Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma

Abstract

Although checkpoint inhibitor therapies have demonstrated significant efficacy in many malignancies, they have not been well studied in patients with a history of solid organ transplant. We describe two patients with recurrent, refractory, and progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation who received programmed cell death protein 1 (PD-1) inhibitor, nivolumab, on a patient access, off-label basis. Both rapidly developed irreversible acute liver rejection shortly after starting therapy, and ultimately died. While checkpoint inhibitors clearly have tremendous potential as a targeted therapy, they should be avoided or used with extreme caution in the context of an organ transplant.

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 . Other reviews have described similar concerning outcomes with the use of ICIs after solid organ transplant . 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.…”

“…Since 2017, there have been several reports of the use of ICIs, such as nivolumab, in solid organ transplant recipients as an adjuvant therapy for recurrent HCC or melanoma. Many of these reports describe a severe and often fatal alloimmune injury, even when the drug was introduced years after transplant . We present in this case report the first published use of nivolumab in the pretransplant setting for HCC.…”

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.…”

Immune checkpoint inhibitors in the management of malignancies in transplant recipients

“…Conversely, 8 out of 15 cases had graft rejection and loss where PD-1 inhibitors are used either as a monotherapy or in sequence 6 7 13 14 17 19 28–35. As seen in table 1, two liver transplant patients treated with nivolumab underwent fatal organ rejection,34 but preemptive glucocorticoids might prevent the onset of rejection 32. As mentioned above, using PD-1 inhibitors is associated with a high risk of transplant rejection which contradicts their usage especially in life-dependent transplants 36…”

“…Anyway, it has been shown that higher PD-1 expression on T-cells is associated with an enhanced risk of rejection 41. Liver transplant patients showed both cellular and antibody-mediated rejection following anti-PD1 inhibitor therapy and also the grafts expressed PD-L1 implicating its role in the rejection 34. Finally, it is also important to consider the consequences of graft rejection, for example, in the postrenal transplant setting, there is the option for haemodialysis as rescue,14 whereas it is possible that immunotherapy in other solid organ transplant patients like heart, liver, lung is potentially more dangerous as there is no 'rescue' option such as haemodialysis.…”