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Wassmer CH, El Hajji S, Papazarkadas X, Compagnon P, Tabrizian P, Lacotte S, Toso C. Immunotherapy and Liver Transplantation: A Narrative Review of Basic and Clinical Data. Cancers (Basel) 2023; 15:4574. [PMID: 37760542 PMCID: PMC10526934 DOI: 10.3390/cancers15184574] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have improved the management of patients with intermediate- and advanced-stage HCC, even making some of them potential candidates for liver transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize the key basic impact of immune checkpoints on HCC and liver transplantation. We analyze the available case reports and case series on the use of ICI therapy prior to and after liver transplantation. A three-month washout period is desirable between ICI therapy and liver transplantation to reduce the risk of acute rejection. Whenever possible, ICIs should be avoided after liver transplantation, and especially so early after a transplant. Globally, more robust prospective data in the field are required.
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Affiliation(s)
- Charles-Henri Wassmer
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Sofia El Hajji
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Xenofon Papazarkadas
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Philippe Compagnon
- Division of Transplantation, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland;
| | - Parissa Tabrizian
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA;
| | - Stéphanie Lacotte
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
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Cui X, Yan C, Xu Y, Li D, Guo M, Sun L, Zhu Z. Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system. Cancer Med 2023; 12:5181-5194. [PMID: 36504294 PMCID: PMC10028127 DOI: 10.1002/cam4.5394] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/13/2022] [Accepted: 10/21/2022] [Indexed: 12/14/2022] Open
Abstract
AIM This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). METHODS Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. RESULTS A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025 : 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. CONCLUSION Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.
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Affiliation(s)
- Xiangli Cui
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cilin Yan
- School of Automation Science and Electrical Engineering, Beihang University, Beijing, China
| | - Ye Xu
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dandan Li
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingxing Guo
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Liying Sun
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhijun Zhu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Abboud K, Umoru G, Esmail A, Abudayyeh A, Murakami N, Al-Shamsi HO, Javle M, Saharia A, Connor AA, Kodali S, Ghobrial RM, Abdelrahim M. Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology. Cancers (Basel) 2023; 15:1433. [PMID: 36900226 PMCID: PMC10000896 DOI: 10.3390/cancers15051433] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.
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Affiliation(s)
- Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Humaid O. Al-Shamsi
- Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ashish Saharia
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Ashton A. Connor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Sudha Kodali
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Rafik M. Ghobrial
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist 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 14853, USA
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Ouranos K, Chatziioannou A, Goulis I, Sinakos E. Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation. World J Transplant 2022; 12:331-346. [PMID: 36437845 PMCID: PMC9693898 DOI: 10.5500/wjt.v12.i11.331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to published clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab–bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of rejection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we summarize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.
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Affiliation(s)
- Konstantinos Ouranos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Anthi Chatziioannou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Wu J, Huang J, Zhu J, He Z, Chen M, Gao S, Liang D, Yu X, Lu C. Immune checkpoint inhibitors increase the risk of kidney transplant rejection: a real-world pharmacovigilance study. Expert Opin Drug Saf 2022; 22:231-235. [PMID: 35929998 DOI: 10.1080/14740338.2022.2110234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Kidney transplant recipients with cancer are at higher risk of kidney transplant rejection (KTR), and the safety of immune checkpoint inhibitors (ICIs) is unclear. The present study investigates the relationship between ICIs and KTR using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS Case reports of KTR inducted by ICIs in FAERS from January 1, 2011, to June 30, 2021, were collected, and a disproportionate analysis was performed to assess the correlation between ICIs and KTR. RESULTS A total of 99 cases of ICI-related KTR were reported in the FAERS database. Most of them were male patients (n=63, 84.0%), and more than half of patients suffered from malignant melanoma (n=46, 52.9%). The median onset time after the medication was 22 days, the withdrawal rates of ICIs were 78.0%, and the overall death rate was 29.3%. In general, there was a significant relevance between ICIs and KTR (ROR=3.92[3.21-4.79] IC025=1.56), of which PD-1 was the most prominent (n=81 ROR=5.26[4.22-6.57] IC025=1.86). CONCLUSIONS ICIs may increase the risk of KTR in organ transplant recipients with cancer.
