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Is it now the time to update treatment protocols for lymphomas with new anti-virus systems?

Leukemia volume 18, pages 1572–1575 (2004)Cite this article

In this issue, Kelaidi et al1 report the achievement of clinical remission in five of eight hepatitis C virus-associated marginal zone lymphomas, following antiviral therapy with interferon alpha and ribavirin. The beneficial effect of antiviral therapy was observed not only in splenic, but also in extranodal (intestinal) and leukemic marginal zone lymphoma subtypes, extending the results from previous studies, which had described the successful treatment of HCV-positive splenic marginal zone lymphomas, mainly those with villous lymphocytes.2, 3, 4 These data, together with the report of a complete remission obtained with sole anti-HCV therapy in a further case of mantle cell lymphoma, resistant to different chemotherapeutic agents as well as to rituximab, highlight the need to explore the effect of interferon alpha and ribavirin in all types of HCV-related lymphomas.5 While the antiviral-based approach for HCV-positive lymphomas is promising and warrants investigation in controlled clinical trials, caution is needed, in considering interferon and ribavirin as the sole first-line treatment in low-grade lymphomas, and accurate distinction should be made among the histologic and clinical subtypes. For example, in the group of non-MALT marginal zone lymphomas, which is one of the most frequent lymphoma types associated with HCV, four clinical subtypes have been recently recognized, with strikingly different clinical outcomes, the splenic and leukemic subtypes being associated with a median time to progression longer than 5 years, even without treatment, while the nodal and disseminated subtypes are associated with a median time to progression of 1 year.6 Thus, different protocols should be designed in which anti-HCV therapy may be combined with chemotherapy or introduced later as maintenance therapy. Much more work is also needed to study the correlation between the clinical and the virologic response in lymphomas treated with interferon alpha and ribavirin. In the series of splenic marginal zone lymphomas with villous lymphocytes, reported by Hermine et al, and in the few anecdotal cases from the literature, clinical response correlated well with the loss of detectable HCV RNA, the occurrence of clinical relapse being associated with the reappearance of detectable viral load in the peripheral blood.2, 3, 4, 5 In the series by Kelaidi et al, different situations were encountered, including the achievement of clinical remission concomitant with the decrease of HCV viral load, but in the absence of a complete virologic response; the lymphoma relapse a time after discontinuation of antiviral treatment despite the persistence of virologic remission; and the achievement, in a patient with splenic marginal zone lymphoma, of a molecular remission, as documented by the disappearance of immunoglobulin gene rearrangement in the peripheral blood, concomitant with disappearance of HCV RNA.1 The latter finding suggests that B-cell clones associated with HCV infection may be eradicated with an antiviral therapy only, not only in HCV-infected patients with liver disease7 or in patients with HCV-associated mixed cryoglobulinemia type II,8 but also in HCV-related lymphomas, in contrast to what has been observed in the series of Hermine et al, in which in all the five patients in whom molecular studies were performed the rearrangement of the monoclonal immunoglobulin gene observed at diagnosis was still detectable in the blood, even after the achievement of a complete hematologic response.2

