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Table 1.  Clinical Characteristics and Laboratory Values
Clinical Characteristics and Laboratory Values
Table 2.  Patients Who Received Liver Biopsy Stratified by Final Diagnosis
Patients Who Received Liver Biopsy Stratified by Final Diagnosis
1.
Brahmer  JR, Lacchetti  C, Schneider  BJ,  et al; National Comprehensive Cancer Network.  Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.   J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385PubMedGoogle ScholarCrossref
2.
Haanen  JBAG, Carbonnel  F, Robert  C,  et al; ESMO Guidelines Committee.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2018;29(suppl 4):iv264-iv266. doi:10.1093/annonc/mdy162PubMedGoogle ScholarCrossref
3.
Dougan  M, Wang  Y, Rubio-Tapia  A, Lim  JK.  AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor (ICI) colitis and hepatitis: expert review.   Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063 PubMedGoogle ScholarCrossref
Research Letter
September 23, 2021

Utility of Liver Biopsy in Diagnosis and Management of High-grade Immune Checkpoint Inhibitor Hepatitis in Patients With Cancer

Author Affiliations
  • 1Division of Gastroenterology, Hepatology, and Endoscopy, Brigham & Women’s Hospital, Boston, Massachusetts
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
JAMA Oncol. 2021;7(11):1711-1714. doi:10.1001/jamaoncol.2021.4342

The utility of liver biopsy in diagnosis and management of immune checkpoint inhibitor (ICI) hepatitis is uncertain.1-3 We examined the association of histology with management and outcomes of high-grade ICI hepatitis.

Methods

A total of 7046 patients with cancer (excluding hepatocellular carcinoma) received ICI treatment between January 2010 and June 2020. We performed a retrospective cohort study of the 213 patients who developed grade 3 or higher (alanine aminotransferase [ALT] level, >200 U/L [to convert to μkat/L, multiply by 0.0167]) liver injury that was associated with ICI treatment. Approval for the study was obtained from the Mass General Brigham institutional review board, and informed consent was waived due to the retrospective nature of the study.

The primary outcome was time to ALT normalization (≤40 U/L), and the secondary outcome was time to ALT improvement to ≤100 U/L (grade 1 injury). A Kaplan-Meier analysis was used for time-to-event data, and Cox regression was used for multivariable adjustment. Analyses were performed using SAS, version 9.4 (SAS Institute), and statistical significance was set at P < .05.

Results

Of 213 patients included in the study, a total of 107 patients (50.2%) underwent liver biopsy a median (interquartile range [IQR]) of 5 (1-14) days after first grade 3 to 4 ALT elevation, of whom 95 (88.8%) had histology results that were compatible with ICI hepatitis as documented by hepatopathologists. There were 2 major biopsy-related complications (splenic biopsy, hemothorax). The remaining 106 patients (49.8%) received a diagnosis of ICI hepatitis after exclusion of other causes of liver injury (eg, viral hepatitis, ischemia, other medications) and appropriate response to corticosteroids. Most patients had melanoma (115 [54%]). Patients who underwent biopsy (Table 1) had higher peak aminotransferase levels (ALT, 499 U/L vs 412 U/L; P = .04; aspartate aminotransferase levels, 329 U/L vs 262 U/L [to convert to μkat/L, multiply by 0.0167]; P = .06), were more likely to develop steroid-refractory hepatitis (39.3% vs 17.0%; risk ratio, 2.32; 95% CI, 1.41-3.79; P < .001), and were less likely to have a prior immune-related adverse event (38.3% vs 56.6%; risk ratio, 0.7; 95% CI, 0.5-0.9; P = .01).

Both groups received similar maximum corticosteroid doses (median [IQR], 1.5 vs 1.5 [1.0-2.0] mg/kg/d; P = .89). However, patients 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 [HR], 0.67; 95% CI, 0.50-0.90; P = .01) after adjusting for ALT, combination anti–cytotoxic T-lymphocyte−protein 4/programmed cell death 1 therapy, and melanoma (vs nonmelanoma cancers). Steroids were administered for 63 patients (58.9%) before biopsy. After biopsy, steroids were administered for 40 patients (37.4%) and discontinued for 8 patients (7.5%).

