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晤瘍:11329753
Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience
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     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

    ABSTRACT

    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

    PATIENTS AND METHODS

    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-JH 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/JH) 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 米g 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 米g 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 {chi}2 calculation and evaluated with Fisher's exact test and {chi}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

    Ten patients were enrolled at first diagnosis, while two were enrolled at first relapse and one at third relapse. Two patients were previously treated with alkylating agents alone, while one was treated with combination chemotherapy with anthracycline. All patients had been infected with HCV for a period of time ranging from several months to several years before the development of lymphoma. Histologic diagnosis of chronic hepatitis by liver biopsy was demonstrated in nine patients, while two showed overt hepatic cirrhosis. Four of 13 patients showed glutamic-pyruvic transaminase (GPT) levels more than twice the normal value at enrollment, and three more patients had levels 1.5 times greater than normal. In all seven patients, except for one, antiviral treatment normalized GPT values. In one patient, interferon treatment alone was previously unsuccessfully employed when lymphoma was not yet present.

    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, {chi}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.

    The observed reduction in viremia was significantly linked to the viral genotype, where genotype 2 did better than genotype 1 (P = .035). Hematologic response did not statistically correlate with any genotype. Age and sex did not affect the probability of achieving a response. Of the responders, one patient died 7 months after completing treatment as a result of pulmonary embolism (patient 13), while one patient relapsed 23 months after achieving CR (patient 2); in the latter patient, HCV viremia reappeared with a viral load of 2.75 x106 U/mL at time of relapse. The overall response at the time of this report is 14.1 ㊣ 9.7 months (range, 2 to 24 months; median time of follow-up, 14 months). Among nonresponders, the patient with PD died 4 months later of lymphoma, while the two patients with SD underwent combination chemotherapy and are alive at 4 and 6 months, respectively, after the end of the study.

    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

    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

    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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