Immune checkpoint inhibitor (CPI) induced acute liver injury (ALI) is a frequently encountered toxicity occurring in up to 30% patients (pts). There is a lack of systemic evaluation of CPI induced ALI pathogenesis, clinical evolution and outcome of patients (pts).
Retrospective analysis was performed on pts with CPI induced ALI presenting to 6 UK oncology centres between 2013-17. Indices of ALI, therapy complications and outcome were recorded. ALI grading was based on Common Terminology Criteria for Adverse Events.
65% (36/57) pts received ipilimumab+nivolumab (N) or pembrolizumab (P) (combo group) and 35% (21/57) P or N alone (mono group). Median therapy duration to ALI onset was 96 days in the mono and 22 days in the combo group. At presentation, all pts had acute elevations in transaminases (ALT, median 325U/L [range 155-543], ALP 111U/L [72-250]). Immunogolulins and autoantibodies were normal. One pt developed acute synthetic dysfunction without encephalopathy (Bilirubin 64umol/L, INR 1.5). 79% received steriods (mean dose 1.3mg/kg); 34% MMF. Steroid refractory ALI was treated with anti-thymocyte globulin (ATG) in 4 pts. Pathological findings (n = 6 liver biopsies) revealed lobular hepatitis and myelo-lymphoid cell infiltrate/aggregates (CD3+,CD8+,CD68+). Pts with severe, refractory (G4) ALI had significant reductions in circulating lymphocytes/monocytes. 63% (n = 35) had a temporal association between recent infection and ALI. 15% (n = 8) also received anti-TNF-a therapy for colitis. This was not associated with more severe ALI, and ALI resolved in all cases. 21% (n = 11) developed bacterial infections. Fungal sepsis (aspergillus) occurred in all ATG (n = 4) treated patients. Overall no deaths were due to liver failure. 14 pts died with 13 due to disease progression and 1 due to immunotherapy related neuropathy. All deaths due to progressive disease were in pts whose ALI peaked at G3-4. Acturial median survival was significantly lower in G3-4 (14.5 months) vs G1-2 (25 months) liver injury.
Our data report on the largest cohort of CPI induced ALI identifying disease evolution, markers of disease severity and strong correlation with increased morbidity and mortality.
Clinical trial identification
Legal entity responsible for the study
The Royal Marsden Hospital.
The Royal Marsden Hospital & Imperial College London.
J. Larkin: Institutional research support: BMS, MSD, Novartis, Pfizer Consultancy: Elsai, BMS, MSD, GSK, Kymab, Pfizer, Novartis, Roche/Genetech, Secarna, Pierre Fabre, EUSA Pharma; Support: NIHR RM/ICR Biomedical Research Centre for Cancer. All other authors have declared no conflicts of interest.