Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Eur J Cancer. 2020 May;130:211-218. doi: 10.1016/j.ejca.2020.02.041. Epub 2020 Mar 28.
Immune-related hepatitis (ir-hepatitis) is a common side-effect of checkpoint inhibitors (CPIs). Here, we characterise ir-hepatitis in a large cohort of patients with metastatic melanoma (MM) treated with CPIs and describe potential risk factors and efficacy of medical management.
The retrospective study included a large cohort of patients with MM treated with CPIs between 2010 and 2019. Patients were retrieved from the national Danish Metastatic Melanoma Database.
Five hundred twenty one patients were included. Ir-hepatitis was found in 6.8% of patients. Combination therapy was associated with a significantly greater risk than monotherapy. Of all patients, 34.9% with hepatitis had a different hepatitis grading, when based on either alanine transaminase (ALT) or aspartate transaminase (AST) levels. Of all patients, 72.1% with hepatitis received steroid treatment, and two patients received additional second-line immunosuppressants. Of all patients, 35.5% experienced hepatitis relapse during steroid tapering. Of all patients, 18.6% and 25% of patients with grade ≥2 and ≥ III3, respectively, developed hepatitis within 7 days after finishing an antibiotic treatment for infection. Patients (62.5%) who received a cumulative dose of >4000 mg steroid experienced cancer progression, compared with 22.7% of patients treated with <4000 mg.
Several observations of clinical importance were made. Infection and antibiotic treatment during CPIs could be a possible risk factor for developing ir-hepatitis. Severity of ir-hepatitis is potentially underestimated in a significant number of patients, if only one liver enzyme is measured. The role of second-line immunosuppressants needs to be further investigated because of the high risk of hepatitis relapse during steroid tapering and the potential negative impact of cumulative steroid dose on response to CPIs.
免疫相关肝炎（ir-hepatitis）是检查点抑制剂（CPIs）的常见副作用。在这里，我们对接受 CPIs 治疗的转移性黑色素瘤（MM）患者的大量队列进行了 ir-hepatitis 特征描述，并描述了潜在的风险因素和医学管理的疗效。
这项回顾性研究包括了 2010 年至 2019 年间接受 CPIs 治疗的大量 MM 患者队列。患者从丹麦转移性黑色素瘤数据库中检索。
共纳入 521 例患者。6.8%的患者出现 ir-hepatitis。联合治疗与单药治疗相比，风险显著增加。在所有患有肝炎的患者中，有 34.9%根据丙氨酸转氨酶（ALT）或天冬氨酸转氨酶（AST）水平，肝炎分级不同。在所有患有肝炎的患者中，72.1%接受了类固醇治疗，有两名患者接受了额外的二线免疫抑制剂治疗。在所有患有肝炎的患者中，有 35.5%在类固醇逐渐减量期间肝炎复发。在所有患者中，分别有 18.6%和 25%的患者在结束抗生素治疗感染后 7 天内出现≥2 级和≥3 级 3 的肝炎。接受>4000mg 累积剂量类固醇的患者（62.5%）发生癌症进展，而接受<4000mg 类固醇治疗的患者为 22.7%。
我们观察到了一些具有临床重要意义的结果。CPIs 期间的感染和抗生素治疗可能是发生 ir-hepatitis 的一个潜在危险因素。如果只测量一种肝酶，ir-hepatitis 的严重程度在相当数量的患者中可能被低估。二线免疫抑制剂的作用需要进一步研究，因为在类固醇逐渐减量期间肝炎复发的风险很高，而且累积类固醇剂量对 CPIs 反应的潜在负面影响。
