Diffuse B-Large Cell Lymphomas (DBLCL) with Hepatitis-C Virus (HCV) Infection: Clinical Outcome and Preliminary Results of a Pilot Study Combining R-CHOP with Antiviral Therapy.
Authors: Musto Pellegrino , Dell’Olio Matteo , La Sala Antonio , Mantuano Saverio , Cascavilla Nicola 
Published: April 2020

Abstract
Epidemiological studies indicate that HCV infection prevalence is higher in patients with B-cell non-Hodgkin’s lymphomas (B-NHL) than in general population or in other hematologic malignancies, thus contributing to confirm a possible pathogenetic role for HCV in lymphomagenesis. Such differences are particularly striking in Italian and Japanese populations, where it has been calculated that 5–12% of all B-NHL could be due to HCV. The relationship between HCV and B-NHL is stronger for some sub-types of low-grade B-NHL (immunocytomas and nodal/extranodal marginal zone lymphomas) where, interestingly, anti-viral therapy may induce regression of lymphoma. However, an association with HCV infection has been observed also within more aggressive histotypes, in particular in DBLCL. We evaluated the clinical outcome of 44 patients with DBLCL and concomitant HCV infection, diagnosed at our Institution from 1992 to 2000. These patients represented 19% of all 231 patients with DBLCL we observed throughout the same period. With respect to HCV- DLBCL, HCV+ DBLCL showed some distinctive clinico-pathological features, such as older age (61 vs 44 years, p &lt; 0.03), signs of liver damage (56.8% vs 6.9%, p &lt; 0.01), presence of monoclonal gammopathy, often with no clinically relevant cryoglobulinemic and/or rheumatoid activity (15.9% vs 4.2%, p &lt; 0.05), increased rate of autoimmune disorders (18.1% vs 2.6%, p &lt; 0.02) and extranodal localizations (61.3% vs 32%, p &lt; 0.04), including, in particular, liver, spleen and some very unusual sites, such as esophagous and vagina. First line chemotherapy for HCV+ DBLCL consisted of CHOP/CHOP-like +/-rituximab or PROMACE-CytaBOM regimens. Intensive chemotherapy followed by autologous peripheral blood stem cell transplantation was also performed in two patients. Response rate was 61.3% (69.5% for HCV- DBLCL, p n.s.). Overall survival (OS) at five years was 50% (53.4% for HCV- DBLCL, p n.s.). However, the evidence of increased ALT levels at diagnosis resulted in a worse prognosis, with a five-years OS of only 34% (p &lt; 0.02). High viral load and evidence of active hepatitis or cirrhosis at liver biopsy also were associated with more frequent hepatic failure under treatment and reduced survival. The concomitant administration of R-CHOP chemotherapy plus anti-viral treatment with peg-interferon (0.5-1 mcg/kg s.c., once-a-week) and ribavirin (1000-1200 mg/d p.o.) to four patients with HCV+ DBLCL showed excessive hematological toxicity. After this initial negative experience, we treated HCV+ DBLCL with R-CHOP (6–8 cycles) followed by a three months period of maintenance therapy with peg-interferon plus ribavirin. Such a sequential treatment was effective, better tolerated and resulted in a high rate of complete virus clearance in the first 12 patients so far treated. Thus, we recommend standard treatments as in their HCV- counterparts (including autologous stem cell transplantation) for HCV+ DBLCL patients without liver dysfunction. Monitoring of viral load and liver biopsy appears also to be useful for an appropriate management of these patients. Dose adaptation of chemotherapy and less intensive treatments are required in patients with sign of liver dysfunction. A sequence of standard chemotherapy followed by a short period of antiviral treatment is a feasible approach, requiring, however, a larger number of patients and a longer follow-up to establish its exact role in HCV+ DBLCL patients.