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Immunosuppression Withdrawal in Adult and Pediatric Liver Transplant Recipients What do we know? What do we not know? Where should we go? Sandy Feng, MD, PhD University of California San Francisco 11th Banff Meeting on Allograft Pathology
What do we know? • A (substantial) proportion of (highly) selected adult and pediatric liver transplant recipients can successfully withdraw from immunosuppression – the definition of operational tolerance • Historically, reports have described single center experiences rather than trials • Patients have been varied • Non-compliant • Contraindication to ongoing immunosuppression • Elective withdrawal • Success has typically been defined as maintaining normal allograft function for one year • Allograft function has been typically assessed by liver tests
What do we know? • Recently, clinical trials of immunosuppression withdrawal have been undertaken • Enrollment of a more homogeneous population • Defined algorithm for withdrawal • Typically accompanied by mechanistic studies to identify biomarker of operational tolerance • Some trials have attempted early withdrawal after induction with a depleting antibody preparation • Thymoglobulin • Alemtuzumab • Other trials have focused on stable long-term adult and pediatric recipients
Tolerance Induction Trials Alemtuzumab / Tacrolimus Thymoglobulin / Sirolimus Thymoglobulin / Tacrolimus
ITN024: Alemtuzumab / Tacrolimus MonotherapyOutcome of Immunosuppression Withdrawal • 27 enrolled • 10 initiated withdrawal
Thymoglobulin / Sirolimus Monotherapy Donckier et al., Transplantation 2009
Thymoglobulin / Sirolimus Monotherapy Outcome of Immunosuppression Withdrawal D246 D163 D280 D140 D206 D124 Donckier et al., Transplantation 2009
Thymoglobulin / Low Dose Tacrolimus Monotherapy vs. Standard Tacrolimus ATG 9mg/kg Tac 5 – 12 ng/mL Months 0 - 3 Tac 10–15ng/mL Months 0 - 3 Assess for IS withdrawal; 10 qualified Tac 7–12ng/mL Months 4 - 12 Benitez et al., AJT, 2010
Thymoglobulin / Low Dose Tacrolimus Monotherapy Acute Rejection Rates Benitez et al., AJT, 2010
Thymoglobulin / Low Dose Tacrolimus Monotherapy Acute Rejection Rates 1 2 3 4 5 6 7 8 9 10 Benitez et al., AJT, 2010
ITN030: Tacrolimus ± Mycophenolate Eligibility
Prospective Study of Immunosuppression Withdrawal 97 stable liver Recipient Stable liver function (TOL) 40 Immunosuppression withdrawal 6-9 months 6-9 months weaning 12 months follow-up >3 years 12 month follow-up Withdrawal Failure Rejection (Non-TOL) 57 Liver Transplantation Participating centers: Hospital Clinic Barcelona, University Tor Vergata Rome, University Hospitals Leuven • PBMC immunophenotyping • PBMC/Whole blood/Liver tissue gene expression
ITN029: Immunosuppression Withdrawal for Pediatric Parental Living Donor Liver Transplant Recipients Single arm, three center pilot trial of 20 patients Sandy Feng, M.D., Ph.D. Phil Rosenthal, M.D. John Roberts, M.D. Udeme Ekong, M.D., Ph.D. Estella Alonso, M.D. Peter Whitington, M.D. Steven Lobritto, M.D. Jean Emond, M.D.
12 of 20 Participants Met the Primary Endpoint:Off Immunosuppression for 30.0 – 50.7 Months
8 of 20 Participants Did Not Meet the Primary Endpoint I/E Violation During Withdrawal After Withdrawal
What do we NOT know? • Who are the appropriate patients to withdraw from immunosuppression? • Demographic factors • Clinical characteristics • Allograft histology • When should immunosuppression be withdrawn? • Minimize risk / maximize withdrawal • When should immunosuppression be re-initiated? • Development of alloantibodies • Allograft histology • Other parameters
Where do we go from here? • Rigorously designed, adequately powered clinical trials to answer critical questions • Sufficiently long follow-up to critically assess evolution of alloantibodies and allograft histology • Intensive effort to derive biomarker(s) of and / or mechanistic insight into operational tolerance • Demonstration that immunosuppression withdrawal is beneficial will be difficult and potentially impossible • Risk reduction will enhance equipoise in favor of withdrawal • Facilitate withdrawal earlier after transplantation
Where do we go from here? • Novel approaches to induce tolerance should be pursued in the liver transplant arena. • Chimerism approaches utilized in (Iiving donor) kidney transplantation are impractical and perhaps excessively toxic for the liver transplant population • Regulatory T cells may, however, offer the opportunity to modulate the allo-immune response. • Enhance frequency of tolerance • Accelerate the development of tolerance
Conclusions (1) • Immunosuppression withdrawal has been undertaken in both adult and children • Results have been particularly encouraging for stable, long-term recipients • Attempts at immunosuppression withdrawal early after transplantation, with or without an induction regimen have met with modest success • In the short term, immunosuppression withdrawal appears to be reasonably safe • Acute rejection has occurred frequently • Chronic rejection has occurred rarely • Allograft histology appears stable • Tolerance has been durable
Conclusions (2) • In spite of an intuitive appeal, there is no evidence that immunosuppression withdrawal is beneficial. • There is substantial concern regarding the long-term safety of withdrawal, particularly relating to allograft histology and the development of alloantibodies. • Therefore, current equipoise does not favor withdrawal for the majority of liver transplant recipients. • Future efforts must focus on • Mitigating short-term risk by identifying a biomarker predictive of operational tolerance • Studying long-term risk
Acknowledgements for ITN029 Site Coordinators • Sharon Blaschka • Therese Hess • Jonah Zaretsky • ITN TADA Group • Vicki Seyfert-Margolis • Deborah Phippard • Mark Mueller • Adam Asare • Jason (Zhugong) Liu • Mary Carmelle-Philogene • Zhong Gao • Larry Turka • A. Jake Demetris • ITN CTG • Nadia Tchao • Peter Sayre • Nariman Nasser • Ross Jamison • Doug Norman • Alberto Sanchez-Fueyo • Rho • David Ikle • Katie Poole • NIAID • Nancy Bridges • Melissa DePaulis