Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet?

Rammohan, Ashwin; Reddy, Mettu S.; Farouk, Mohammed; Vargese, Joy; Rela, Mohamed

doi:10.1002/hep.29575

Cited by 61 publications

(42 citation statements)

References 4 publications

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“…As of January 2019, 64 cases (including the present 2 cases) from 36 case series and case reports were found eligible for the present analysis (Table ) . The median age was 63.8 years (range 14–85) and 75% were males.…”

Section: Resultsmentioning

confidence: 99%

The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature

et al. 2020

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Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD‐1), programmed death‐ligand 1, or cytotoxic lymphocyte antigen‐4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD‐1 inhibitors, 20/42 (48%)—13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. Implications for Practice Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti‐programmed death‐ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.

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Section: Resultsmentioning

confidence: 99%

The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature

et al. 2020

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“…It remains to be investigated about the relationship between the dose of ICIs and liver graft rejection. As suggested in the currently available articles, most patients receiving LT have received ICIs at a dose of 3 mg/kg, and some of them have experienced graft rejection while others have not [44,55,56]. Ipilimumab at a dose of 5 mg/kg was once applied to 15 patients, in whom the objective response rate (ORR) was reported as 23%, and liver graft rejection was seen in 6 patients (including 1 acute and 5 chronic), indicating that increasing the antibody dose could enhance the efficacy, but more patients were susceptible to the risk of GVHD [57].…”

Section: The Dose and Administration Time Of Icismentioning

confidence: 99%

Liver graft rejection following immune checkpoint inhibitors treatment: a review

Yang

Sang

2019

Med Oncol

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Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.

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“…There have been some cases of successful use of ICIs other than nivolumab after transplant. 19 Given that these medications have similar mechanisms of action, we cannot clearly say whether one may have more risk than another; however, a recent systematic review indicates that nivolumab may pose a higher risk than others. 20 It is our opinion that organ transplant recipients undergo allograft biopsy to assess the degree of PD-L1 expression before the initiation of ICIs.…”

Section: Discussionmentioning

confidence: 99%

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

Nordness

Hamel

Godfrey

et al. 2020

American Journal of Transplantation

121

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Nivolumab is an immune checkpoint inhibitor (ICI) currently in phase 3 clinical trials for hepatocellular carcinoma. The safety of ICIs in recipients of organ allotransplant is unclear, and several reports of fatal alloimmune injury after posttransplant ICI use have been published. We present the first published case of nivolumab used in the pretransplant setting for HCC resulting in fatal acute hepatic necrosis in the immediate postoperative period from a profound immune reaction likely propagated by nivolumab. Further investigation and significant caution are needed in the evaluation of patients awaiting transplant who are receiving ICI therapy.

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Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet?

Cited by 61 publications

References 4 publications

The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature

The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature

Liver graft rejection following immune checkpoint inhibitors treatment: a review

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

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