Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy

Abstract

Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during anti-CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).

Conflict of interest statement

Conflict-of-interest disclosure: A.D.Z. reports consulting or advisory roles for Adaptive Biotechnologies, Amgen, Celgene, Genentech, Gilead Sciences, and Dr. Reddy's Laboratories and research funding from Bristol-Myers Squibb, Genentech, Gilead Sciences, and Roche. E.U. reports employment and stock ownership from Chugai Pharmaceutical. G.F.-R. reports employment and stock ownership from Roche. G.S. reports employment from Roche. H.K. reports employment and stock ownership from Chugai Pharmaceutical. H.P.-L. reports employment from Roche. K.T. reports consulting fees from HUYA Bioscience International and Zenyaku Kogyo and grants, honoraria, and consulting fees from Celgene; grants and honoraria from Chugai Pharmaceutical, Eisai, Janssen, Kyowa Hakko Kirin, Mundipharma, Ono Pharmaceutical, and Takeda; and grants from AbbVie, GlaxoSmithKline, and Servier. L.A. reports consulting or advisory roles for Bayer, Celgene, Gilead Sciences, Roche, and Sandoz, research funding from Gilead Sciences, and participation in a speakers bureau for Celgene. M.G.P. reports that her spouse is an employee of Roche. S.K. reports honoraria and research funding from Bristol-Myers Squibb, Chugai Pharmaceutical, Roche, and Kyowa Hakko Kirin. T.N. reports employment and stock ownership from Roche. Y.L.K reports advisory roles for Abbvie, Amgen, Bristol-Myers Squibb, Janssen, Novartis, Roche, and Takeda. Y.T. reports honoraria and research funding from Bristol-Myers Squibb, Chugai Pharmaceutical and Gilead Sciences. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Analysis population and patient flow. benda, bendamustine; CVP, cyclophosphamide, vincristine, prednisone; G, obinutuzumab; MZL, marginal zone lymphoma; R, rituximab. *The 2 patients with HBV reactivation who had received prophylactic NAT had their study treatment withheld until their HBV DNA returned to undetectable levels; neither patient developed HBV-related hepatitis. †None of 25 patients with HBV reactivation who were treated with preemptive NAT developed HBV-related hepatitis.

Figure 2.

Time to HBV reactivation in anti–HBc-positive patients by receipt of prophylactic NAT (analysis population, n = 326).