免疫检查点抑制剂诱发肿瘤患者免疫介导性肝损伤的临床分析

摘要/Abstract

摘要： 目的评价接受免疫检查点抑制剂(ICIs)治疗的肿瘤患者免疫介导性肝损伤(IMH)的发生率及其危险因素。方法收集2019年6月—2022年8月中国科学技术大学附属第一医院(安徽省立医院)肿瘤化疗科接受ICIs治疗的肿瘤患者148例[男性115例、女性33例,年龄67(41, 82)岁],其中非小细胞肺癌67例、肾细胞癌43例、尿路上皮癌25例及恶性黑色素瘤13例;ICIs包括纳武单抗77例,帕博利珠单抗42例,度伐利尤单抗9例,阿特珠单抗8例,伊匹木单抗5例,纳武单抗联合伊匹木单抗7例。肝损伤CTCAE分级≥2级为排除其他原因所致肝损伤外,ALT/AST>3倍正常值上限,定义为IMH组,其余为非IMH组,多元回归分析探讨IMH风险增加的影响因素。结果 IMH组、非IMH组分别为25例、123例。接受ICIs治疗后发生IMH时间为51(7, 207) d。IMH组中CTCAE分级2、3及4级分别为9例、11例及5例,所有病例均停用ICIs,其中5例应用熊去氧胆酸对症处理,11例予以使用皮质醇激素,其余9例联合使用熊去氧胆酸及皮质醇激素。对所有IMH组患者进行随访,肝功能均改善,其中6例患者在肝损伤改善后重新开始接受ICIs治疗,其余病例或是因为IMH,或是因为其他免疫相关不良事件(irAEs)而停止治疗。IMH组中非小细胞肺癌、恶性黑色素瘤、纳武单抗联合伊匹木单抗、既往ICIs治疗史、肝转移例数为3例(12.0%)、12例(48.0%)、6例(24.0%)、5例(20.0%)及9例(36.0%),分别与非IMH组[64例(52.0%)、1例(7.7%)、1例(0.8%)、2例(1.6%)及13例(10.6%)]相比,差异具有统计学意义(P<0.05);IMH组ALT、AST为137(78, 401)U/L、151(91, 522)U/L,均显著高于非IMH组[33(16, 92)U/L、44(20, 139)U/L,P<0.05]。多元回归分析显示,恶性黑色素瘤[OR(95%CI):11.3(3.5, 38.0),P<0.05、纳武单抗联合伊匹木单抗[OR(95%CI):60.2(7.9, 475.3),P<0.05]与IMH风险增加独立相关。结论接受ICIs治疗的肿瘤患者中有16.9%的病例出现了CTCAE分级≥2级肝损伤。皮质醇激素治疗可以有效改善IMH患者肝损伤。IMH的发生与肿瘤类型、所使用ICIs药物有关,在恶性黑色素瘤和接受纳武单抗-伊匹木单抗联合治疗的患者中IMH发生风险明显增加。

关键词: 免疫检查点抑制剂, 免疫介导性肝损伤, 恶性黑色素瘤, 纳武单抗

Abstract: Objective To evaluate the incidence and risk factors of immune-mediated hepatotoxicity (IMH) based on the clinical data of tumor patients treated with immune checkpoint inhibitors (ICIs). Methods A total of 148 tumor patients [115 males and 33 females, aged 67 (41, 82) years] who received ICIs treatment in our hospital from June 2019 to August 2022 were collected, including 67 cases of non-small cell lung cancer, 43 cases of renal cell carcinoma, 25 cases of urothelial carcinoma and 13 cases of malignant melanoma. ICIs included 77 cases of nivolumab, 42 cases of pembrolizumab, 9 cases of durvalumab, 8 cases of atezolizumab, 5 cases of ipilimumab and 7 cases of nivolumab combined with ipilimumab. The CTCAE grade of liver injury ≥2 was used to exclude liver injury caused by other causes, and ALT/AST ratio> 3 times the upper limit of normal value was defined as the IMH group, and the rest were classified as non-IMH groups. Multiple regression analysis was performed to explore the influencing factors of IMH risk increase. Results There were 25 cases in the IMH group and 123 cases in the non-IMH group. The mean time to develop IMH after receiving ICIs treatment was 51 (7, 207) days after ICIs treatment. In IMH group, CTCAE grade =2, 3 and 4 were 9 cases, 11 cases and 5 cases respectively. All cases discontinued ICIs; among them, 5 cases were treated with ursodeoxycholic acid, 11 cases were treated with cortisol, and the remaining 9 cases were treated with a combination of ursodeoxycholic acid and cortisol. All patients in the IMH group were followed up, and their liver function improved. Six patients resumed ICIs treatment after their liver injury improved, while the rest discontinued treatment either due to IMH or other immune-related adverse events (irAEs). In the IMH group, the numbers of cases of non-small cell lung cancer, malignant melanoma, treatment with nivolumab combined with ipilimumab, prior ICIs treatment history, and liver metastasis were 3 cases (12.0%), 12 cases (48.0%), 6 cases (24.0%), 5 cases (20.0%) and 9 cases (36.0%) respectively. When compared with the non-IMH group [64 cases (52.0%), 1 case (7.7%), 1 case (0.8%), 2 cases (1.6%) and 13 cases (10.6%)], the difference was statistically significant (P<0.05). The levels of ALT and AST in the IMH group were significantly higher than those in the non-IMH group(all P<0.05). Multiple regression analysis showed that malignant melanoma [OR (95% CI): 11.3 (3.5, 38.0), P<0.05] and the combination of nivolumab and ipilimumab [OR (95% CI): 60.2 (7.9, 475.3), P<0.05] were independently associated with the increased risk of IMH. 16.9% of tumor patients treated with ICIs had liver injury with CTCAE grade> 2. Conclusion Cortisol therapy can effectively improve liver injury in IMH patients. The occurrence of IMH is related to tumor type and ICIs drugs used, and the risk of IMH is significantly increased in patients with malignant melanoma and those receiving combination therapy of nivolumab and ipilimumab.

Key words: Immune checkpoint inhibitors, Immune-mediated hepatotoxicity, Malignant melanoma, Nivolumab

钱祥云, 黄大兵, 王峰. 免疫检查点抑制剂诱发肿瘤患者免疫介导性肝损伤的临床分析[J]. 肝脏, 2023, 28(6): 694-697.

QIAN Xiang-yun, HUANG Da-bing, WANG Feng. Clinical analysis of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in tumor patients[J]. Chinese Hepatolgy, 2023, 28(6): 694-697.

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