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Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

From the Department of Oncology and Hematology, G. da Saliceto Hospital, Piacenza; Division of Hematology, IRCCS Policlinico San Matteo, University of Pavia, Paiva; Department of Oncology and Hematology, University of Modena, Modena; Haematology Division, Azienda Ospedaliera of Reggio Calabria, Reggio Calabria, Italy

Address reprint requests to Daniele Vallisa, MD, Department of Oncology and Hematology, G. da Saliceto Hospital, Piacenza, Via Taverna 49, 29100 Piacenza, Italy; e-mail: d.vallisa{at}ausl.pc.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated.

PATIENTS AND METHODS: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months.

RESULTS: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 ± 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response.

CONCLUSION: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

	INTRODUCTION

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Hepatitis C virus (HCV) represents a viral pandemia and is a well known etiologic agent of chronic viral hepatitis.¹ Moreover, chronic hepatitis C infection has been linked to development of hepatocellular carcinoma.^2,3 HCV has been detected not only within infected hepatocytes, but also in blood cells such as lymphocytes,⁴ and has been implicated as a putative agent of cryoglobulinemia.⁵ The virus has shown to sustain clonal expansion of B lymphocytes in HCV-infected patients.⁶ This observation, together with the appearance of several reports that highlighted a possible association of HCV with B-cell non-Hodgkin's lymphoma (B-NHL),^7–12 raised the question whether HCV is a lymphomagenic virus. So far, no definitive answer is available, because while numerous reports attest a significant association between HCV and B-NHL, several sporadic observations do not confirm this association.^13–16 These contrasting results could find an explanation in the variable prevalence of HCV throughout the world.¹ In the last few years, an increasing amount of biologic data have supported the role of the virus in lymphomagenesis, such as the finding of viral sequences in lymphoma tissue,⁸ and the disclosure of a specific receptor (CD81) on lymphocyte B surface for the HCV envelope glycoprotein E2¹⁷ that allows the internalization of the virus. Moreover HCV-positive, marginal zone, B-cell lymphomas preferentially express the V(H)1-69 gene of immunoglobulin repertoire, which is also employed by lymphocytes in the physiologic response against HCV infection.^18,19 Furthermore, chronic HCV infection may dramatically increase the expression of migration inhibitory factor, which can overcome p53 function.³ Lastly, HCV core protein interacts with signal transducer and activator of transcription 3 protein.²⁰ In a patient affected by HCV infection, the same clonal lymphocytic population was shown to first sustain cryoglobulinemia and then shift to NHL, thus attesting to a chronologic link between HCV infection, clonal lymphocytic proliferation, and lymphoma.²¹ Moreover, Zuckerman et al²² found an increased prevalence of t(14,18) translocation and clonal immunoglobulin gene rearrangement in HCV-infected patients. Following interferon treatment, these biologic markers disappeared. The experience of successful treatment of HCV related lymphoproliferative disorders by antiviral treatment, such as interferon alfa alone or together with ribavirin, concerns cryoglobulinemia²³ and splenic lymphoma with villous lymphocytes.²⁴ Our aim was to extend this experience to a wider setting of patients affected by HCV-related, low-grade, B-cell lymphoma. Finally interferon has been reported as an efficacious antitumor agent in low- and intermediate-grade lymphoma,^25–27 without any correlation to HCV infection, both in induction and maintenance treatment, alone or combined with cytotoxic chemotherapy. The best results in induction treatment were achieved in combination with chemotherapy. However, in the French study by Hermine et al,²⁴ interferon was only efficacious in splenic lymphoma associated with HCV infection, while no hematologic response to interferon was registered when HCV infection was not present.

