Department of Pharmacology, CHU de Caen, Caen, France.
Université Caen Normandie, Medical School, EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-reperfusion Myocardique, Caen, France.
Am J Hematol. 2021 Sep 1;96(9):1101-1111. doi: 10.1002/ajh.26259. Epub 2021 Jun 23.
Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n = 1378, IC = 4.24), neurological disorders (n = 963, IC = 2.42), hematological disorders (n = 532, IC = 3.32), infections (n = 287, IC = 2.38), cardiovascular disorders (n = 256, IC = 2.81), pulmonary disorders (n = 186, IC = 3.80), reno-metabolic disorders (n = 123, IC = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC = 5.01) and hepatic disorders (n = 32, IC = 2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.
嵌合抗原受体 T 细胞（CAR-T）针对 CD19 的治疗在血液学方面的应用已经崭露头角，但有关其总体安全性的资料却很少。本研究旨在确定与 CAR-T 相关的不良药物反应（ADR）的临床特征和发生率。本观察性、横断面、药物警戒队列研究对世界卫生组织数据库 VigiBase 的个别病例安全报告进行了分析，并对文献中的 CAR-T 试验和队列进行了荟萃分析。主要目的是确定与已批准的 CAR-T（axicabtagene-ciloleucel；tisagenlecleucel）相关的 ADR。我们采用贝叶斯不成比例分析，置信区间信息分量（IC，显著性>0）的下限为 95%。我们还对文献中的 CAR-T 试验和队列进行了系统评价和荟萃分析，以评估 ADR 的发生率。有 9 个 ADR 类别与 CAR-T 相关：细胞因子释放综合征（CRS，n=1378，IC=4.24）、神经障碍（n=963，IC=2.42）、血液系统障碍（n=532，IC=3.32）、感染（n=287，IC=2.38）、心血管障碍（n=256，IC=2.81）、肺部障碍（n=186，IC=3.80）、肾代谢障碍（n=123，IC=1.89）、噬血细胞性淋巴组织细胞增生症（n=36，IC=5.01）和肝障碍（n=32，IC=2.49）。ADR 相关的死亡占报告的 1783 例中的 99 例（5.5%），占所有原因死亡的 1783 例中的 262 例（14.7%）。这些与 ADR 相关的死亡与噬血细胞性淋巴组织细胞增生症、脑血管疾病、感染和呼吸衰竭有关。在荟萃分析中，最常见的任何等级 ADR 是 CRS、血液系统障碍和神经障碍。与神经障碍、CRS 和感染相关的 ADR 导致的死亡最多。需要注意的是，CAR-T 输注可能与严重的 ADR 相关，主要发生在给药后的一周内，虽然很少致命。感染、噬血细胞性淋巴组织细胞增生症和终末器官衰竭，包括神经系统或肺部受累，需要仔细观察。
