Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, Texas, USA.
Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.
Am J Gastroenterol. 2020 Feb;115(2):251-261. doi: 10.14309/ajg.0000000000000398.
We conducted this study to characterize the incidence, clinical features, treatment, and outcomes of immune checkpoint inhibitor (ICI) hepatotoxicity.
Patients who received ICIs (with either single-agent or combination regimens) from January 1, 2010, to March 31, 2018, were identified. Hepatotoxicity was defined as alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), in the absence of an alternate cause, and categorized as grade 3 (ALT 5-20× ULN) or grade 4 (ALT >20× ULN), according to Common Terminology Criteria for Adverse Events 4.03.
Among 5,762 patients, 100 (2%) developed hepatotoxicity, occurring in a higher proportion of recipients of combination therapy (9.2%) compared with monotherapy (up to 1.7%, P < 0.001). ICIs were discontinued permanently in 69 and temporarily in 31 patients. Sixty-seven patients received steroids, 10 of whom (14%) had recurrent hepatotoxicity after the steroid taper. Thirty-one patients resumed ICIs after ALT improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with and 62 without possible pre-existing liver disease. The severity and outcome of hepatotoxicity due to combination therapy were not significantly different from monotherapy. There were 36 deaths. Two had liver failure at the time of death, both with progression of liver metastases and grade 3 hepatotoxicity.
Clinically significant ICI-related hepatotoxicity was uncommon but led to permanent ICI discontinuation in the majority. ICIs were restarted in a sizable proportion of patients, most of whom did not experience recurrent hepatotoxicity.
本研究旨在描述免疫检查点抑制剂（ICI）肝毒性的发生率、临床特征、治疗方法和转归。
我们筛选了 2010 年 1 月 1 日至 2018 年 3 月 31 日期间接受 ICI（单药或联合治疗）治疗的患者。肝毒性定义为丙氨酸氨基转移酶（ALT）>正常值上限（ULN）的 5 倍，且无其他原因，并根据不良事件通用术语标准 4.03 分为 3 级（ALT 5-20×ULN）或 4 级（ALT>20×ULN）。
在 5762 例患者中，有 100 例（2%）发生了肝毒性，联合治疗组（9.2%）的发生率明显高于单药治疗组（最高为 1.7%，P<0.001）。69 例患者永久停用 ICI，31 例患者暂时停用 ICI。67 例患者接受了类固醇治疗，其中 10 例（14%）在类固醇减量后出现肝毒性复发。31 例患者在 ALT 改善后恢复使用 ICI，其中 8 例（26%）出现肝毒性复发。有和无潜在肝脏疾病的 38 名和 62 名患者的肝损伤特征、对类固醇的反应和结局相似。联合治疗引起的肝毒性的严重程度和结局与单药治疗无显著差异。共有 36 例死亡。其中 2 例死亡时发生肝衰竭，均伴有肝转移进展和 3 级肝毒性。
临床上显著的 ICI 相关肝毒性并不常见，但导致大多数患者永久停用 ICI。在相当一部分患者中重新开始使用 ICI，其中大多数患者未出现肝毒性复发。
