Transplant rejections associated with immune checkpoint inhibitors: A pharmacovigilance study and systematic literature review.

Background: Solid organ transplant recipients are at increased risk of cancer due to long-term immunosuppression. Immune-checkpoint inhibitors (ICI) showed clinical benefits but increased risk of transplant rejection. Our work aims to assess the main features of reported rejection events.
Methods: A disproportionality analysis of the World Health Organisation pharmacovigilance database, VigiBase, to identify drugs associated with rejection events. The estimate of this analysis is the information component for which the lower end of the 95% credibility interval (IC ₀₂₅ ) indicates significance when positive. We combined a systematic literature review of case reports to obtain additional information regarding treatment management and histopathological findings.
Results: A total of 96 reports of transplant rejections following ICI were included, including kidney (n = 65), liver (n = 23), cornea (n = 2) and heart (n = 5). The main indication reported for ICI was malignant melanoma (39/89, 43.8%). The time to onset between first ICI administration and rejection was 21 [interquartile range: 13; 56] days. Kidney transplant rejection was associated with nivolumab (IC ₀₂₅  = 1.32), pembrolizumab (IC ₀₂₅  = 1.17) and ipilimumab (IC ₀₂₅  = 0.33); while liver transplant rejection was mostly over-reported with nivolumab (IC ₀₂₅  = 1.95). Overall, anti-PD-1 and anti-PD-L1 were more involved than anti-CTLA-4 drugs (93.0% versus 7.0%). Subsequent mortality was 36.5% and involved liver-transplant recipients more than other organ recipients (p < 0.0001). When performed, all biopsies reported acute cellular rejections, but only a few showed concomitant antibody-mediated lesions (6/28, 21.4%). Management mainly consisted in intravenous corticosteroid boluses and ICI cessation.
Conclusion: ICI-associated transplant rejections were mostly reported in kidney and liver transplant recipients. Rejections were T-cell mediated with low participation of humoral response.
Competing Interests: Conflict of interest statement The authors declare the following financial int erests/personal relationships that may be considered as potential competing interests: JJM received fees from Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron, and is supported by R01 HL141466. JES has participated to BMS advisory boards. Other authors declare no competing interests.
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