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Affiliation(s)
- Junyan Wu
- School of Pharmacy, Guangdong Medical University.,Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | | | - Jianhong Zhu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | - Zhichao He
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | | | - Siyuan Gao
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | - Dan Liang
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | - Xiaoxia Yu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
| | - Chengyu Lu
- School of Pharmacy, Guangdong Medical University
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Vulasala SSR, Onteddu NK, Kumar SP, Lall C, Bhosale P, Virarkar MK. Advances and effectiveness of the immunotherapy after liver transplantation. World J Gastrointest Surg 2022; 14:629-631. [PMID: 35979423 PMCID: PMC9258234 DOI: 10.4240/wjgs.v14.i6.629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Transplant recipients usually have increased chances of graft rejection and graft vs host disease, requiring chronic immunosuppressive therapy. Nonetheless, long-term immunosuppression risks malignancies such as skin cancer, lymphoma, and Kaposi sarcoma. However, there are very few studies that included solid organ transplant recipients while studying the efficacy of immunotherapy. "Immunotherapy after liver transplantation: Where are we now?" is a study, where the authors described the mechanism of action and outcomes of immune checkpoint inhibitors specific to liver transplant recipients. The authors reported the graft rejection rates and the factors contributing to the rejection in the liver transplant recipients.
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Affiliation(s)
- Sai Swarupa R Vulasala
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Nirmal K Onteddu
- Department of Internal Medicine, Flowers Hospital, Dothan, AL 36305, United States
| | - Sindhu P Kumar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Chandana Lall
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Priya Bhosale
- Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Mayur K Virarkar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
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7
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021; 13:1267-1278. [PMID: 34754394 PMCID: PMC8554723 DOI: 10.4240/wjgs.v13.i10.1267] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/25/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is limited evidence on the safety of immunotherapy use after liver transplantation and its efficacy in treating post-liver transplant hepatocellular carcinoma (HCC) recurrence.
AIM To assess the safety of immunotherapy after liver transplant and its efficacy in treating post-liver transplant HCC recurrence.
METHODS A literature review was performed to identify patients with prior liver transplantation and subsequent immunotherapy. We reviewed the rejection rate and risk factors of rejection. In patients treated for HCC, the oncological outcomes were evaluated including objective response rate, progression-free survival (PFS), and overall survival (OS).
RESULTS We identified 25 patients from 16 publications and 3 patients from our institutional database (total n = 28). The rejection rate was 32% (n = 9). Early mortality occurred in 21% (n = 6) and was mostly related to acute rejection (18%, n = 5). Patients who developed acute rejection were given immunotherapy earlier after transplantation (median 2.9 years vs 5.3 years, P = 0.02) and their graft biopsies might be more frequently programmed death ligand-1-positive (100% vs 33%, P = 0.053). Their PFS (1.0 ± 0.1 mo vs 3.5 ± 1.1 mo, P = 0.02) and OS (1.0 ± 0.1 mo vs 19.2 ± 5.5 mo, P = 0.001) compared inferiorly to patients without rejection. Among the 19 patients treated for HCC, the rejection rate was 32% (n = 6) and the overall objective response rate was 11%. The median PFS and OS were 2.5 ± 1.0 mo and 7.3 ± 2.7 mo after immunotherapy.
