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Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.

ABSTRACT: For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-specific mortality, and all-cause mortality, adjusting for recipient ethnicity, calendar year of transplant, total tumor volume, alpha-fetoprotein, transplant center size, use of interleukin 2 induction therapy, and allocated and calculated Model for End-Stage Liver Disease score. We performed stratified analyses among recipients who met Milan criteria, among those without renal failure, among those with deceased liver donors, by age at transplantation, and by tumor size. Among the 3936 included HCC LTs, 234 (6%) were SRL users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in SRL users and nonusers (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.73-1.39). HCC recurrence and cancer-specific mortality rates appeared lower in SRL users, but associations were not statistically significant (recurrence aHR, 0.86; 95% CI, 0.45-1.65; cancer-specific mortality aHR, 0.80; 95% CI, 0.43-1.50). Among recipients >55 years old, associations were suggestive of better outcomes for SRL users (all-cause mortality aHR, 0.62; 95% CI, 0.38-1.01; recurrence aHR, 0.52; 95% CI, 0.19-1.44; cancer-specific mortality aHR, 0.34; 95% CI, 0.11-1.09), whereas among recipients ?55 years old, SRL users had worse outcomes (all-cause mortality aHR, 1.76; 95% CI, 1.12-2.75; recurrence aHR, 1.49; 95% CI, 0.62-3.61; cancer-specific mortality aHR, 1.54; 95% CI, 0.71-3.32). In conclusion, among HCC liver recipients overall, SRL did not appear beneficial in reducing all-cause mortality. However, there were suggestions of reductions in recurrence and cancer-specific mortality, and effects appeared to be modified by age at transplantation. Liver Transplantation 22 627-634 2016 AASLD.

SUBMITTER: Yanik EL

PROVIDER: S-EPMC4846564 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.

Yanik Elizabeth L EL Chinnakotla Srinath S Gustafson Sally K SK Snyder Jon J JJ Israni Ajay K AK Segev Dorry L DL Engels Eric A EA

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20160501 5

For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-speci ...[more]

PMID: 26784951

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Project description:Background and aimsAs conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.Approach and resultsWe performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group.ConclusionsThis study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

Project description:ImportanceMedian survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus.ObjectivesTo compare survival between patients receiving sirolimus?plus?tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival.Design, setting, and participantsThis cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance.ExposuresCell cycle inhibitor maintenance therapies, including sirolimus (n?=?219), mycophenolate mofetil (n?=?5782), mycophenolate sodium (n?=?408), azathioprine (n?=?2556), and concurrent sirolimus plus mycophenolate mofetil (n?=?54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared.Main outcomes and measuresSurvival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes.ResultsAmong this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus?plus?tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR],?0.71; 95% CI, 0.56-0.89; P?=?.003). Chronic rejection incidence (aHR,?0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR,?0.52; 95% CI, 0.31-0.81) were lower with sirolimus?plus?tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR,?1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR,?0.95; 95% CI, 0.77-1.17), and azathioprine?plus?tacrolimus (aHR,?0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus?plus?tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR,?0.48; 95% CI, 0.31-0.76; P?=?.002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]).Conclusions and relevanceSirolimus?plus?tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus?plus?tacrolimus was associated with maximal survival.

Project description:The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

Project description:Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ? 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion.TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal.

Dataset Information

Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.

Publications

Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.

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