A Case-Control Study on the Role of an Antiviral Treatment with Interferon and Ribavirin after Conventional Chemotherapy in Diffuse Large B-Cell Lymphomas with Hepatitis C Virus (HCV) Infection
Authors: Guariglia Roberto , Luminari Stefano , De Renzo Amalia , Iannitto Emilio , Dell’Olio Matteo , Pozzi Samantha , Pierri Teresa , D’Amato Lucia , Traficante Antonio , Sacchi Stefano , Musto Pellegrino 
Published: April 2020

Abstract
Antiviral therapy (AVT) with interferon +/− ribavirin can induce neoplastic regression without chemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (in particular, immunocytomas and nodal/extranodal marginal lymphomas) with associated HCV infection (HCV+). High grade, diffuse large B-cell non- Hodgkin’s lymphomas (DLBCL) are HCV+ in about 12% of cases in Italian population. These patients show peculiar clinical characteristics, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders and extranodal localizations. Their clinical outcome, however, is generally considered not significantly different, in terms of response rate, progression free survival (PFS) and overall survival (OS), from that of subjects with HCV negative (HCV−) DLBCL when treated with standard or even high dose CT and if significant signs of liver dysfunction are absent. In the present study we aimed to determine the possible role of AVT, performed after a standard CT treatment, in HCV+ DLBCL. We evaluated 40 HCV+ DLBCL patients (male/female ratio 25/15; median age 63 years, range 39–71) who received AVT after first complete (27 patients) or partial (13 patients) remission was achieved by frontline standard CT. Classic or modified CHOP+/− rituximab regimens were generally employed. Twenty-two patients (55%) showed a higher (3–4) IPI score and twenty patients (50%) evidenced increased ALT/AST values. A favourable HCV genotype (type 2–3) and a low viral load (&lt; 600.000 copies) were observed in 19 (47.5%) and 15 (37.5%) patients, respectively. In the large majoriry of cases AVT consisted of peg-interferon 1 mg/kg (1.5 mg/kg for genotype 1) s.c. once-a-week, plus ribavirin 1000/1200 mg/d p.o., according to body-weight &lt; or &gt; 70/kg. A small number of patients received interferon-alpha with or without ribavirin. The planned duration of AVT ranged from 3 to 12 months and was modulated according to viral genotype and molecular response (genotype 2: 3 months, if viral clearance obtained after 1 month, otherwise continued for 6 months; other genotypes: 3 months of treatment with following suspension if viral clearance not obtained, otherwise continued for 12 months). Sequential treatment (CT followed by AVT) was generally well tolerated. Six patients, however, interrupted AVT before three months, mainly because of general malaise or myelotoxicity. HCV clearance was obtained in 22 patients (55%). A case-control comparison was made with a similar cohort of 40 HCV+ DBLCL patients, who did not receive AVT, matched for age, sex, IPI score, liver function, type of prior CT and response, viral load and HCV genotype. Three-year PFS was not statistically different between the two groups (52.5% vs 57.5%, p n.s.), while a trend in favour of AVT treated patients was observed in terms of three-year OS (67.5%% vs 57.5%, p=0.055). A weak correlation between viral clearance and longer OS duration was also observed (p=0.048). Interestingly, during the follow up period, severe hepatic failure developed in 5 (12.5%) out of patients who had not received AVT and in only one (2.5%) of those treated with AVT. Seventy-nine percent of relapsed patients not treated with AVT received salvage CT, compared to 100% of AVT treated patients. Our currently available data indicate that a sequential treatment with CT followed by AVT is feasible in HCV+ DLBCL and may induce complete virus clearance in more than half of these patients. We hypothesize that a better control of the viral infection, rather than a direct or indirect antineoplastic activity of AVT, could have positive effects on the clinical outcome of patients with HCV+ DLBCL and, possibly, on their survival, i.e. by allowing the possibility of further salvage therapies and reducing that of hepatic failure.