	PATIENTS AND METHODS

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Patients
In January 2001, we began a prospective multicenter pilot study in order to evaluate the effect of antiviral therapy alone on the course of a subset of HCV-related B-NHL. Criteria for patients' selection were the following: low-grade B-NHL at first diagnosis or relapse, indolent course, and concomitant HCV infection. HCV-related NHL was defined as positive HCV polymerase chain reaction (PCR) and serology before or at time of lymphoma diagnosis. The diagnosis of lymphoma was established according to Revised European-American Lymphoma Classification criteria²⁸ revised by Harris.²⁹ Low-grade lymphomas included lymphocytic lymphoma, marginal-zone lymphoma (nodal, extranodal and splenic), lymphoplasmocytoid, and follicular grade 1 lymphoma.²⁹ Stage and extranodal involvement were determined at enrollment according to Ann Arbor classification by physical examination, total body computed tomography (CT) scan, and bone marrow biopsy. Indolent course was defined by a disease double time no less than 1 year, no "B" symptoms, and no lymphomatous mass size more than 10 cm (bulky disease). Further inclusion criteria were: age between 18 and 75 years; absence of hepatitis B virus (HBV) and acquired HIV infections; no concomitant neoplastic disease; and no antineoplastic treatment for at least 6 months. All patients gave written informed consent at the time of enrollment. The treatment was in accordance with the guidelines of the Italian Department of Health for chronic active hepatitis C treatment. The major end points of our study were to evaluate the role of antiviral treatment on the clinical course of the lymphoma and its correlation with antiviral response.

Laboratory Analysis
Antibodies against hepatitis C virus were tested at enrollment with enzyme-linked immunosorbent assay (EJA-3, Ortho HCV third generation; Ortho Diagnostic Systems, Raritan, NJ) and confirmed by recombinant-based immunoblot assay (Riba-3; Chiron, Emeryville, CA; Ortho Diagnostic Systems). RNA sequences of hepatitis C virus were investigated using a one-tube nested PCR assay; primers located in the 5' noncoding highly-conserved sequences of viral genome were employed.⁸ Genotyping was performed using the Innogenetics Line Probe Assay (Innogenetics, Zwijndrecht, Belgium). HCV viremia was tested by HCVRNA 3.0 Assay (bDNA; Bayer, Diagnostic Division, Tarrytown, NY) at diagnosis and then every 3 months. All the patients were tested for cryoglobulins.³⁰ Mixed cryoglobulinemia was classified as type II in the presence of polyclonal immunoglobulin (Ig) G complexed with IgM monoclonal immunoglobulins.

MBR bcl2-J_H translocation t(14;18) was detected in peripheral and medullary blood mononuclear cells by a nested-PCR slightly modified according to Gribben et al.³¹

Clonal rearrangement of immunoglobulin heavy chain gene (IgH; FR3-FR2/J_H) was detected in peripheral and medullary blood mononuclear cells at diagnosis and at the end of treatment by a seminested PCR approach as previously described.²² Safety was assessed by blood cell counts, hemoglobin, platelets, serum aminotransferases, and creatinine together with physical examination weekly in the first month of treatment, and then every 3 weeks. Toxicity was evaluated according to the WHO scale; treatment dose was reduced when toxicity grade 2 developed, and withheld when grade 3 developed, until toxicity had resolved to grade 2. Toxicity grade 4 caused a definitive stop of the treatment.

Antiviral Treatment
Treatment consisted of pegilated interferon alfa-2b (PEG-INTRON; Schering-Plough, Brussells, Belgium) 50 µg subcutaneously once a week and ribavirin 1,000 mg (REBETOL; Schering-Plough) orally daily when the patient weighed under 60 kg, otherwise pegilated interferon was increased to 70 µg weekly and 1,200 mg ribavirin daily, as previously described.^32,33 Treatment was scheduled for at least 6 months. After 6 months it was stopped, when either a complete hematologic response together with viremia clearance or no response was achieved. Otherwise, partial hematologic response and/or no viremia clearance at the sixth month were indications for maintenance of treatment for another 6 months. No response was not a criterion for discontinuation of treatment before the sixth month, but progressive disease was a criterion for discontinuation.

Response Criteria
Patients underwent clinical and abdominal ultrasonographic examination, biochemical evaluation, and quantification of HCV-RNA viremia at 3-month intervals. At the sixth month, hematologic response was evaluated according to the standard response criteria (ie, by physical examination, biochemical evaluation, CT scan, and bone marrow biopsy).³⁴ Complete response (CR) was defined as no evidence of lymphoma; partial response (PR) was defined as a 50% decrease in lymph node size. Appearance of new lesions or 50% increase in size of lymph nodes was considered as progressive disease (PD). Stable disease was not considered as positive as a PR, but it was a better response than PD.

