Pegylated‐interferon plus ribavirin for HCV‐positive indolent non‐Hodgkin lymphomas

Hepatitis C virus (HCV) causes not only chronic liver disease, but is also implicated in several lymphoproliferative disorders (Pozzato et al, 1994). The identification of CD81 as the main HCV receptor could explain this lymphotropism because this receptor is expressed in B lymphocytes (Pileri et al, 1998). The CD81 engagement determines cell activation with overexpression of CD69, CD71, CD86, and the chemokinereceptor CXCR3 (Rosa et al, 2005). In addition, an increased prevalence of t(14,18) translocation has been reported in HCV-patients, even in the absence of lymphoproliferative disorders (Zignego et al, 2002). This interaction of HCV with the immune system might explain the role of HCV in several extra-hepatic diseases, such as non-Hodgkin lymphoma (NHL). As HCV-positive lymphoproliferative disorders have been successfully treated with antiviral therapy (Gisbert et al, 2005), we compared the traditional treatment of interferon plus ribavirina (IFN + RIBA) with the newest antiviral therapy i.e. pegylated interferon alpha plus ribavirina (PEG-IFN +RIBA) in a small group of indolent NHL. Eighteen patients affected by HCV-related B-NHL were consecutively included in the study from February 1998 to January 2004. Criteria for patient’s selection were: (i) lowgrade B-NHL at first diagnosis or relapse, (ii) indolent course, (iii) HCV infection (HCV-RNA positivity in serum). Patients that carried the hepatitis B surface antigen (HBsAg) or were positive for anti-human immunodeficiency virus antibodies were excluded. All patients gave their informed consent before entry in the study. B cell monoclonality was analysed in the peripheral blood mononuclear cells and bone marrow samples of four cases by the previously described isotype-specific IGH VDJ Gene Scanning technique: briefly, a forward primer labelled with 6-carboxyfluorescein (FAM) fluorochrome in the second VDJ polymerase chain reaction (PCR) round was used. The VDJ PCR product and the internal size standard GeneScan 400 HD (Applied Biosystem, Forster City, CA, USA) were added to deionized formamide, and then subjected to capillary electrophoresis. The detection of IGHV gene segments was performed using VDJ FR1 PCR protocol, in which a second multiplexing PCR, IGHV3, IGHV4, IGHV5, IGHV6 primers and the IGHJ region were added. IGHV1-IGHV4, and IGHV3-IGHV6 primers were each labelled with a different fluorescent dye: FAM, HEX, NED or ROX. PCR products were added to the internal GeneScan 500 LIZ size standard. This mixture was subjected to capillary electrophoresis. When a monoclone was found, the PCR product was sequenced by standard methods. Eight patients (Group A) received 3 MU of IFN alpha-2b three times a week for 48 weeks. Ten patients (Group B) received PEG-IFN alpha-2b 1Æ5 lg/kg once a week for 48 weeks. Both groups received ribavirin 1000 mg or 1200 mg daily according to body weight (lower or greater than 75 kg) for 48 weeks (Manns et al, 2001). The patients were randomized on the basis of a computer-generated random list. The patient diagnoses were: one follicular lymphoma, one splenic lymphoma with villous lymphocytes, and 16 lymphoplasmacytoid lymphomas. The follicular lymphoma and the splenic lymphoma had node involvement (axillary and mediastinal/retroperitoneal, respectively). HCV genotyping showed genotype 1b in 11 cases (61%) while genotype 2a/2c was detected in the others. Eleven cases had chronic hepatitis at liver biopsy. Thirteen patients had dosable levels of cryoglobulins (from 2% to 35%) and high rheumatoid factor levels (from 30 to 21 700 U/l). Therapy outcome (Table I) was as follows: