Table_1_Risk of HBV Reactivation in Patients With Resolved HBV Infection Receiving Anti-CD19 Chimeric Antigen Receptor T Cell Therapy Without Antiviral Prophylaxis.docx

BackgroundChimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for hematologic malignancies and is predicted to experience widespread use in the near future. However, not all risks associated with this novel approach are well defined. There are few data in the risk of HBV reactivation and limited experience in management in patients with resolved HBV infection who undergo CAR-T cell therapy.
MethodsWe performed a post-hoc analysis of a prospective clinical trial of anti-CD19 CAR-T (CART19) cell therapy in patients with relapsed or refractory (r/r) B-cell malignancies, and aimed at exploring the actual risk of HBV reactivation in a cohort of patients with resolved HBV infection receiving CART19 cell therapy in the absence of antiviral prophylaxis.
ResultsIn this study, we investigated the risk of HBV reactivation after CART19 cell therapy in 30 consecutive patients with B-cell malignancies and resolved HBV infection without antiviral prophylaxis, in the Tongji Hospital of Tongji University. In this cohort, two patients developed HBV reactivation 2 months and 14 months after CAR-T cell infusion, respectively, the latter of whom developed severe hepatitis. These findings showed that the incidence of HBV reactivation was 6.67% (95% CI, 0.8–22.1). Specifically, none of the 21 patients who were HBsAb positive (0.0%) versus two of nine patients who were HBsAb negative (22.2%) experienced HBV reactivation (p = 0.03), suggesting HbsAb seronegativity at baseline is a possible risk factor in this population. Although use of tocilizumab or corticosteroids has been associated with increased risk of HBV reactivation, none of the patients who received these agents had HBV reactivation in this study.
ConclusionThis is the first and largest study to assess the true incidence of HBV reactivation in patients with resolved HBV infection receiving CART19 cell therapy without antiviral prophylaxis. This study highlights that this population are at risk of developing HBV reactivation and indicates that close monitoring of HBV DNA is required in the absence of antiviral prophylaxis. In addition, antiviral prophylaxis is recommended in the HBsAb-negative subpopulation.

【背景】嵌合抗原受体（Chimeric antigen receptor, CAR）T细胞疗法已成为血液系统恶性肿瘤的新型治疗手段，预计未来将得到广泛应用。然而，该新型疗法相关的诸多风险尚未完全明确。对于既往乙型肝炎病毒（HBV）感染已康复、且接受CAR-T细胞治疗的患者，目前关于其HBV再激活风险的相关数据较为匮乏，临床管理经验也十分有限。
【方法】本研究对一项针对复发或难治性（r/r）B细胞恶性肿瘤患者的抗CD19 CAR-T（CART19）细胞疗法前瞻性临床试验进行了事后分析，旨在探索未接受抗病毒预防治疗、既往HBV感染已康复的患者群体接受CART19细胞治疗后，HBV再激活的实际发生风险。
【结果】本研究在同济大学附属同济医院开展，共纳入30例经确诊为B细胞恶性肿瘤、既往HBV感染已康复且未接受抗病毒预防治疗的连续入组患者，分析其接受CART19细胞治疗后的HBV再激活风险。本队列中，2例患者分别在CAR-T细胞输注后2个月和14个月出现HBV再激活，其中后者进展为重型肝炎。研究结果显示，HBV再激活的发生率为6.67%（95%置信区间，95% CI：0.8~22.1）。具体而言，21例乙型肝炎表面抗体（hepatitis B surface antibody, HBsAb）阳性患者中无1例发生HBV再激活（0.0%），而9例HBsAb阴性患者中有2例发生HBV再激活（22.2%），组间差异具有统计学意义（p=0.03），提示基线HBsAb血清学阴性是该人群发生HBV再激活的潜在危险因素。尽管既往研究显示托珠单抗与糖皮质激素的使用与HBV再激活风险升高相关，但本研究中接受上述药物治疗的患者均未出现HBV再激活事件。
【结论】本研究是目前首项且规模最大的、针对未接受抗病毒预防治疗、既往HBV感染已康复的患者接受CART19细胞治疗后HBV再激活真实发生率的评估研究。本研究明确了该人群存在HBV再激活风险，提示在未开展抗病毒预防治疗的情况下，需对患者进行密切的HBV DNA监测。此外，建议对HBsAb阴性的亚组患者实施抗病毒预防治疗。