Biologic markers of disease such as t(14;18) presence or clonal IgH-FR3 rearrangement were evaluated at diagnosis, and every 6 months, but were not employed as response criteria according to the literature.³⁴

Follow-Up
At the end of treatment, clinical and biochemical evaluations were continued every 3 months, and HCV-RNA load every 6 months and/or at the time lymphoma relapse occurred.

Statistical Analysis
Statistical comparison of hematologic responses among different HCV genotypes, as well as among antiviral responses, was based on ² calculation and evaluated with Fisher's exact test and ² Pearson test. Student’s t test for unpaired data was employed to evaluate differences among males and females. Significance level was set at two-tailed P values of less than .05. Statistical analyses were performed by employing SPSS package 10.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Patient Characteristics
Thirteen patients entered the study (Table 1). These included seven consecutive patients from a single center (Piacenza, Italy), three from GISL (Gruppo Italiano Studio Linfomi, Modena, Italy) centers, and three from University of Pavia (Pavia, Italy). Eight patients were female and five male; the mean age was 57.6 ± 11.6 years, with females 56.7 ± 11.4 years and males 59.5 ± 13.7 years (no significant statistical differences). Patients' diagnoses were as follows: one follicular lymphoma, four lymphoplasmacytoid lymphomas, and eight marginal-zone lymphomas. Among marginal-zone lymphomas, there were two nodal marginal lymphomas, four splenic marginal lymphomas, and two extranodal marginal zone lymphomas (Table 1). The two marginal nodal lymphomas showed medullary involvement, one with right axillary and left superficial parotid positive lymph nodes (patient 1), the other with retroperitoneal nodal localizations (patient 2). Interestingly, follicular lymphoma presented as an extensive cutaneous relapse that involved both the right and left side of the back and right axillary lymph nodes (patient 3). All four plasmacytoid lymphomas carried monoclonal components (two IgM and two IgM); in three patients, the lymphoma was detected in the bone marrow while in one patient, it was only detected in the liver (patient 6). Hepatic biopsy disclosed lymphomatous involvement in two of four patients affected by splenic marginal-zone lymphoma (patients 10 and 11). Among the two extranodal marginal lymphomas, one showed significant lymphomatous involvement of right and left maxillary sinuses and ethmoid sinuses (patient 9), and in the other patient, the diagnosis was achieved by biopsy of a left periorbital lymphomatous mass with concomitant medullary involvement (patient 13).

Response to Antiviral Treatment
Eleven patients were able to complete the planned treatment in a period ranging from 6 to 12 months. The other two patients developed severe adverse effects causing a definitive discontinuation of the treatment: One of the patients, who discontinued the treatment after 4 months, was available for response assessment and achieved complete response; the other patients was not assessable for response since duration treatment was only 2 months. Of the 12 assessable patients, seven achieved a CR, two had PRs (CR + PR = 75%), two had stable disease, and one PD (Table 2). Response was achieved with a mean time of 7.7 ± 3.2 months. Lymphoma response significantly correlated to decrease or disappearance of HCV viremia (P = .005, ² Pearson; P = .035, Fisher's exact test). Among the nine responders, seven achieved disappearance of detectable viremia in the serum (77%), one had a 2x log reduction of viremia while one responder had no change (PR). All nonresponders had no virologic response.

At diagnosis, 11 patients were tested for clonal IgH rearrangement and bcl-2 translocation. Of those, four patients were positive only for clonal IgH rearrangement, two for IgH rearrangement and bcl-2 translocation, and one for bcl-2 translocation only. Five of these seven patients were fully assessable at the end of treatment; none of them cleared these biologic markers, although three were responders.

Toxicity
Six patients experienced grade 3 leukopenia and four patients grade 3 low platelet count, all of them reversible. Only one patient developed grade 4 anemia that prompted interruption of the treatment. In another patient, extra hematologic toxicity (grade 3 depression associated with grade 3 asthenia) caused definitive interruption of the treatment. Grade 1 and grade 2 depression was also registered in two and four patients, respectively.

