Fig 1.
Flow diagram illustrating identification of patients with liver enzyme elevation for inclusion in the study.
ICI, checkpoint inhibitor; ALT, alanine aminotransferase; ALP, alkaline phosphatase; PD-1, programmed death protein 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-L1, programmed death-ligand 1; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Fig 2.
Final diagnoses of liver enzyme elevation after exposure to checkpoint inhibitor immunotherapy (ICI).
Range and frequency of diagnoses that were made by the treating clinician, based on clinical assessment and results of investigations performed. Dark grey bars show patients with each diagnosis as a percentage of all patients with elevated lever enzymes after ICI exposure. Light grey bars show patients with each diagnosis as a percentage of all patients treated with ICI.
Table 1.
Laboratory values and checkpoint inhibitor (ICI) therapy exposure in patients with liver enzyme elevations (LEE) attributed to immunotoxicity compared with other causes.
Table 2.
Comparison between patients diagnosed with liver immunotoxicity and patients exposed to checkpoint inhibitor (ICI) therapy who did not develop immunotoxicity.
Fig 3.
Management of patients diagnosed with liver immunotoxicity due to checkpoint inhibitor (ICI) immunotherapy, according to severity of enzyme elevation.
A, duration and route of immunosuppressive therapy and time to resolution of elevated liver enzymes. B, management of ICI therapy following diagnosis of liver immunotoxicity. ULN, upper limit of normal; irAE, immune-related adverse event; LirAE, liver immune-related adverse event; MMF, mycophenolate mofetil.
Fig 4.
Proposed algorithm to guide diagnostic evaluation of immune checkpoint inhibitor (ICI)-treated patients with liver enzyme elevation.
Stratification of ALT, AST, ALP and bilirubin elevation is as per CTCAE (v. 5.0; S1 Table) [6]. Definitions of Grade 2, 3 and 4 enzyme elevation as they relate to management of ICI-associated hepatotoxicity are as per European Society for Medical Oncology and American Society of Clinical Oncology Practice Guidelines [9, 10]. ALT, alanine transaminase, AST, aspartate aminotransferase; ALP, alkaline phosphatase.