. This wasower than the studies which HCV detected by anti-HCVntibody [12].

. What is the route of HCV transmission?

HCV is a single stranded RNA virus without DNA inter-ediate in its replicative cycle, so integration of HCV

ucleic acid sequences into host genome seems unlikely.herefore, it cannot be considered a typical oncogenicirus but it can exert its oncogenic potential indirectly by


ontributing to the modulator effects of the host immuneystem [46,47]. In fact, viral transmission routes are impor-ant in the development of NHL related HCV. Intravenousrug use transmission is the predominant route among



4 S. Paydas / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx

Fig. 1. Pathogenesis of HCV related lymphoproliferative disorders.R

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ounger population in the Northern countries while iatro-enic transmission is important in older population in theouthern countries [48].

. What is the pathogenetic role of HCV in NHL?

It has been suggested that HCV can exert a chronic stimu-us on the immune system, which facilitates the developmentnd selection of abnormal clones and this scenario looks likehe role of H Pylori for MALT lymphomas [49]. The regres-ion of HCV related B-NHL following anti-viral treatmentepresents the etiologic association between HCV and lym-homas. It has been reported complete or partial responsesfter anti-viral therapy in HCV (+) cases but not in HCV (−)atients [9,50–52].

In early 1990s, HCV-RNA has been demonstrated inerum/plasma and liver tissues and also in peripheral bloodononuclear cells of patients with HCV [53,54]. Peripheral

lood cells serve as reservoirs for persistent HCV infec-ion. Long lasting HCV infection in B cells may cause toymphoproliferative disorders [55]. It has been proposedhat sustained antigenic stimulation of B cell compartmentas a role in viral lymphotrophism [56]. Fig. 1 shows theteps for lymphomagenesis after antigenic stimulation. Viralymphotropism has been suggested with the presence of



iral replication in lymphatic cells [53]. HCV infection inone marrow has been shown by Galli in 100% and 43%f the patients with or without MC, respectively [57]. Itas been shown that HCV-E2 protein interacts with CD81

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hich is also present on the B cell surface. This binding isesponsible for sustained polyclonal B cell activation low-ring the B cell activation threshold [58,59]. Fig. 2 showshe role of connections between HCV proteins, CD81-E2,hromosomal aberrations, apoptotic inhibition, cytokines andhronic antigenic stimulation. HCV-CD81 interaction plays

central role for virus adaptation to the human host [59].ai used an in vitro model for HCV infection in B cell andhowed the enhanced mutation rate of Ig genes [60]. Thetudy showed the dramatically increased copy of activationnduced cytidine deaminase (AID) in the B cells in HCVnfected patients. HCV enhances AID expression by NFKBctivation through the expression of viral core proteins. It haseen found 100 fold increased levels of AID mRNA levels inD19 (+) cells. This finding shows that HCV infects periph-ral blood CD19 (+) cells and this is the reservoir during HCVnfection in humans: suggesting HCV infects and may repli-ate in B cells [61]. These findings suggest that inappropriatexpression of AID acts as a DNA mutator which enhancesenetic susceptibility to mutagenesis [55]. Fig. 3 shows theole of activation induced cytidine deaminase (AID) in the

cells in HCV infected patients. This finding suggests thatID activation may be a factor in the lymphomagenic pro-

ess mediated by HCV. Also significantly higher expressionf several lymphomagenesis related genes have been shownn patients with HCV [19]. In transgenic mice expressing theull HCV genome in B cells was established by Tsuhiyama


nd 25% incidence of diffuse large B cell lymphoma within00 days of birth was shown [62]. Oncogenic potential andymphotrophism of different HCV genotypes are variable



S. Paydas / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx 5

Fig. 2. The role of connections between HCV proteins, CD81-E2, chromosomal abReprinted from reference [56].

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ig. 3. The role of activation induced cytidine deaminase (AID) in the Bells in HCV infected patients.eprinted from reference [55].

nd results are conflicting [63–66]. Although HCV does notirectly transform human B cells in vitro, transgenic micexpressing the full HCV genome in B cells spontaneouslyevelop B cell lymphomas in vivo [67].

The most commonly investigated genetic aberration is(14:18) and this is associated with type II or monoclonal

C. The presence of this translocation in MC has been foundo be correlated with the overexpression of the anti-apoptoticcl-2/Bax ratio. Abnormal B cell clones following effectiventi-viral treatment and in some cases a new expansion of theame clones have been shown [68]. Aneuploidy and chromo-omal instability and reduced expression of retinoblastomaave been reported in HCV-infected patients [69,70]. Someytokines and chemokines including CXCL10, CXCL13 aremportant in B cell trafficking and have been found to bencreased in serum of MC patients [26]. High levels of B cell



ctivator factor (BAFF or BLyS) is essential for B cell devel-pment/survival and has been found to be higher in HCVatients with lymphoproliferative disorders [71].

