Since the introduction of the anti-CD20 monoclonal antibody rituximab, the outcomes of B-cell non-Hodgkin lymphoma (B-NHL) have improved markedly. However, fulminant hepatitis due to reactivation of hepatitis B virus (HBV) infection has emerged as a serious problem. Recently, rituximab plus corticosteroid containing chemotherapy (R-chemo) has been identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg)-negative B-NHL patients. Currently, there is no standard management to prevent HBV reactivation in HBV-resolved patients without HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc) and/or HBsAg (anti-HBs).
We conducted a multicenter prospective observational study to estimate the incidence of HBV reactivation by serial monthly monitoring of HBV DNA in HBV-resolved patients with B-NHL during and just after R-chemo, and to establish preemptive antiviral therapy guided by this monitoring. The major eligibility criteria included previously untreated CD20-positive B-NHL with prior HBV-resolved infection, and planned treatment with 6 to 8 cycles of R-chemo defined by protocol. The baseline HBV status was evaluated on enrollment at each institute, comprising HBsAg, anti-HBc, and anti-HBs serology. Patients were excluded if they were seropositive for hepatitis C virus or human immunodeficiency virus. Plasma HBV DNA levels were measured independently at a central laboratory, using an automated real-time TaqMan polymerase chain reaction assay after enrollment. The primary end point was the incidence of HBV reactivation defined as HBV DNA levels of 1.8 log copies per mL or more. If HBV DNA levels of less than 1.8 log copies per mL were confirmed at baseline, the serial monitoring of HBV DNA (without prophylaxis of antiviral drugs) was performed with assessments every 4 weeks after enrollment for 1.5 years. Prompt antiviral treatment with an anti-HBV nucleoside analogue (entecavir, 0.5 mg per day) was highly recommended in patients with confirmed HBV reactivation. An ancillary study was conducted to identify risk factors for HBV reactivation using the preserved specimens. The protocol was approved by the Institutional Review Board of each participating institution. All patients gave written informed consent. The planned interim analysis was performed after the enrollment of 200 patients, using data available up to June 30, 2011.
Between Sept. 2008 and Sept. 2010, a total of 187 patients (50.8% male) with a median age of 63 years (range, 26 to 79) from 45 institutes were analyzed. Histologic subtypes of B-NHL were diffuse large B-cell lymphoma (n=121, 64.7%), follicular lymphoma (n=57, 30.5%), MALT lymphoma (n=5, 2.7%) and other types (n=4, 2.0%). The number (%) of patients positive for both anti-HBc and anti-HBs was 132 (70.6%), 35 (18.7%) were positive for anti-HBc but negative for anti-HBs, and 19 (10.2%) were negative for anti-HBc but positive for anti-HBs. One patient was positive for anti-HBc but lacked anti-HBs measurement. 168 (89.8%) patients received 6 to 8 cycles of R-CHOP (n=151) or other R-chemo (n=17). With a median follow-up of 549 days (range, 35 to 939), HBV reactivation was observed in 16 out of 187 analyzed patients. The incidence of HBV reactivation at 1 year was 7.7% (95% confidence interval [CI], 4.7 to 12.7). HBV reactivation was diagnosed at a median time of 158 days (range, 33 to 490) after enrollment. No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were 1.8 to 3.1 log copies per mL. Multivariate analysis of the ancillary study showed that an anti-HBs baseline titer less than 10 mIU per mL was an independent risk factor for HBV reactivation, compared to a titer of 100 mIU per mL or more (adjusted hazard ratio, 5.3; 95% CI, 1.3 to 21.8; p=0.02). HBV mutations of precore (G1896A) or basal core promoter (A1762T/G1764A) that enhanced HBV replication were identified in 4 patients, two of whom had both mutations. Our strategy could inhibit such highly replicative clones and prevent hepatitis.
Monthly monitoring of HBV DNA is highly effective for preventing hepatitis due to HBV reactivation in HBV-resolved B-NHL patients treated with R-chemo. (UMIN-CTR 000001299) (This study was supported by the Ministry of Health, Labour and Welfare of Japan.)
Kusumoto:Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo: Honoraria; Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kinoshita:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Ogura:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Mizokami:Chugai Pharmaceutical Co., LTD.: Honoraria; Abbott laboratories: Honoraria. Ueda:Chugai Pharmaceutical Co., LTD.: Research Funding.
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