CONCLUSION Rejection risk is the major obstacle to immunotherapy use in liver transplant recipients. Further studies on the potential risk factors of rejection are warranted.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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8
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021. [DOI: 10.4240/wjgs.v13.i10.1266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Cosmai L, Porta C, Foramitti M, Rizzo M, Gallieni M. The basics of onco-nephrology in the renal clinic. J Nephrol 2021; 33:1143-1149. [PMID: 33242211 DOI: 10.1007/s40620-020-00922-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Onconephrology is a rapidly evolving subspecialty that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well-defined multidisciplinary management by a dedicated team. Patients with cancer frequently suffer from concurrent chronic kidney disease (CKD), with a prevalence ranging from 12% to 53% at the time of cancer diagnosis. Taking into account the incidence of cancer and the prevalence of CKD in the Italian population, we estimate that about 44,000 patients suffered from both diseases in 2020. Since there is an increasing necessity to address the needs of this population in dedicated outpatient clinics, it is critical to highlight some basic characteristics and to suggest areas of development. Our experience in the nephrological management of cancer patients clearly suggests the need to implement dedicated multidisciplinary teams and to create onconephrology clinics (at least within larger, referral, hospitals). Furthermore, it must be kept in mind that not only is CKD common in cancer patients, but also that the concomitant presence of these two conditions too often excludes cancer patients from clinical trials, thus limiting their access to therapies that could potentially improve their outcomes. Indeed, the Renal Insufficiency and Cancer Medications (IRMA) study found that cancer patients with CKD or on dialysis are often undertreated, or are exposed to either ineffective or toxic anticancer agents. Finally, the aim of this article is to initiate a debate about what an onconephrology outpatient clinic might look like, in order to ensure the highest quality of care for this growing patient population.
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Affiliation(s)
- Laura Cosmai
- Nephrology and Dialysis Unit, Onco-Nephrology Outpatient Clinic, ASST Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Piazzale Principessa Clotilde, 320121, Milan, Italy.
| | - Camillo Porta
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari 'A. Moro, Bari, Italy.,Policlinico Consorziale di Bari, Bari, Italy
| | - Marina Foramitti
- Division of Nephrology and Dialysis, ASST Cremona, Cremona, Italy
| | - Mimma Rizzo
- Division of Translational Oncology, IRCCS Istituti Clinici Scientifici 'Maugeri', Pavia, Italy
| | - Maurizio Gallieni
- Nephrology and Dialysis Unit, Onco-Nephrology Outpatient Clinic, ASST Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Piazzale Principessa Clotilde, 320121, Milan, Italy.,Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy
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10
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Freeman SC, Satish M, Walters RW. Comorbidity burden on receipt of adjuvant immunotherapy and survival in patients with stage III melanoma: an analysis of the National Cancer Database. Int J Dermatol 2020; 59:1381-1390. [PMID: 32592609 DOI: 10.1111/ijd.15019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 04/09/2020] [Accepted: 05/27/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Comorbidity burden is associated with development of cancer, stage at diagnosis, and treatment outcomes. We evaluated the association between comorbidity burden, receipt of adjuvant immunotherapy, and survival in patients with stage III melanoma. METHODS Using the National Cancer Database, we identified 16,906 patients with stage III melanoma who underwent surgery of the primary site. Outcomes included receipt of adjuvant immunotherapy and overall survival; independent variables included Charlson/Deyo comorbidity index (CDI) and receipt of adjuvant immunotherapy. RESULTS Patients with CDI scores of two or more averaged 30.0% and 30.9% lower adjusted odds of receiving adjuvant immunotherapy relative to patients with a CDI score of zero or one, respectively (P = 0.001 and 0.002, respectively). Longer survival was associated with lower CDI scores (all P < 0.001) and receipt of adjuvant immunotherapy (P < 0.001). Patients who received adjuvant immunotherapy averaged 16.0% lower adjusted risk of death compared to patients who did not (P < 0.001), which was constant within all CDI cohorts. Patients with a CDI score of two or more averaged 53.4% and 39.1% higher adjusted risk of death relative to patients with a CDI score of zero or one (both P < 0.001). CONCLUSION Greater comorbidity burden was associated with lower receipt of adjuvant immunotherapy; however, adjuvant immunotherapy provided similar survival benefit for patients' irrespective comorbidity burden. Our findings suggest that patients with stage III melanoma who have a greater comorbidity burden may benefit from adjuvant immunotherapy but should not replace careful patient selection by the clinician.
