In a retrospective cohort study reported in a research letter in JAMA Oncology, Li et al found that the performance of liver biopsy in patients with grade ≥ 3 alanine aminotransferase (ALT) elevations during immune checkpoint inhibitor therapy was associated with a delayed start of corticosteroid treatment and delayed time to ALT resolution.
Study Details
The study included 213 patients from Massachusetts General Hospital and Brigham and Women’s Hospital who developed grade ≥ 3 ALT elevation (> 200 U/L) in association with immune checkpoint inhibitor treatment. Most patients (55%) had melanoma. Of the 213 patients, 107 (50.2%) underwent liver biopsy. The primary outcome measure was time to ALT normalization (≤ 40 U/L) and the secondary outcome measure was time to ALT improvement to ≤ 100 U/L (grade 1).
Key Findings
Among the 107 patients undergoing biopsy, the procedure was performed at a median of 5 days (interquartile range = 1–14 days) after the first grade ≥ 3 ALT elevation; 95 (88.8%) had histology indicative of immune checkpoint inhibitor hepatitis. Major biopsy complications occurred in two patients (splenic biopsy and hemothorax).
Biopsy vs nonbiopsy patients had higher peak ALT (499 U/L vs 412 U/L, P = .04) and aspartate aminotransferase levels (329 U/L vs 262 U/L, P = .06), were more likely to develop steroid-refractory hepatitis (39.3% vs 17.0%, risk ratio = 2.32, P < .001), and were less likely to have had a prior immune-related adverse event (38.3% vs 56.6%, risk ratio = 0.7, P = .01).
Maximum corticosteroid doses did not differ between the two groups (median = 1.5 vs 1.5 mg/kg/d, P = .89). In analysis adjusting for ALT level, combination anti–CTLA-4/PD-1 therapy, and melanoma vs nonmelanoma cancers, biopsy patients were significantly less likely per day to begin taking steroids after the first grade ≥ 3 ALT elevation (hazard ratio = 0.67, P = .01).
Biopsy patients had a significantly longer median time to ALT normalization (42 days vs 33 days, P = .01) and to ALT levels ≤ 100 U/L (21 days vs 15 days, P = .01). In analysis adjusting for ALT level, combination anti–CTLA-4/PD-1 therapy, liver metastases, steroid-refractory hepatitis, and prior immune-related adverse events, the hazard ratio for time to ALT normalization was 0.76 (P = .07) and the hazard ratio for time to ALT ≤ 100 U/L was 0.78 (P = .10).
The investigators stated, “The results of this cohort study suggest that liver biopsy in immune checkpoint inhibitor–treated patients who develop grade 3 or higher liver injury delays the initiation of corticosteroids and is not associated with faster hepatitis resolution…. In patients with a hepatocellular pattern of liver injury and absence of other likely causes, empirical initiation of corticosteroids appears reasonable. Liver histology may be informative in patients who fail to improve with empirical corticosteroids before initiating additional immunosuppressive agents, or in those with elevated bilirubin levels without radiographic evidence of biliary obstruction.”
Michael Li, MD, MPH, of the Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, is the corresponding author for the JAMA Oncology article.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