	DISCUSSION

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The significant prevalence of HCV infection in B-NHL in several areas of the world may suggest a link between viral infection and this subset of lymphoproliferative disorders. Controversial results among different studies may be explained by the low probability of HCV carriers who develop lymphoma, so that an accurate assessment of the exact risk could only come from a large cohort study.³⁵ Moreover, environmental factors that interfere with the lymphomagenic role of the virus could explain geographical variations. Recent reports, attesting to the efficacy of antiviral treatment on the course of HCV-related B-NHL,^24,36 strengthen the hypothesis of a link between HCV infection and B-cell lymphoma. The antiviral approach in HCV-related lymphoma has so far been tested only in a series of splenic villous lymphomas (a very rare lymphoma entity) and as a case report in mantle-cell lymphoma.

The aim of this report was to extend these fragmentary experiences to a more conspicuous subset of lymphomas, such as the group of indolent lymphomas. Furthermore, our interest among low-grade lymphomas was focused to neoplasia with an indolent course. It can be argued that such subset of lymphomas does not require chemotherapy, but indeed our treatment was not cytostatic, and therefore neither were leukemogenic effects delivered to patients nor would further cytotoxic treatment be precluded. This report indeed attests to the efficacy of antiviral therapy in HCV-related low grade B-cell lymphoma with no significant differences within these subtypes of lymphomas. On the other hand, previous unpublished data (our group) failed to show a role for antiviral therapy alone in HCV-related diffuse large B-cell lymphoma. These observations again underline the pivotal role of HCV infection in the course of the lymphoma, and may suggest that when an HCV-related lymphoma acquires a more aggressive course either in terms of increasing doubling time or achieving a more aggressive histology, the role of the virus is likely to be overcome by other factors, and antiviral therapy has no place in the treatment, at least on its own. It has to be tested, in aggressive HCV-related lymphoma, if antiviral therapy associated with cytostatic treatment may be useful. The relationship between HCV and lymphoma is comparable to the relationship between Helicobacter pylori and gastric lymphoma. Helicobacter pylori provides a chronic antigenic stimulus for B-lymphocytes in the stomach mucosa. Chronic stimulation is the first step to clonal proliferation. In accordance with this theory, antibiotic treatment of the Helicobacter infection in mucosa-associated lymphoid tissue lymphoma of the stomach³⁷ often results in cure of the lymphoma.

In the five available patients with biologic markers of disease (clonal IgH rearrangement and/or bcl-2 translocation), we did not detect disappearance of their disease in any case; similar results were achieved by the Hermine et al.²⁴ At this point we are not yet able to affirm if clonal IgH rearrangements are markers of the neoplastic disease, or if they simply attest to the physiologic presence of a clonal lymphocytic population against the virus.

The greatest accomplishment of this study could be summarized in the efficacy of antiviral treatment in low-grade B-NHL other than splenic villous lymphoma. We have been able to show that hematologic response to antiviral treatment was related to decrease or disappearance of viremia. In other words, antiviral treatment was efficacious against the lymphoma when it was efficacious against the virus, while a lack of virologic response was associated to persistence of disease. The confounding role of interferon as antiproliferative agent (such as in follicular lymphoma) did not play any role since it was equally employed in responders and nonresponders, and its efficacy was only seen in association with the clearance of the virus. It is also possible that a synergistic effect between the antiviral and antitumor effects of the interferon in this kind of patient group could contribute to its relevant activity. Although genotype 1 is less susceptible to response to antiviral treatment, we did not find a statistical correlation between genotype and overall hematologic response. The lack of irreversible adverse side effects may further support the choice of antiviral treatments as first-line therapy in HCV-related low-grade B-NHL.

Finally, in this report, the role of antiviral treatment in HCV-related lymphoma has been tested and proven in a larger series than has been previously reported. Moreover, some specific indications have emerged: The indolent course of a low-grade B-cell lymphoma in the setting of HCV infection should be an indication for initiation of antiviral treatment, both in genotype 1 and 2, and systematic viremia evaluation may be seen as a predictor of clinical response.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Dr M.L. Palomba (Memorial Sloan-Kettering Cancer Center, New York, NY) for critical review of the manuscript and editorial changes.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

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				D. Vallisa, P. Bernuzzi, A. Lazzaro, E. Trabacchi, E. Anselmi, A. L. Arcari, C. Moroni, R. Berte, and L. Cavanna In Reply: J. Clin. Oncol., July 1, 2005; 23(19): 4471 - 4471. [Full Text] [PDF]

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