【ASH 2012】使用利妥昔单抗应接受HBV筛查

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2012-12-20

美国血液病学会（American Society of Hematology，ASH）第54届会议上，一项研究报告称，针对麻省大学纪念医疗中心的调查显示，半数接受利妥昔单抗治疗肿瘤患者未接受乙型肝炎病毒（HBV）筛查。

       在该中心2005年1月1日至2011年8月1日接受利妥昔单抗治疗的103例肿瘤患者中，HBV筛查率仅有51.4%。并且，在这些患者中，分别仅有7例、19例患者在接受利妥昔单抗治疗前9个月、治疗30天内接受了HBV筛查。中位筛查时间为196天，未及指南推荐标准。

       虽然如此，该调查数据显示，与2009年相比，2010-2011年的筛查率有所升高。

       利妥昔单抗为单克隆抗体，用于多种淋巴瘤和慢性淋巴细胞白血病的治疗，选择性耗竭B细胞。基于这种机制，该药的应用可能会诱发HBV感染。

       目前包括美国临床肿瘤学会（ASCO）、美国肝病学会（AASLD）在内的数个学术组织均作出以下推荐：在应用利妥昔单抗治疗前或启动治疗短时间内应筛查HBV感染。

       AASLD同时建议，对HBV筛查阳性患者须预防性应用抗病毒药物，如恩替卡韦或拉米夫定；在此方面，ASCO暂时“沉默”，仅声称预防性抗病毒治疗可考虑（considered）用于接受利妥昔单抗或其他免疫抑制剂治疗患者。

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研究论文摘要：

Background: The CD20 monoclonal antibody, rituximab, has been implicated in the reactivation of hepatitis B virus (HBV) when given either combined with chemotherapy or as a single-agent. This potentially fatal complication has been documented in patients (pts) with high risk of HBV reactivation (i.e., HBV surface antigen (HBSAg) positive), and in lower risk populations (i.e., HBsAg negative, HBV core antibody (HBcAb) positive), the latter where the risk of reactivation with rituximab-based therapy is approximately 15–20% (Yeo W, et al. J Clin Oncol 2009; Evens AM et al, Ann Onc 2011). Published recommendations on HBV screening and anti-viral prophylaxis related to rituximab vary considerably, leaving practicing clinicians without clear consensus. In addition, HBV screening and prophylaxis have not been universally implemented into clinical practice. We sought to determine our institutional frequency of HBV screening and rates of HBV reactivation in Hematology/Oncology pts treated with rituximab-based therapy who underwent appropriate screening and prophylaxis.

METHODS: We completed a single center, retrospective analysis at a large academic center to examine pts >17 years of age who received rituximab for a hematologic or oncologic disorder from January 1, 2005 through August 1, 2011. We reviewed drug administration records to identify pts who received rituximab for a malignancy or other hematological disorder. Pts were evaluated for documented HBV screening, HBV diagnosis, number of doses of rituximab received, vaccination status, baseline characteristics, and relevant past medical history and laboratory values. A ‘cycle’ of rituximab was defined as 1 dose given in combination with chemotherapy, 4 consecutive weeks given as a single agent, or 1 dose given q2-4 months as part of maintenance therapy. Data regarding use of prophylactic therapy for HBV were also collected.

RESULTS: 212 pts were identified as having received rituximab; 109 were excluded as they received rituximab for other indications (n=86 multiple sclerosis, n=11 rheumatoid arthritis, and n=17 other), leaving a total of 103 pts who met study inclusion criteria. The median age was 63 years (19-90), median number of rituximab ‘cycles’ received was 3 (1-9); 45% of pts had diffuse large B-cell lymphoma (DLBCL), 15% other high-grade lymphoma, 14% follicular lymphoma (FL), and 26% other hematologic malignancy. Among the 103 pts, a total of 53 (51.4%) were screened for HBV at some point before or after initiation of therapy. Only 6.8% of pts were screened (within 9 months) prior to initiation of treatment, while 18.4% had HBV screening within 30 days of the 1st rituximab dose. Of the pts screened for HBV after 30 days, the median time to screening was 196 days (32-2660) after rituximab initiation. Notably, there were no differences in rates of HBV screening based on the year of therapy. Among the 53 pts screened for HBV prior to or within 30 days of rituximab initiation, eight (15.1%) were positive for HBV infection. Three pts were positive for HBsAg, all of whom received HBV anti-viral prophylaxis. Five pts were negative for HBsAg, but positive for HBcAb (1/5 also with positive HBV surface antibody); one HBcAb+ pt received anti-viral prophylaxis. These four pts received anti-viral prophylaxis for a median time of 17.1 months, which included a median of 7.9 months after the last rituximab dose. Among the 53 pts who underwent HBV screening, there were no cases of HBV reactivation observed with a median follow-up time of 15.6 months (5.9-16.5).

CONCLUSION: At our academic institution, we identified an occult HBV infection rate of 15% in Hematology/Oncology pts who received rituximab treatment. A relatively low rate of pre-treatment HBV screening was performed, while approximately 45% of pts had screening after initiation of therapy. Among pts who were screened, appropriate anti-viral prophylaxis was instituted, and there were no cases of HBV reactivation. Altogether, there remains a critical need for standardized recommendations and consensus for screening and prophylaxis of HBV infection in pts who receive rituximab therapy. This is particularly evident given recent data regarding cost effectiveness of this approach (Zurawaska U, et al, J Clin Oncol 2012). In addition, continued efforts are needed to implement evidence-based HBV screening and prophylaxis guidelines in clinical practice.