Biopsy May Not Be Needed to Treat Immune Checkpoint Inhibitor-Associated Hepatitis

By Marilynn Larkin

October 07, 2021

NEW YORK (Reuters Health) - In patients taking immune checkpoint inhibitors (ICIs) who developed moderate-to-severe liver injury, a biopsy delayed steroid initiation and was not associated with more rapid hepatitis resolution of hepatitis, an observational study shows.

"Current medical society guidelines recommend liver biopsy be performed in patients who are receiving ICI and develop significant elevations in liver enzymes in order to establish the diagnosis of ICI hepatitis," Dr. Stephen Zucker at Brigham and Women's Hospital in Boston told Reuters Health by email. "Our goal was to examine whether obtaining a liver biopsy actually altered the clinical management or outcomes in these situations."

"The findings suggest that, in patients who develop moderate-to-severe liver injury, initiation of empiric treatment for ICI hepatitis without performing a liver biopsy may the most appropriate initial management," he said.

"An elevated serum bilirubin level should enhance suspicion for an alternative diagnosis (such as bile duct obstruction), especially if greater than 3 mg/dL," he added. "Liver biopsy may be informative in patients who fail to demonstrate an adequate response to empiric corticosteroids or in those who have elevated bilirubin levels without radiographic evidence of bile duct obstruction."

As reported in JAMA Oncology, Dr. Zucker and colleagues analyzed data on 213 patients (mean age, 60; 53% women) who received ICI treatment between 2010-2020 and developed grade 3 or higher ICI-associated liver injury. About half (50.2%) underwent liver biopsy a median of 5 days after first grade 3-to-4 ALT elevation, of whom 95 (88.8%) had a histology result that was compatible with ICI hepatitis.

The primary outcome was time to ALT normalization (40 U/L or less) and the secondary outcome was time to ALT improvement to 100 U/L or less (grade 1 injury).

Two major biopsy-related complications (splenic biopsy, hemothorax) occurred.

The remaining patients received a diagnosis of ICI hepatitis after exclusion of other causes of liver injury (e.g., viral hepatitis, ischemia, other medications) and appropriate response to corticosteroids.

Those who underwent biopsy had higher peak aminotransferase levels (ALT, 499 U/L vs. 412 U/L; aspartate aminotransferase levels, 329 U/L vs. 262 U/L); were more likely to develop steroid-refractory hepatitis (39.3% vs. 17.0%; risk ratio, 2.32); and were less likely to have a prior immune-related adverse event (38.3% vs. 56.6%; RR, 0.7).

Both groups received similar maximum corticosteroid doses (median 1.5).

However, after adjustment for ALT, combination anti-cytotoxic T-lymphocyte−protein 4/programmed cell death 1 therapy, and melanoma (vs. nonmelanoma cancers), those who underwent a biopsy were significantly less likely per day to begin taking steroids after the first grade 3-to-4 ALT elevation (hazard ratio, 0.67).

Patients with ICI hepatitis who underwent a biopsy also had a significantly longer median time to ALT normalization (42 vs. 33 days) and to ALT levels of 100 U/L or less (21 vs. 15 days).

Overall, liver biopsy was associated with trends toward a longer time to ALT normalization (HR, 0.76) and to ALT levels of 100 U/L or less (HR, 0.78).

The most common liver injury in ICI hepatitis patients was panlobular inflammation (65%). Among 12 biopsied patients who did not have ICI hepatitis, four were diagnosed with malignant biliary obstruction, four had liver injury from a contemporaneous drug, and two had diffuse malignant infiltration.

After adjustment, the injury cause was unclear in two patients.

Dr. Minhhuyen Nguyen, Director, Clinical Gastroenterology at Fox Chase Cancer Center in Philadelphia, told Reuters Health by email, "I agree with the findings since they do mirror my clinical experience. Despite the observational study design, these findings provide real-world evidence that could effectively guide our clinical practice."

"As ICI therapy becomes a mainstay treatment for many cancers, cases of liver abnormalities have become more common," she said. "In cases where significant liver enzyme elevations appear to be temporally related to the initiation of ICI, use of steroid therapy after consideration of other possible etiologies is reasonable, even without liver biopsy."

"Other possible etiologies for liver abnormalities should be promptly ruled out," she noted. "Prior to ICI treatment, possible underlying advanced liver disease/cirrhosis should be investigated."

"Liver biopsy should always be considered in cases where the response to steroids is not robust as expected," she added. "The turnaround time of the liver biopsy results should be quick so other therapies can be instituted as needed."

SOURCE: https://bit.ly/3v0HGLv JAMA Oncology, online September 23, 2021.

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