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Affiliation(s)
| | - Mohan Satish
- Creighton University School of Medicine, Omaha, NE, USA
| | - Ryan W Walters
- Division of Clinical Research and Evaluative Sciences, Creighton University Department of Medicine, Omaha, NE, USA
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11
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Hu B, Yang XB, Sang XT. Liver graft rejection following immune checkpoint inhibitors treatment: a review. Med Oncol 2019; 36:94. [DOI: 10.1007/s12032-019-1316-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023]
Abstract
Abstract
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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12
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Abdel-Wahab N, Safa H, Abudayyeh A, Johnson DH, Trinh VA, Zobniw CM, Lin H, Wong MK, Abdelrahim M, Gaber AO, Suarez-Almazor ME, Diab A. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer 2019; 7:106. [PMID: 30992053 PMCID: PMC6469201 DOI: 10.1186/s40425-019-0585-1] [Citation(s) in RCA: 198] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/01/2019] [Indexed: 02/06/2023] Open
Abstract
Background Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. Methods Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. Results Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14–79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92–32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3–22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. Conclusions SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0585-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Noha Abdel-Wahab
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt
| | - Houssein Safa
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel H Johnson
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Van Anh Trinh
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chrystia M Zobniw
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heather Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael K Wong
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Maria E Suarez-Almazor
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Adi Diab
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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13
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Affiliation(s)
- Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York
| | - Rimda Wanchoo
- Division of Kidney Diseases and Hypertension, Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York
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14
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Cosmai L, Porta C, Perazella MA, Launay-Vacher V, Rosner MH, Jhaveri KD, Floris M, Pani A, Teuma C, Szczylik CA, Gallieni M. Opening an onconephrology clinic: recommendations and basic requirements. Nephrol Dial Transplant 2018; 33:1503-1510. [DOI: 10.1093/ndt/gfy188] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Indexed: 12/26/2022] Open
Affiliation(s)
- Laura Cosmai
- Onco-Nephrology Clinic, Nephrology and Dialysis Unit, San Carlo Borromeo Hospital, ASST Santi Carlo e Paolo, Milan, Italy
| | - Camillo Porta
- Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy
| | - Mark A Perazella
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven and Veterans Administration Medical Center, West Haven, CT, USA
| | | | - Mitchell H Rosner
- Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Matteo Floris
- Nephrology and Dialysis Unit, G. Brotzu Hospital, Cagliari, Italy
| | - Antonello Pani
- Nephrology and Dialysis Unit, G. Brotzu Hospital, Cagliari, Italy
| | - Cécile Teuma
- Nephrology Department, Centre Hospitalier Lyon Sud Pierre-Bénite, France
| | - Cèzary A Szczylik
- Department of Oncology, University of Warsaw School of Medicine, Warsaw, Poland
| | - Maurizio Gallieni
- Onco-Nephrology Clinic, Nephrology and Dialysis Unit, San Carlo Borromeo Hospital, ASST Santi Carlo e Paolo, Milan, Italy
- Department of Clinical and Biomedical Sciences “Luigi Sacco”, University of Milan, Milan, Italy
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15
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Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature. J Immunother 2018; 40:341-344. [PMID: 29028789 DOI: 10.1097/cji.0000000000000188] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.
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16
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Affiliation(s)
- H Kaan Akturk
- University of Colorado School of Medicine, Aurora, CO
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17
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Friend BD, Venick RS, McDiarmid SV, Zhou X, Naini B, Wang H, Farmer DG, Busuttil RW, Federman N. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr Blood Cancer 2017. [PMID: 28643391 DOI: 10.1002/pbc.26682] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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.