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errations, apoptosis inhibition, cytokines and chronic antigenic stimulation.

Recently Ng et al. looked for B cell receptors expressedy HCV associated lymphomas and interestingly they foundhat these lymphomas use a restricted immunoglobulin vari-ble region gene repertoire. Also they found no evidence forheir binding to the HCV antigens. With these results theyuggested that most of the HCV associated lymphomas doot arise from B cells eliminating the virus [72].

It is very well known that miRNAs are important inathogenesis of many malignant and inflammatory disorders.mong miRNAs, miR-26b has been shown to be downreg-lated in HCV (+) lymphomas as compared to HCV (−)plenic marginal zone lymphomas. This finding suggests

possible speculative mechanism in malignant lymphoma45]. Additionally, in recent times it has been shown the pos-ible contribution of NF-KB signaling and down regulationf miR-26b in the development of HCV associated B cellymphomas in transgenic mice [73]. miRNA profile has beentudied in HCV associated DLBCL in a comprehensive studynd has been found decreased expression of miR-138-5p andncreased expression of miR-147-a, miR-147b and miR-511-p and these alterations have been found to be poor prognosticactors in HCV related DLBCL [74]. These results suggesthat miRNA profiles are related with clinical and pathologicalarameters and have a potential for therapeutic opportunityn HCV associated with DLBCL in near future.

In summary as proposed for the last two decades, sus-


ained HCV-driven antigenic stimulation plays a key role innducing B cell clonal expansion and indicates a mechanismf HCV-related lymphomagenesis. Lymphatic follicles in the



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iver in HCV infection is the main site for B cell clonal expan-ion [75]. Intra-hepatic B cell clones are associated withxtrahepatic manifestations of HCV. During the multi-stepymphomagenic process, chromosomal aberrations and otherenetic aberrations occur [76].

. What is the clinical/pathological/genotypicroperties of HCV related NHL?

It is not clear which lymphoma subtype is more preva-ent in cases with HCV infection. The most frequentlyescribed subtypes are marginal zone lymphoma especiallyplenic marginal zone lymphoma, lymphoplasmacytic lym-homa and DLBCL [77]. Clinical data of patients withCV related lymphoma is variable in different series. In

ome series more aggressive behavior, including extranodalnvolvement, higher LDH, and older age have been found toe increased in HCV related lymphoma, but other studiesid not find such relationship [30,78–85]. Liver involve-ent was more common in patients with active infection

nd was seen in one fourth of the cases with hepatitis orirrhosis at diagnosis. This finding suggests that active viralnfection may be related with lymphomagenesis in the liver78]. In some series, splenomegaly was found to be morerequent as compared to HCV (−) patients. The cause ofhis finding was portal hypertension due to impaired liverirculation in HCV infected patients. The other cause maye related with transformation from marginal zone lym-homa.

An important point is the association between HCV geno-ypes and B-NHL. In most studies, no link has been foundetween specific viral genotypes and B-NHL. However, wenow that this point has not been addressed in many of thetudies and in some of these studies association has been eval-ated more carefully [35]. Genotype II has been found to bemportant for the development of lymphoma [83]. In anothertudy genotype Ib has been found to be most prevalent sub-ype and OR for the development of NHL has been founds 4.2 while OR was 2.9 for whole group [12]. Luppi docu-ented an unexpectedly lower prevalence of HCV genotype

b/3 in patients with B-NHL. In contrast the prevalence ofenotypes 2a/3 and 2b/4 were found to be higher in B-NHL84]. These findings suggest that some HCV genotypes areore lymphomagenic. Another interesting point is the dura-

ion of HCV infection and subtype of lymphoma. Pallicellieported a higher prevalence of genotype 1 and shorter dura-ion of HCV infection in cases with DLBCL as compared toigher prevalence of genotype 2 and longer duration of HCVnfection in patients with indolent-low grade lymphoma. It isnown that HCV genotype 2 is related with longer durationf viral infection. It has been speculated that it may induce aersistent chronic immune-stimulation of B cells over time.



n contrast, direct lymphocyte transformation for HCV geno-ype 1 in aggressive lymphomas may occur on the basis ofhe shorter duration of viral exposure [79].

