Liver Allograft Failure After Nivolumab Treatment—A Case Report With Systematic Literature Research

Abstract

BackgroundOrthotopic liver transplantation (OLT) is a potential curative treatment in patients with hepatocellular carcinoma (HCC); however, treatment options for recurrent HCC after OLT are limited. Immune checkpoint inhibitors, such as nivolumab, an inhibitor of programmed cell death protein 1, have been successfully used for metastatic HCC but data on safety of nivolumab following solid organ transplantation are limited.MethodsWe report a 53-year-old woman with HCC who was treated with OLT. After 2 years, HCC recurred. Initial treatment with sorafenib was discontinued due to side effects and disease progression. Progressive HCC in the lung and lymph nodes was subsequently treated with nivolumab. One week after the first nivolumab dose, rapid progressive liver dysfunction was noted. Liver biopsy revealed severe cellular graft rejection prompting treatment with intravenous steroids and tacrolimus. Liver function continued to decline, leading to severe coagulopathy. The patient succumbed to intracranial hemorrhage.ResultsA systematic PubMed search revealed 29 cases treated with a checkpoint inhibitor following solid organ transplantation. Loss of graft was described in 4 (36%) of 11 cases with OLT and in 7 (54%) of 13 cases after kidney transplantation. However, cases with favorable outcome were also described. Eighteen cases with adverse events were identified upon searching the World Health Organization database VigiBase, including 2 cases with fatal outcome in liver transplant recipients due to graft loss.ConclusionExperience with checkpoint inhibitors in solid organ transplant recipients is limited. Published cases so far suggest severe risks for graft loss as high as 36% to 54%.

Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient?

“…In 1 review, 3 of 4 liver transplant recipients aged 14 to 53 years who received nivolumab for recurrent HCC died within 5 weeks of treatment because of what was described as combined cellular and antibody-mediated rejection. 16 Other reviews have described similar concerning outcomes with the use of ICIs after solid organ transplant. [9][10][11]17 Thus, although the rate of allorejection is not well defined in large-scale clinical trials, this and other cases highlight the need for extreme caution surrounding ICI use in the peritransplant or posttransplant setting.…”

“…There have been recent case reports of patients with recurrent HCC after liver transplant receiving treatment with nivolumab and sustaining severe alloimmune injury that was, in many cases, fatal. In 1 review, 3 of 4 liver transplant recipients aged 14 to 53 years who received nivolumab for recurrent HCC died within 5 weeks of treatment because of what was described as combined cellular and antibody‐mediated rejection . Other reviews have described similar concerning outcomes with the use of ICIs after solid organ transplant .…”

Liver transplantation for hepatocellular carcinoma: Management after the transplant

“…[166][167][168][169][170][171][172] There has only been one small case series from the Mayo Clinic on their single-center experience of PD-1 inhibitor therapy in seven liver transplant recipients, six with HCC and one with metastatic melanoma. There is also one multicenter retrospective series demon- kidney, heart, and corneal transplants, for several tumor types including HCC, melanoma, and non-small cell lung cancer.…”

“…These reports have been in liver, kidney, heart, and corneal transplants, for several tumor types including HCC, melanoma, and non-small cell lung cancer. [166][167][168][169][170][171][172] There has only been one small case series from the Mayo Clinic on their single-center experience of PD-1 inhibitor therapy in seven liver transplant recipients, six with HCC and one with metastatic melanoma. 170 Overall, the reported graft rejection rates in the literature have ranged from 25%-54%, with median time to graft rejection 8-19 days after initiation of therapy.…”

“…170 Overall, the reported graft rejection rates in the literature have ranged from 25%-54%, with median time to graft rejection 8-19 days after initiation of therapy. 168,172 Several reports have detailed successful treatment of graft rejection with steroids, mycophenolate mofetil, and antithymocyte globulin, but there have also been several reports of rapid graft failure and death from severe allograft rejection. Although there are reports of tumor response in transplant recipients with immune checkpoint inhibitors, it seems that the response rates are lower than that seen in nontransplant patients.…”