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Affiliation(s)
- Brian D Friend
- Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, California
| | - Robert S Venick
- Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, California
| | - Sue V McDiarmid
- Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, California
| | - Xiaoyan Zhou
- Department of Pathology, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Bita Naini
- Department of Pathology, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Hanlin Wang
- Department of Pathology, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Douglas G Farmer
- Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Ronald W Busuttil
- Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Noah Federman
- Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, California.,UCLA's Jonsson Comprehensive Cancer Center, Los Angeles, California.,Department of Orthopaedics, UCLA David Geffen School of Medicine, Los Angeles, California
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18
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Varkaris A, Lewis DW, Nugent FW. Preserved Liver Transplant After PD-1 Pathway Inhibitor for Hepatocellular Carcinoma. Am J Gastroenterol 2017; 112:1895-1896. [PMID: 29215617 DOI: 10.1038/ajg.2017.387] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Andreas Varkaris
- Department of General Internal Medicine, Lahey Clinic, Burlington, Massachusetts, USA.,TUFTS Medical School, TUFTS University, Boston, Massachusetts, USA.,Alexandra General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - David W Lewis
- Hepatobiliary Surgery and Liver Transplantation, Lahey Medical Center, Burlington, Massachusetts, USA
| | - Francis W Nugent
- Department of Oncology, Lahey Clinic, Burlington, Massachusetts, USA
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19
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Małyszko J, Kozlowski L, Kozłowska K, Małyszko M, Małyszko J. Cancer and the kidney: dangereoux liasons or price paid for the progress in medicine? Oncotarget 2017; 8:66601-66619. [PMID: 29029541 PMCID: PMC5630441 DOI: 10.18632/oncotarget.18094] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 04/23/2017] [Indexed: 01/10/2023] Open
Abstract
A long time ago, the links between renal disease and malignancy were observed, however, quite recently, their importance was recognized and 'new' subspecialty in nephrology, namely 'onconephrology' was established. In the XXI century, patients with malignancy make up the most growing number of the subjects seen for nephrology consult and/or critical care nephrology services. A plethora of renal problems may be found in patients with malignancy. They may influence not only their short-term outcomes but also the adequate therapy of the underlying oncological problem. Thus, all these kidney-related issues pose an important challenge for both specialities: oncology and nephrology. In the review a spectrum of acute and chronic renal injury caused by the malignancy is presented as well as the associations between renal disease and cancer. Assessment of kidney function and its importance in patients with malignancy is also discussed as medical oncologists should check the appropriate dose of chemotherapeutic drugs in relation to the actual renal function before prescribing them to the patients. Moreover, effects of kidney function on outcomes in oncology is presented. In addition, nephrology services should better understand both the biology of malignancy with its treatment to become a valuable part treating team to yield the best possible outcome. It is important for nephrology services to be acknowledged and to take an active participation in care of oncology patients.
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Affiliation(s)
- Jolanta Małyszko
- Second Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland
| | - Leszek Kozlowski
- Department of Oncological Surgery, Ministry of Interior Affairs, Bialystok, Poland
| | - Klaudia Kozłowska
- Second Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland
| | - Maciej Małyszko
- Second Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland
| | - Jacek Małyszko
- First Department of Nephrology and Transplantology with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland
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20
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Abstract
INTRODUCTION Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique. Areas covered: Herein we will profile nivolumab's efficacy and safety both as a combination therapy and a monotherapy and discuss the results of relevant clinical trials in this respect. Expert opinion: The future of immunotherapy in melanoma will evolve around the development of biomarkers, the refinement of criteria to define patterns of response and toxicity and the combination of current immunotherapies with existing and novel agents to maximise responses.
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Affiliation(s)
- Aine O'Reilly
- a Department of Renal and Melanoma , Royal Marsden Hospital , London , United Kingdom of Great Britain and Northern Ireland
| | - James Larkin
- a Department of Renal and Melanoma , Royal Marsden Hospital , London , United Kingdom of Great Britain and Northern Ireland
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