Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis

Mohammad Saeid Rezaee-Zavareh; Yee Hui Yeo; Tielong Wang; Zhiyong Guo; Parissa Tabrizian; Stephen C Ward; Fatma Barakat; Tarek I Hassanein; Shravan Dave; Veeral Ajmera; Sherrie Bhoori; Vincenzo Mazzaferro; David M H Chascsa; Margaret C Liu; Elizabeth S Aby; John R Lake; Miguel Sogbe; Bruno Sangro; Maen Abdelrahim; Abdullah Esmail; Andreas Schmiderer; Yasmina Chouik; Mark Rudolph; Davendra Sohal; Heloise Giudicelli; Manon Allaire; Mehmet Akce; Jessica Guadagno; Clara Y Tow; Hatef Massoumi; Paolo De Simone; Elise Kang; Robyn D Gartrell; Mercedes Martinez; Ricardo Paz-Fumagalli; Beau B Toskich; Nguyen H Tran; Gabriela Azevedo Solino; Dra Mariana Poltronieri Pacheco; Richard S Kalman; Vatche G Agopian; Neil Mehta; Neehar D Parikh; Amit G Singal; Ju Dong Yang

doi:10.1016/j.jhep.2024.06.042

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis

J Hepatol. 2025 Jan;82(1):107-119. doi: 10.1016/j.jhep.2024.06.042. Epub 2024 Jul 10.

Authors

Mohammad Saeid Rezaee-Zavareh¹, Yee Hui Yeo², Tielong Wang³, Zhiyong Guo³, Parissa Tabrizian⁴, Stephen C Ward⁵, Fatma Barakat⁶, Tarek I Hassanein⁶, Shravan Dave⁷, Veeral Ajmera⁷, Sherrie Bhoori⁸, Vincenzo Mazzaferro⁹, David M H Chascsa¹⁰, Margaret C Liu¹¹, Elizabeth S Aby¹², John R Lake¹², Miguel Sogbe¹³, Bruno Sangro¹³, Maen Abdelrahim¹⁴, Abdullah Esmail¹⁵, Andreas Schmiderer¹⁶, Yasmina Chouik¹⁷, Mark Rudolph¹⁸, Davendra Sohal¹⁸, Heloise Giudicelli¹⁹, Manon Allaire²⁰, Mehmet Akce²¹, Jessica Guadagno²², Clara Y Tow²³, Hatef Massoumi²⁴, Paolo De Simone²⁵, Elise Kang²⁶, Robyn D Gartrell²⁷, Mercedes Martinez²⁸, Ricardo Paz-Fumagalli²⁹, Beau B Toskich³⁰, Nguyen H Tran³¹, Gabriela Azevedo Solino³², Dra Mariana Poltronieri Pacheco³³, Richard S Kalman³⁴, Vatche G Agopian³⁵, Neil Mehta³⁶, Neehar D Parikh³⁷, Amit G Singal³⁸, Ju Dong Yang³⁹

Affiliations

¹ Middle East Liver Diseases Center, Tehran 1417935840, Iran.
² Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA.
³ Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China.
⁴ Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY, USA.
⁵ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Southern California Liver Centers, 131 Orange Avenue, Suite 101, Coronado, CA, 92118, USA.
⁷ Division of Gastroenterology & Hepatology, Department of Medicine, University of California, San Diego, La Jolla CA, USA.
⁸ HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
⁹ HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Department of Oncology, and Hemato-Oncology University of Milan, Milan, Italy.
¹⁰ Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA; Transplant Center, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
¹¹ Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
¹² Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA.
¹³ Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain.
¹⁴ Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Internal Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
¹⁵ Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA.
¹⁶ Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
¹⁷ Cancer Research Center of Lyon (CRCL), INSERM U1052, Centre National de la Recherche Scientifique UMR5286, Lyon, France; Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
¹⁸ Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
¹⁹ AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France.
²⁰ AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France; INSERM UMR 1138, Centre de recherche des Cordeliers, 75006 Paris, France.
²¹ Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA.
²² Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
²³ Division of Hepatology, Montefiore Medical Center, Bronx, New York; Albert Einstein College of Medicine, Bronx, NY, USA.
²⁴ Division of Hepatology, Northwell 261 East 78th Street, Floor 4, New York, NY 10075, USA.
²⁵ Hepatobiliary Surgery and liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, Pisa, 56124, Italy.
²⁶ Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA.
²⁷ Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA; Department of Oncology, Division of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁸ Department of Pediatrics. Vagelos College of Physician and Surgeons. Columbia University, USA.
²⁹ Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.
³⁰ Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
³¹ Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
³² Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Internal Medicine - Vitória/ES - Brazil.
³³ Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Gastroenterology and Hepatology - Vitória/ES - Brazil.
³⁴ Division of Hepatology, Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania, USA.
³⁵ The Dumont-University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
³⁶ Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, USA.
³⁷ Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
³⁸ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.
³⁹ Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA. Electronic address: [email protected].

PMID: 38996924
PMCID: PMC11655254 (available on 2025-01-01)
DOI: 10.1016/j.jhep.2024.06.042

Abstract

Background & aims: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes.

Methods: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection.

Results: Among 91 eligible patients, with a median (IQR) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years 0.72, 95% CI 0.53-0.99, p = 0.044) and ICI washout time (aHR per 1 week 0.92, 95% CI 0.86-0.99, p = 0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p = 0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8] vs. 8.0 [9.0]; p = 0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p = 0.032).

Conclusion: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations.

Impact and implications: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitor use prior to liver transplantation suggest acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without immune checkpoint inhibitor exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies.

Keywords: Graft Rejection; Hepatocellular Carcinoma; Immune Checkpoint Inhibitors; Liver Neoplasms; Liver Transplantation; Recurrence.

Publication types

Systematic Review
Meta-Analysis

MeSH terms

Carcinoma, Hepatocellular* / mortality
Carcinoma, Hepatocellular* / surgery
Female
Graft Rejection* / immunology
Graft Rejection* / prevention & control
Humans
Immune Checkpoint Inhibitors* / adverse effects
Immune Checkpoint Inhibitors* / therapeutic use
Liver Neoplasms* / mortality
Liver Neoplasms* / surgery
Liver Transplantation* / adverse effects
Liver Transplantation* / methods
Male
Middle Aged
Neoplasm Recurrence, Local / epidemiology
Risk Factors
Treatment Outcome

Substances

Immune Checkpoint Inhibitors

Grants and funding

K23 MD017217/MD/NIMHD NIH HHS/United States