The Impact of Outcome and Hepatic Toxicity in HCV-Infected Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab Plus CHOP Therapy; A Retrospective Multicenter Japanese Analysis.

Hepatitis B virus reactivation after systemic chemotherapy including rituximab is a well-documented complication. However, no studies have investigated the influence of hepatitis C virus (HCV) infection for hepatic toxicity of diffuse large B-cell lymphoma (DLBCL) patients treated by rituximab containing chemotherapy. The prognostic value of HCV infection in DLBCL in the era of rituximab was also unclear. Herein we conducted a multicenter retrospective analysis to compare the outcome and hepatic toxicity of DLBCL patients with and without HCV infection treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) as an initial therapy.

We analyzed 548 patients: HCV-positive (n=126) or -negative (n=422) patients with CD20-positive DLBCL receiving RCHOP between January 2004 and March 2008. HCV-negative patients treated during same period with HCV-positive patients in each institute were enrolled. Hepatitis B surface antigen positive patients were excluded in this study. For survival analysis, event-free survival (EFS) and overall survival (OS) were compared according to HCV infection. The definition of severe hepatic toxicity was more than Grade 3 transaminases increase according to National Cancer Institute of Canada criteria. The change of serum HCV-RNA levels was examined in 33 HCV-positive patients.

Before the treatment, HCV-positive patients had higher age (P<0.001), more frequently elevated lactate dehydrogenase levels (P=0.004), spleen involvement (P=0.001) and higher international prognostic index (P=0.01) than HCV-negative patients. HCV infection was not a significant risk factor for EFS and a borderline risk factor for OS (3-year EFS, 66% vs. 74%, P=0.20; OS, 77% vs. 84%, P=0.07). Cox multivariate analysis showed that HCV was not a significant poor risk factor. Thirty-three out of 126 (26%) HCV-positive patients had severe hepatic toxicity, compared to 3% HCV-negative patients, and multivariate analysis revealed that HCV infection was significantly strong risk factor for hepatic toxicity (HR:14.72 (95%CI: 6.34–34.02)) (Table 1). The severe hepatic toxicity was not significantly associated with poor prognosis of HCV-positive patients, but chemotherapy was stopped in four of 33 patients due to severe hepatic toxicity and died of disease progression. The monitoring of HCV viral load demonstrated that HCV-RNA significantly increased during rituximab treatment (P=0.006) (median: 320 to 2000KIU/ml) and then decreased after treatment (1200KIU/ml) (P=0.003). The results of HCV viral load showed that liver dysfunction might be due to HCV activation.

Our data show that HCV infection is not prognostic factor, but was the significantly influential for hepatic toxicity in the patients with DLBCL treated by RCHOP therapy. Further prospective studies are warranted to clear whether antiviral therapy should be added to rituximab and chemotherapy.

Kinoshita:Chugai Pharmaceutical Co Ltd, Zenyaku Kogyo Co. Ltd: Honoraria; Zenyaku Kogyo Co. Ltd: Research Funding.