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. Anti-viral treatment for HCV associated NHL:hen and whom?

Anti-viral treatment (AVT) has been found to be effec-ive in low grade lymphomas. Interestingly HCV infectedatients treated by interferon and achieved sustained viralesponse (SVR) had a lower rate of lymphoma than who hadot received AVT. This finding suggests that AVT may bereventive for lymphomagenesis in HCV infected patients.ew anti-viral drugs may be attractive at this situation

85,86,87,88]. Subcutaneous pegylated intereferon alpha 2a,80 �g weekly plus oral ribavirin (800, 1000 and 1200 mgaily dose have been recommended for patients <65 kg,5–85 kg and >85 kg, respectively) is the therapy of choicen these cases. Erythropoietin alpha 2a 40.000 IU weeklyubcutaneously has been added in cases if hemoglobin levelecreased by more than 2 g. Duration of treatment has beenecommended as 1 year in patients HCV genotype 1 or 4, and

months for patients genotype 2 or 3. Definition of responseo anti-viral treatment is important: SVR has been defined asCV RNA negativity (<12 IU/ml) 24 weeks after stopping

herapy. If HCV RNA is positive after 3 months from theeginning of AVT this has been accepted as nonrespondance.n this study response rate been found as 71% as SVR [30].ymphoma regression has been found to be correlated witheduction of viral load [9]. This approach is valid for asymp-omatic indolent lymphomas. A systematic review showedhat complete responses were achieved in 75% of the HCV+) cases [89].

There is no prospective study about the efficacy of AVT inases with HCV related NHL. Arcaini et al. recently reportedpdated results of Fundazione Italiana Linfomi. They fol-owed 704 HCV (+) cases with indolent NHL between 1993nd 2009 in 39 centers. Among these cases, 134 were man-ged with AVT. For entire cohort 5 year overall survival (OS)nd progression free survival (PFS) were found to be 78%nd 48%, respectively. In multivariate analysis the use ofVT during the patients’ life had positive impact on OS.ith the use of AVT, HR was 0.21 and 0.80 for OS and

FS, respectively. Overall response rate was 77% with 44%omplete response. HCV-RNA clearance was detected in0% of the cases and this was found to be associated withymphoma regression. This is the largest study focused onnti-lymphoma efficacy of AVT in HCV (+) indolent lym-homa [90].

. Management of DLBCL associated with HCV

HCV eradication is not the only option for aggressiveymphomas and/or symptomatic indolent lymphomas. Theseatients require rituximab containing chemotherapy (CT)


30]. It has been reported that CT is tolerated relatively well.reatment must be given for cure intent. Higher completeesponse and event-free survival have been reported in someeries [79]. However in some cases, CT cannot be given



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ue to impaired liver function [78]. AVT for the eradica-ion of HCV may be an option after successful lymphomaherapy [35]. La mura et al. retrospectively analyzed a studynd found that PFS and OS were slightly longer in patientseceiving anti-virals after immuno-chemotherapy. SVR wasbtained in 32% of the HCV (+) cases receiving anti-viralherapy. None of the patients who eradicated HCV infectionad relapse while one third of the cases who did not respondo anti-viral treatment showed relapse [91]. Similar outcomeor aggressive lymphomas has been reported in Japan [92].

0. Potential benefits/harms of rituximab andnti-viral using in cases with HCV associated NHL

The addition of rituximab to chemotherapy is considereds the greatest advance in the treatment of B-NHL in the pastwo decades. However it is not clear the benefit of rituximabn cases with HCV associated NHL due to potential increasen hepatic toxicity and we need to know the early and lateoxicity of rituximab using in these cases and one of the mostritical points in these cases is the safety of rituximab usingn addition to the efficacy.

It is believed that in contrast to HBV infection, rituximabs well tolerated in cases with HCV [35,78]. However HCVeactivation in patients receiving immuno-chemotherapy (I-T) is not clear as observed in HBV reactivation in HBV

nfected cases [9]. HCV-RNA levels increase during I-CT as result of viral reactivation, but HCV-RNA decrease within

