How to Manage Immune Checkpoint Inhibitor Hepatotoxicity

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia medical School in Norfolk, Virginia.

Immune checkpoint inhibitors have dramatically contributed to oncologic success. This treatment represents a newer pathway in cancer therapy, effectively enhancing the immune response against tumor cells. Checkpoint inhibitors are increasingly utilized for dermatologic diseases like melanoma, non–small cell lung cancer, and — in the gastrointestinal world — for colorectal cancer with microsatellite instability.

These inhibitors block the immune checkpoint pathways, which normally regulate the immune responses that our body would intrinsically use to prevent harm from antigens and other immune-related damage. However, in selectively blocking this process, these agents can create tumor lysis.

This process also creates a risk for adverse events. This is something we've certainly seen in the treatment of checkpoint colitis. We're now seeing increasing reports of hepatotoxicity associated with these drugs.

Checkpoint inhibitor hepatotoxicity was the topic of a recent review article published in the journal Hepatology, for which I'll provide some highlights today.

Immune-Related Adverse Events

Depending on the drug used, the rate of immune-related adverse events may be as high as 85%, whereas for severe toxicities it's in the 20%-30% range. Liver toxicity is fairly common in patients receiving these treatments, occurring in up to 25%.

The pathophysiology underpinning immune-related adverse events occurs as a result of tumor lysis, which causes the release of numerous proteins and host antigens in a process called "epitope spreading." T-cell upregulation can then occur in any given target organ, which can result in an autoimmune response and a potentially inflammatory response.

In this discussion, we'll be focusing on immune-related adverse events occurring in the liver.

Hepatotoxicity Resulting From Checkpoint Inhibitors

The liver is very vulnerable to risk because it's constantly exposed to foreign antigens through portal venous blood flow. Immune tolerance to this nonpathogenic material is essential to avoid a state of constant inflammation. Hence, when we block this pathway, it potentially leads to an increased risk for hepatotoxicity.

When it comes to patient-specific risk for liver toxicity, the only clearly identified factor to date is whether a patient has had preexisting autoimmune disease. This makes sense, given that they're already upregulated. Metastatic disease to the liver doesn't seem to increase the risk.

The type of immune checkpoint inhibitor therapy may have an association with risk for immune-related hepatoxicity. There are a couple different classes of checkpoint inhibitors to consider, including CTLA-4 inhibitors such as ipilimumab, and anti–PD-1/PD-L1 drugs such as pembrolizumab, which is often used in melanoma therapy. However, the relative risk they pose for adverse events doesn't appear significant.

Making the Diagnosis

The diagnosis of checkpoint inhibitor–related hepatotoxicity is really a clinical one.

Hepatotoxicity resulting from the use of these agents ranges up to 28%. However, you need to be discriminant and put on your differential hat, because cancer progression is the most common cause of liver enzyme elevation in these patients.

Liver biopsy is rarely indicated, other than to look for exclusionary alternate causes. This requires you to differentiate between viral, drug, and immune-mediated causes of livery injury. Differentiation by liver histology is very challenging. This tends to uncover a panlobular or zone 3 type of liver inflammation, which is not necessarily in any way categoric for the diagnosis.

Management Strategies

There are clinical diagnostic measures you can employ, particularly looking at the liver enzymes and categorizing them using the Common Terminology for Clinical Adverse Events criteria. These are graded on a 1-4 scale, ranging from mild to severe.

Grade 1 can be monitored without interruptions of the immune checkpoint inhibitor therapy, which is good news. With higher grades, it's typically recommended to administer steroids. This is steroid responsive, although not nearly at the level we see with autoimmune hepatitis.

Steroid-responsive disease will typically begin with a 1 mg/kg dose of prednisone. With that, you should see some improvement within 48-72 hours. If not, you can increase the dose to 2 mg/kg and consider switching to an intravenous formulation, according to current recommendations.

It's reported that 70%-80% of patients respond to an initial course of steroids, but this means that 20%-30% of patients with high-grade (grades 3 and 4) hepatotoxicity do not respond or are refractory with withdrawal. Therefore, in such patients you would increase the dose from 1 mg/kg to 2 mg/kg.

We're starting to see an increasing need for a second-line immunotherapy. In treating patients with autoimmune hepatitis, you've perhaps used drugs like mycophenolate mofetil or tacrolimus. These may be added to the immune checkpoint inhibitor therapy.

If you're not able to stop the therapy, you should discuss the best approach with your oncologists.

Cholestatic Liver Injury

It's increasingly recognized that there is an associated immune-mediated cholangitis that can occur with the use of checkpoint inhibitors. On biopsy, it's very similar to the appearance of primary sclerosing cholangitis.

Patients with immune-mediated cholangiopathy seem to be augmented by the addition of ursodeoxycholic acid, which we've used in other cholestatic liver injuries. That's an easy treatment to add.

Another pattern of cholestatic presentation to be aware of, as it can be very severe, is vanishing bile duct–like syndrome. We see this with other drug-induced liver injuries, where it has a very poor prognosis.

Patients treated with these agents can also develop fulminant hepatitis. This is not well managed by standard therapy and may require that patients undergo some version of plasma exchange. In such cases, this is where advanced transfer to a hepatologist really needs to be considered.

Weighing the Impact of Checkpoint Inhibitor Use

When we see these adverse events following the use of immune checkpoint inhibitors, though, is that really a bad thing? Because this actually means that there's an increased response to directed tumor therapy, so it's a good thing in that regard.

And when it comes to rechallenging with immune checkpoint inhibitors, do we need to throw away the baby with the bathwater?

Societal recommendations suggest that permanent discontinuation of these drugs for severe toxicity is the way to go. However, there is no strong evidence that rechallenge is harmful. Even in patients with grade 3-4 hepatotoxicity, the risk for rechallenge-related consequences is less than 30%. Therefore, I think this is where you need to weigh in with your oncologist.

Even if the patients are restarted on the same monotherapy that caused hepatoxicity, the majority seemingly have a low risk for rechallenge aggravation. However, it must be noted that there are some potentially catastrophic consequences to rechallenge, even with lower grades, albeit extremely rare.

The current literature does not appear to support the beneficial use of prophylactic prednisone or budesonide, which we use as a relatively steroid-sparing option in liver disease.

Balancing Risk and Benefit

Hepatotoxicity resulting from immune checkpoint inhibitors is something you need to consider and perhaps even expect to see in your patients.

Fulminant liver failure is extremely rare.

The good news is that rechallenge, even in patients with higher-grade hepatotoxicity, is potentially worth the risk to be gained from these life-extending therapies. This isn't absolute but it's still promising, as it doesn't necessarily require having to change the course of therapy.

When it comes to balancing risk and benefit, we need to put into perspective the idea that hepatotoxicity can actually be a sign that these drugs are improving outcomes. Nonetheless, I think the benefit for this class of therapies is huge.

I highly recommend that you refer to this article when you see your patients receiving immune checkpoint inhibitors, as it may answer many questions. I think it's the state of the art at the present time. Hopefully, you've found this summary of its key findings helpful.

I'm Dr David Johnson. Thanks again for listening.

David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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