Liver transplantation for hepatocellular carcinoma following checkpoint inhibitor therapy with nivolumab

Abstract

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single‐center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy‐proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61–71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune‐mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune‐mediated outcomes and graft loss.

Current status of liver transplantation for non‐B non‐C liver cirrhosis and hepatocellular carcinoma

“…11,88 The washout period between the last dose of ICI and LT is an essential factor to consider to avoid the potential risk of acute rejection after LT. 90,91 One of the current large series of patients with ICI use prior to LT suggested that pretransplant use of ICIs within 90 days of LT was associated with biopsy-proven acute cellular rejection and immune-mediated hepatic necrosis. 92 Several case reports support the validity of a withdrawal period of 90 days or more, 93,94 and a case with a short washout period of 8 days resulted in fatal acute hepatic necrosis. 95 On the other hand, a case series reported no increase in rejection or graft injury, although 89% of patients received ICI treatment within 4 weeks of LT. 96 In contrast, one case with fatal acute hepatic necrosis was observed, and this outcome is likely related to the acute immune rejection caused by the pre-LT ICI treatment despite 93 days of withdrawal.…”

Immunotherapy Use Prior to Liver Transplant in Patients with Hepatocellular Carcinoma

“…In another case reported by Schnickel et al, the patient experienced acute rejection after receiving a liver transplant for HCV cirrhosis who had received treatment with nivolumab 10 days prior. However, the graft was able to be salvaged after receiving rATG, steroid pulse, rituximab and IVIG [ 32 ]. Aby et al described a case of a 64-year-old male with HCV cirrhosis who was treated with nivolumab 16 days prior to liver transplant and experienced acute rejection that resolved with treatment with solumedrol and thymoglobulin [ 22 ].…”

“…There was one case reported by Chen et al in which a patient received a liver transplant 7 days after treatment with nivolumab who did not experience acute rejection [ 24 ]. It is notable that this patient received only one cycle of nivolumab for his total treatment course prior to transplant whereas the other patients who experienced acute rejection received extended courses of treatment ranging from 8 months to 2 years [ 22 , 24 , 29 , 32 ].…”

“…Peterson et al reported a patient with HCV cirrhosis who was successfully transplanted 304 days after treatment with nivolumab [ 30 ]. Another patient with HCV cirrhosis described by Schnickel et al was transplanted 6 months following treatment with nivolumab and had no evidence of rejection [ 32 ]. As plasma drug concentrations typically decline below clinically significant levels after 3 half-lives, we compared the rates of acute graft rejection among patients transplanted before and after 3 half-lives of nivolumab [ 21 ].…”

“…Steroids were used as the primary treatment modality in three of the four cases with concomitant use of anti-thymocyte globulin in two cases. In a case reported by Schnickel et al, the patient additionally received rituximab, an anti-CD20 antibody, and IV immunoglobulin for moderate rejection, which resulted in salvage of the donor liver graft [ 32 ]. Tabrizian et al described a case of mild acute rejection that responded to increased dosage of tacrolimus, a calcineurin inhibitor [ 35 ].…”