Patients who underwent a biopsy with ICI hepatitis had a significantly longer median (IQR) time to ALT normalization (42 [33-55] vs 33 [28-39] days; P = .01) and to ALT levels of 100 U/L or less (21 [17-26] vs 15 [14-17] days; P = .01). Liver biopsy was associated with trends toward a longer time to ALT normalization (HR, 0.76; 95% CI, 0.56-1.03; P = .07) and to ALT levels of 100 U/L or less (HR, 0.78; 95% CI, 0.58-1.05; P = .10) after adjusting for ALT level, combination anti–cytotoxic T-lymphocyte−protein 4/programmed cell death 1 therapy, liver metastases, steroid-refractory hepatitis, and prior immune-related adverse events using a Cox regression.

The most common pattern of liver injury in patients with ICI hepatitis was panlobular inflammation (61 [64.9%]) (Table 2). Of the 12 patients who underwent a biopsy who were determined not to have ICI hepatitis, 4 received a diagnosis of malignant biliary obstruction, 4 were judged to have liver injury from a contemporaneous drug, and 2 had diffuse malignant infiltration. The cause of injury remained unclear in the final 2 patients. Patients without ICI hepatitis were more likely to have portal-predominant inflammation (50.0% vs 8.5%; P = .001) and less likely to have panlobular hepatitis (8.3% vs 64.9%; P < .001) compared with patients with ICI hepatitis. Patients without ICI hepatitis also were more likely to manifest grade 3 bilirubin elevation (>3 mg/dL [to convert to μ mol/L, multiply by 17.104]) (50% vs 11.6%; P = .004) and higher peak total bilirubin levels before biopsy (median [IQR], 4.4 [1.2-6.9] vs 0.8 [0.5-1.6]; P = .002).

Discussion

The results of this cohort study suggest that liver biopsy in ICI-treated patients who develop grade 3 or higher liver injury delays the initiation of corticosteroids and is not associated with faster hepatitis resolution. A limitation of the study is its retrospective nature, which raises the possibility of unmeasured confounders. 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.

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Article Information

Accepted for Publication: July 7, 2021.

Published Online: September 23, 2021. doi:10.1001/jamaoncol.2021.4342

Corresponding Author: Michael Li, MD, Division of Gastroenterology, 513 Parnassus Avenue, Room S-357, San Francisco, CA 94143 (michael.li@ucsf.edu).

Author Contributions: Dr Li had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Grover and Zucker shared senior authorship.

Concept and design: Li, Sack, Grover, Zucker.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Li, Zucker.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Li.

Administrative, technical, or material support: Bell, Zucker.

Supervision: Rahma, Srivastava, Grover, Zucker.

Conflict of Interest Disclosures: Dr Rahma reported personal fees from Imvax, GSK, Bayer, Genentech, Sobi, Boehringer Ingelheim, Puretech, and Maverick Therapeutics as well as a patent pending for methods of using pembrolizumab and trebananib outside the submitted work. Dr Grover reported personal fees from UpToDate and Wolters Kluwer Health Inc outside the submitted work. No other disclosures were reported.

Additional Contributions: We thank Danny Wong, MD, Brigham & Women’s Hospital, for his contributions to data collection and F. Stephen Hodi, MD, Dana-Farber Cancer Institute, for his editing assistance. These individuals were not compensated for their contributions.

References
1.
Brahmer  JR, Lacchetti  C, Schneider  BJ,  et al; National Comprehensive Cancer Network.  Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.   J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385PubMedGoogle ScholarCrossref
2.
Haanen  JBAG, Carbonnel  F, Robert  C,  et al; ESMO Guidelines Committee.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2018;29(suppl 4):iv264-iv266. doi:10.1093/annonc/mdy162PubMedGoogle ScholarCrossref
3.
Dougan  M, Wang  Y, Rubio-Tapia  A, Lim  JK.  AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor (ICI) colitis and hepatitis: expert review.   Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063 PubMedGoogle ScholarCrossref
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