2235 Nivolumab-Induced Severe Allograft Rejection in Recurrent Post-Transplant Hepatocellular Carcinoma

Abstract

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but recurrent HCC post LT presents a unique therapeutic challenge. Nivolumab is an immune checkpoint inhibitor (ICPI) approved for treatment of HCC, but data on its safety following LT is limited. We present a case of Nivolumab-induced severe, steroid-resistant acute cellular rejection (ACR) in a patient with recurrent HCC post LT, treated successfully with thymoglobulin and plasmapheresis. CASE DESCRIPTION/METHODS: A 64-year-old male was noted to have evidence of locally advanced recurrent HCC on surveillance imaging two years post-LT. Systemic therapy using Sorafenib had to be discontinued due to severe proteinuria. Given limited therapeutic options and evidence of progressive disease, a decision was made to initiate Nivolumab. A week later, liver tests were elevated and continued to worsen significantly (peak values 3 weeks post infusion: ALT 424 U/L, AST 215 U/L, ALP 1074 IU/L, Br 16 mg/dL). Further infusions were discontinued. Liver biopsy revealed features of ACR with moderate portal inflammation, patchy bile duct injury and endotheliitis. Since ACR was resistant to high dose steroids, thymoglobulin was administered with some improvement. However, given persistent liver test elevation, we proceeded with plasmapheresis and after 5 sessions, marked improvement was noted and repeat biopsy showed resolution of ACR (Figure 1). DISCUSSION: Nivolumab, a monoclonal antibody that targets programmed cell death protein 1, was FDA approved in 2017 for the treatment of HCC in patients previously treated with Sorafenib. However, there is limited experience with its use in solid organ transplant recipients. The immunological mechanism of nivolumab induced ACR is unclear and there is no consensus on management. As with our patient, none of the reported cases responded to high-dose steroid therapy. Use of thymoglobulin and plasmapheresis has not been reported in this setting previously. Even though plasmapheresis would likely not impact nivolumab-induced T cell–mediated immune rejection, given its long half- life, we hypothesized that plasmapheresis could help by removing the medication from the circulation. Severe ACR with ICPI therapy could result in allograft failure, with limited therapeutic options. Factors that contribute to ACR and whether this may be impacted by length of time after LT remain unclear. There is a critical need for safe and effective systemic options for treatment of recurrent HCC post-LT.