Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
Department of Dermatology, Venereology and Allergology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, CH-9007, St. Gallen, Switzerland.
Cancer Immunol Immunother. 2021 Apr;70(4):1089-1099. doi: 10.1007/s00262-020-02768-5. Epub 2020 Oct 28.
Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4-22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations.
GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment.
In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050).
The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.
接受免疫检查点抑制剂（ICPI）治疗的黑色素瘤患者中，1.4%至 22.3%会出现肝免疫相关不良事件（irAE），包括肝功能检查（转氨酶）升高，这是一种潜在的严重毒性，治疗具有挑战性。与肝转氨酶丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）不同，人们对谷氨酰转移酶（GGT）升高的频率和影响知之甚少。
回顾性评估了接受 ICPI 治疗的转移性黑色素瘤患者治疗前和治疗期间的 GGT，在两个独立队列中进行（PD-1：n=218，Ipi+Nivo：n=148）。根据基线和治疗期间的免疫相关 GGT（irGGT）升高情况，分析总生存期（OS）和最佳客观缓解。
多变量分析显示，基线 GGT 升高的患者 OS 降低（PD-1 组：风险比 [HR] 1.76，p=0.0073；Ipi+Nivo 组：HR 1.77，p=0.032）。免疫相关 GGT 升高发生率为 17%（PD-1 组）和 38.5%（Ipi+Nivo 组）。其中大多数（分别为 81%和 68%）患者 ALT 和 AST 正常，无肝毒性临床迹象。经历 irGGT 升高的患者具有更好的反应（PD-1 组：比值比 [OR] 3.57，p=0.00072；Ipi+Nivo 组：OR 1.74，p=0.12）和 OS（PD-1 组：HR 0.37，p=0.0016；Ipi+Nivo 组：HR 0.33，p=0.00050）。
目前对肝 irAE 的频率估计不足。在接受 ICPI 治疗之前和期间，将敏感酶 GGT 添加到实验室面板中，可检测到比目前已知的两倍或三倍更多的发生肝或肝胆毒性的患者。免疫相关的 GGT 升高与反应和有利的生存相关。建议在免疫检查点抑制剂患者的实验室面板中添加γ-谷氨酰转移酶，以检测肝胆毒性。
