Checkpoint inhibitor hepatotoxicity: pathogenesis and management

Abstract

Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients. Although ICI-associated hepatotoxicity is clinically and pathologically distinct from idiopathic autoimmune hepatitis, our understanding of its pathogenesis continues to evolve. Pending greater understanding of the pathophysiology, mainstay of management remains through treatment with high-dose corticosteroids. This approach works for many patients, but up to 30% of patients with high-grade hepatotoxicity may not respond to corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, and rare cases of fulminant hepatitis due to ICI hepatotoxicity have been reported. Optimal management for these challenging patients remains uncertain. Herein, we review the current understanding of pathogenesis of ICI-associated toxicities, with a focus on hepatotoxicity. Based on the existing literature, we propose evolving management approaches to incorporate strategies to limit excess corticosteroid exposure, and address rare but important presentations of cholestatic hepatitis and fulminant liver failure. Finally, as ICI hepatotoxicity frequently occurs in the context of treatment for advanced malignancy, we review the impact of hepatotoxicity and its treatment on cancer outcomes, and the overall safety of re-challenge with ICI, for patients who may have limited treatment options.

Immune Checkpoint Inhibitor-Induced Liver Injury

“…Furthermore, recent reviews have outlined data from clinical trials demonstrating that combination CPI therapy with anti-CTLA-4 and anti-PD-1 conferred a higher risk of all CPI-H events and grade 3 and 4 reactions than monotherapy. 29 30…”

“…These recommendations have been consolidated into guidelines by oncology societies. 30 Grading the severity of CPI-H is crucial as it guides the management approach. Currently, two grading systems exist: the CTCAE and the Drug-Induced Liver Injury Network (DILIN).…”

“…Patients with CPI-H tend to recover after administration of corticosteroid therapy with recovery time typically between 5 and 9 weeks, although more protracted clinical courses can be seen and are particularly notable in cholangiopathic liver injury. 30 38…”

“…Furthermore, recent reviews have outlined data from clinical trials demonstrating that combination CPI therapy with anti-CTLA-4 and anti-PD-1 conferred a higher risk of all CPI-H events and grade 3 and 4 reactions than monotherapy. 29,30 The use of CPI therapy in conjunction with adjuvant or neoadjuvant chemotherapy options has also been associated with an increased risk of hepatotoxicity in these patients. It remains uncertain whether this hepatotoxicity is solely due to immune-mediated reaction, a direct result of concurrent chemotherapy or an interaction between two different toxicity mechanisms.…”

“…Azathioprine, has a less favorable profile, given the length of time for the onset of maximal immunosuppressive effects, which make it inappropriate for induction of immunosuppression in rapidly progressive acute liver injury. 30,48 Azathioprine also confers a risk of idiosyncratic hepatotoxicity, the requirement for regular blood monitoring and has been associated with an increased malignancy risk in the longer term, unlike MMF. 69 For those patients in whom dual therapy has failed, additional or alternate immunosuppressive therapy (IST) regiments may be considered.…”