Clinical analysis of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in tumor patients

Abstract

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

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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