months, generally without major clinical problem [93].owever, there is possibility of liver toxicity due to eitherirect cytotoxicity or increased drug toxicity from suboptimalrug metabolism. These are important points and it has beeneported higher toxic deaths in HCV (+) cases. This may beue to withdrawal of chemotherapy or reduction of steroids,ndicating an immune mediated mechanism of liver damage81,87,93]. For this reason monitoring of liver function testsnd viral load must be performed carefully and also if nec-ssary modification of the treatment must be done [35,82].f there is no liver dysfunction at the beginning HCV (+),atients faired similarly with HCV (−) patients after I-CT93,94]. Anti-viral prophylaxis has not shown to provide arotective effect to suppress HCV replication while patientseceiving chemotherapy [9,93]. We need prospective con-rolled trials to determine this controversial issue. WhetherCV eradication after I-CT may impact survival outcome isot clear [9]. HBV co-infection, advanced stage disease andodal origin are the strongest adverse prognostic indicators78]. These and additional risk factors must be determined toecrease the risk of hepatic toxicity. An important questionas not been answered: is it necessary to give concomitantibavirin or interferon while patient receiving anti-neoplastic



reatment or anti-virals must be given after the end of treat-ent? Further studies are needed to answer this question.The benefits and risks of using rituximab in cases with

CV related NHL is not clear and available results are

owtc

/Hematology xxx (2014) xxx–xxx 7

onflicting. An important large retrospective multicentrictudy has been reported from Italy in the last year. In thistudy, 535 consecutive cases with HCV associated DLBCLreated by anthracycline based CT have been evaluated.evere hepatotoxicity has been observed in 14% of theases and it has not been found an association betweensing rituximab and hepatotoxicity. Three factors have beenound to be significant in multivariate analysis: ECOG per-ormance status ≥2, serum albumin <3.5 g/dl, HCV viraload >1000 KIU/ml. At the end authors suggested a newrognostic score named HCV prognostic score: low = 0, inter-ediate = 1, high ≥2. This score was found to be better than

nternational prognostic score. This new prognostic scoreetained prognostic value in the subgroup of patients treatedith and without rituximab [95]. This is an important resultut we need more absolute results, especially prospectiveandomized studies compating I-CT and CT in these cases.

In a retrospective analysis from GELA studies (LNH 93nd LNH98) the outcome of the patients with HCV has beenound to be poor. The short term hepatic toxicity has beenound to be strongly increased and has been found in 15 ofhe 23 cases [81]. In another retrospective study, 160 HCV (+)HL patients (101 aggressive and 59 indolent lymphomas)ave been evaluated for rituximab using. Hepatic toxicity waseported in 18% of the cases receiving I-CT (this was 7% inases receiving chemotherapy only) and median PFS wasound to be significantly shorter in cases requiring interrup-ion of chemotherapy due to hepatic toxicity. With this studyuthors suggested a limitation but not absolute contraindica-ion for the use of rituximab in cases with HCV infection96]. Hepatic toxicity associated with rituximab has beenvaluated retrospectively in another study by Marignani et al.n cases with B-NHL. Hepatic toxicity has been reported in

of 9 cases with HCV (+) NHL while none of the 95 casesith HCV (−). Although HCV flares were found to be signifi-

ant risk factor in HCV patients receiving rituximab there waso difference in 12 months follow up [97]. In large study from

centers in Northern Italy, 132 of 156 consecutive HCV (+)LBCL cases followed between 1994 and 2004 were treatedith curative intent. The addition of rituximab was not found

o be associated with decreased tolerance to chemotherapy;ncrease in liver enzyme levels (grade I) was detected in only 5f 35 cases (14%) treated with rituximab containing regimen78]. Nishikawa et al. from Japan retrospectively analyzed48 patients with DLBCL treated between 2004 and 2011;20 of these cases were HCV (−) and 28 were HCV (+).n terms of OS and PFS, there were no significant differ-nces according to the HCV status. Although hepatic toxicityas found in 25% and 15.9% of the cases with HCV (+)

nd (−) cases, respectively, none of the cases discontinuedreatment due to hepatic toxicity [98]. Recently Zaky et al.nalyzed 137 cases with HCV (+) DLBCL and compared the


utcome of the patients treated with chemotherapy with orithout rituximab. They found significantly increased hepatic

oxicity (28% vs 18%) receiving rituximab and worse out-ome for PFS and OS [99]. However all of these studies are


Please

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as:

Paydas

S.

Hepatitis

C

virus

and

lym

phoma.

C

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Rev

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ncol/Hem

atol

(2014),http://dx.doi.org/10.1016/j.critrevonc.2014.10.008

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Table 2Hepatic toxicity in cases with B cell lymphoma treated with or without rituximab containing regimens.

