Drug-induced liver injury under immune checkpoint inhibitors – The challenge of causality assessment

Background Drug-induced liver injury (DILI) during therapy with immune checkpoint inhibitors (CPI) is an increasing phenomenon. However, exclusion of competing diagnoses and identification of the causative agent is challenging and especially identifying the causative agents in suspected DILI is of special interest in oncologic patients with multiple co-medications as well as the possible use of alternative medicine.

Methods Patients included in the ongoing study on the effects of potentially hepatotoxic drugs (NCT02353455) treated with CPI were selected for analysis. DILI diagnosis and causality assessment was based on a test system established in our centre using monocyte-derived hepatocyte-like cells (MH cells) [1–3] and the Roussel Uclaf Causality Assessment Method (RUCAM) as well as expert assessment.

Results We identified six patients with liver injury during CPI therapy. In five of the six patients, MH cell testing yielded positive results for one of the CPI implicated. Interestingly, however, in the remaining patient, who declared concomitant use of herbal and dietary supplements (HDS), MH cell testing was positive for a component of the herbal used ([Fig. 1]). After discontinuation of the HDS, CPI treatment could be resumed.

Conclusion Immune checkpoint inhibitor treatment is a promising therapeutic method in many advanced stage cancers. However, immune-related adverse events such as liver injury can lead to permanent discontinuation of anticancer treatment. Diagnosis of liver injury due to checkpoint inhibitor can be challenging, especially if drug-induced liver injury by concomitant medication or HDS has to be excluded. We identified a patient with liver injury due to therapeutics other than the checkpoint inhibitors by using the MH cell test as a causality assessment method who could continue oncological treatment without recurrence of liver injury.

Abb. 1Figure 1 Results of the MH cell test in Patient 3 with DILI due to HDS showing a positive result for emodin and a negative result for pembrolizumab (Green line: Test cut-off = 2). APAP (acetaminophen) is standard part of the test for demonstrating dose-dependent DILI.

Publication History

Article published online:
10 June 2021