The regression of HCV-related lymphomas following antiviral therapy probably represents the strongest argument in favour of an etiologic link between HCV infection and certain human lymphomas. Evans and Mueller proposed that either epidemiologic or virologic guidelines need to be fulfilled to support an etiologic role for a virus in a given human cancer.9 Suggested epidemiologic guidelines included the following: (1) the geographic distribution of viral infection should coincide with that of the tumor; (2) the presence of viral markers should be higher in case subjects than in matched control subjects; (3) viral markers should precede the tumor, with a higher incidence of tumors in persons with the marker than in those without; (4) prevention of viral infection should decrease tumor incidence.9 Suggested virologic guidelines included the following: (1) the virus should be able to transform human cells in vitro; (2) the viral genome should be demonstrated in tumor cells and not in normal cells; and (3) the virus should be able to induce the tumor in an experimental animal.9 Most of the epidemiologic guidelines for causality from Evans and Mueller are met: HCV infection is associated with certain B-cell non-Hodgkin lymphoma (NHL) types (lymphoplasmacytic, marginal zone and diffuse large-cell lymphoma) in geographical areas with HCV endemicity, like Italy and Japan, where HCV prevalence rates range from 20 to 40%, while in nonendemic areas elsewhere in Europe and in North America the prevalence of HCV infection in NHLs is far less than 5%; the prevalence of anti-HCV antibodies and/or HCV RNA sequences is significantly higher in patients with B-cell NHL than in patients with other lymphoid neoplasias or in age-matched healthy subjects; HCV infection often precedes by years the occurrence of lymphomas.10, 11, 12 Limited data are available, however, to apply Evans and Mueller's epidemiologic guidelines, as neither in vitro nor animal models of HCV transformation have been developed. Moreover, neither HCV RNA nor proteins have so far been detected in lymphomatous cells in vivo, with the exceptions of two cases, namely a primary diffuse large-cell lymphoma of the liver, found to harbor viral nucleic acids by in situ hybridization and a mantle cell lymphoma, from which a lymphoma cell line could be established in vitro.5, 13 Thus, the mechanisms exploited by HCV to induce B-cell lymphoproliferation are new and differ from the classical mechanisms of herpesviral induced lymphomagenesis, which require the maintenance of either Epstein–Barr virus (EBV) or human herpesvirus 8 (HHV-8) genomes in the transformed B cells as clonal episomes, together with the expression of an array of latent and, to a lesser extent, of lytic proteins.14 One possible mechanism of HCV-induced lymphomagenesis has been described by Quinn et al, who obtained the cloning of the B-cell receptor from one HCV-positive diffuse large-cell lymphoma, and its expression as a soluble immunoglobulin.15 The immunoglobulin rescued was shown to bind the HCV E2 envelope glycoprotein in a manner identical to a bona fide human anti-E2 antibody, suggesting that some HCV-associated lymphomas may originate from B cells that were initially activated by the HCV E2 protein.15 Similarly, in a recently reported case of an HCV-associated plasma cell leukemia, immunoblotting showed that the monoclonal IgG kappa detected in the serum was directed against a viral protein, namely the HCV core protein, again suggesting an indirect lymphomagenetic role of HCV.16 These findings are consistent with the receptor-mediated lymphomagenesis hypothesis, by which chronic antigenic stimulation by retroviral env protein was suggested to be sufficient to induce virus-specific T-cell proliferation, eventually evolving in frank T-cell lymphomas.17 Of interest, the behavior of HCV in these lymphoma/leukemia cases is also reminiscent of the behavior of the human T-cell lymphotropic virus-I (HTLV-I), in two Jamaican patients with chronic lymphocytic leukemia (CLL).18 The hybridoma cells that resulted from the fusion of CLL cells from these patients produced an IgM that reacted on Western blots, with the p24 gag protein in one case and with the large envelope protein (gp61) of HTLV-I in the other case, respectively.18 The reactivity of the tumor-associated immunoglobulin (Ig) to HTLV-I-specific proteins suggests a specific antigen commitment of the leukemic B cells to the retroviral antigens at least in these CLL patients, providing an indirect mechanism for HTLV-I in B-cell leukemogenesis, in contrast to the postulated direct leukemogenic role of HTLV-I in adult T-cell leukemia (ATL), which, conversely, requires the retroviral integration into the host T cells.

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Authors and Affiliations

  1. Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy

    M Luppi, P Barozzi, L Potenza, G Riva, M Morselli & G Torelli

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Luppi, M., Barozzi, P., Potenza, L. et al. Is it now the time to update treatment protocols for lymphomas with new anti-virus systems?. Leukemia 18, 1572–1575 (2004). https://doi.org/10.1038/sj.leu.2403447

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