Author(Reference)

Study type Study years N (evaluated HCV Rituximab Hepatic toxicity (Grade III–IV) PFS (months) OS (months) Medianfollow up(month)

Generalcomment forHT

(+) (−) (+) (−) R(+) R (−) R (+) R(−) R(+) R(−)

Salah-Eldin[100]

Prospective 2008–2013 280DLBCL: 280

280 0 200 80 53/200(26.5%)

11/80(13.75%)

40 35 51 43 41 Pretreatmentliverdysfunctionimportant

Marignani[97]

Retrospective 2004–2006 104DLBCL: 56FL: 56SLL: 11MCL: 6Other: 3

9 95 104 0 3/9: HCV (+)

0/95: HCV(−)

0 NA – NA – NA Despiteincrease inLFT, no majorclinicallimitation

Visco [78] Retrospective 1994–2004 132DLBCL: 132

132 0 35 97 5/35(14%)Grade I

0 NA NA NA NA 12 R did notaffecttolerance

Nishikawa[98]

Retrospective 2004–2011 248DLBCL: 248

28 220 248 0 7/28: HCV (+)35/220HCV (−)

0 64%a

HCV(+)65%HCV(−)

– 66%a

HCV(+)77%HCV(−)

– 36 No patientrequired dis-continuationI-CT

Merli [95] Retrospective 1995–2010 535DLBCL: 535

535 0 255 280 16% 14% 55%b 45%b 70%b 60%b 24 HCVprognosticscoreimportant

Zaky [99] Retrospective 137DLBCL: 137

137 0 28% 18% 55% 80% Highincidence ofHT withRituximab

Besson [81] Retrospective LNH-93LNH-98

Among 5586DLBCL

26 72 NA NA 65%(15/23)

24 2 year OS-PFS56%-53%HCV (+) vs80%-74%HCV (−)

Abbreviations: DLBCL, diffuse large B cell lymphoma; NHL, non-Hodgkin lymphoma; R, rituximab; PFS, progression free survival; OS, overall survival; I-CT, immuno-chemotherapy; HT, hepatotoxicity.a 3 years PFS and OS NS.b 4 years PFS(Sig) OS (NS).



cology

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etrospective, sample sizes are relatively small and rituximabsing is not balanced in study groups and also late compli-ations associated with rituximab in these cases are not clearue to the limited time of follow ups. The only prospectivetudy from Egypt found no significant difference for PFSnd OS according to the rituximab administration. This studyas carried out on 280 HCV (+) cases with DLBCL; 200 of

hem received I-CT while 80 cases received CT only. Rit-ximab using caused severe hepatic toxicity in 26.5% of theases although severe hepatotoxicity developed in 13.75% ofhe cases not receiving rituximab. In this study patients withCV associated DLBCL have no benefit from addition of

ituximab to chemotherapy [100]. Table 2 shows the studiesvaluating hepatic toxicity with rituximab using in cases withCV related NHL.In summary rituximab is an important monoclonal anti-

ody in the management of cases with DLBCL. Howeverlose monitoring of liver function tests and viral load, espe-ially in cases with abnormal liver function tests at theeginning, necessary.

1. Conclusion

HCV is a global health problem affecting 180 million peo-le. Higher HCV prevalence has been found in Southern andastern Europe, Japan and Southern United States and Egypt.his is associated with HCV prevalence, ranging from 1 to 2%

o more than 10%. The detection of HCV antibodies withoutCV-RNA analysis in serum or tissue samples may under-

stimate the true rate of HCV infection. Three factors haveeen found to be significant in multivariate analysis: ECOGerformance status ≥2, serum albumin <3.5 g/dl, HCV viraload >1000 KIU/ml and a new prognostic score has beenuggested for these cases. Anti-viral treatment is the treat-ent of choice in cases with low grade lymphoma while

mmuno-chemotherapy is necessary in cases with aggressiveymphomas.

eviewers

Dr. Pellegrino Musto, Head, IRCCS Centro Riferimentoncologico Basilicata, Onco-Hematology, Via Padre Pio, 1,

-85028 Rionero in Vulture, PZ, Italy.Dr. Luca Arcaini, Assistant professor, Department of

ematology Oncology, Fondazione IRCCS Policlinico Sanatteo, Pavia, Italy; Department of Molecular Medicine,niversity of Pavia, Pavia, Italy, Viale Golgi 19 Pavia,

taly.



Dr. Pier Luigi Zinzani, M.D., Ph.D., University ofologna, Institute of Hematology and Medical Oncology, viaassarenti, 9, I-40138 Bologna, BO, Italy.


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Documents

Hepatitis C virus and lymphoma