Immunosuppression Withdrawal in Adult and Pediatric Liver Transplant Recipients What do we know?...
-
Upload
austin-copeland -
Category
Documents
-
view
215 -
download
1
Transcript of Immunosuppression Withdrawal in Adult and Pediatric Liver Transplant Recipients What do we know?...
![Page 1: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/1.jpg)
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
![Page 2: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/2.jpg)
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
![Page 3: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/3.jpg)
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
![Page 4: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/4.jpg)
Tolerance Induction Trials
Alemtuzumab / Tacrolimus
Thymoglobulin / Sirolimus
Thymoglobulin / Tacrolimus
![Page 5: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/5.jpg)
ITN024: Alemtuzumab / Tacrolimus Monotherapy
TxMonth
0 - 3
Month
4 - 12
Month
12 - 24
Corticosteroids
Alemtuzumab 30 mg days 0 & 4
Tacrolimus8 - 12 ng/mL
5 - 10 ng/mL
Withdrawal
![Page 6: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/6.jpg)
ITN024: Alemtuzumab / Tacrolimus MonotherapyOutcome of Immunosuppression Withdrawal
27 enrolled
10 initiated withdrawal
![Page 7: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/7.jpg)
Thymoglobulin / Sirolimus Monotherapy
Donckier et al., Transplantation 2009
TxMonth
1Month
2Month
3Month
4 - 6
CorticosteroidsDiscontinue by
end of Month 1
ATG3.75 mg/kg days 1-5
SRL 8-12 ng/mLWithdrawal to discontinue SRL between months 4 - 6
![Page 8: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/8.jpg)
Thymoglobulin / Sirolimus Monotherapy
Outcome of Immunosuppression Withdrawal
D140 D206 D124
D280 D246 D163
Donckier et al., Transplantation 2009
![Page 9: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/9.jpg)
Thymoglobulin / Low Dose Tacrolimus Monotherapy vs. Standard Tacrolimus
ATG 9mg/kgTac 5 – 12 ng/mL
Months 0 - 3
Assess for IS withdrawal;10 qualified
Tac 10–15ng/mL Months 0 - 3
Tac 7–12ng/mL Months 4 - 12
Benitez et al., AJT, 2010
![Page 10: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/10.jpg)
Thymoglobulin / Low Dose Tacrolimus Monotherapy Acute Rejection Rates
ATG-F Control P value
Intention-to-treat analysis
Overall 67% 31% 0.033
Months 0 - 3 52% 25% 0.09
Months 4 - 12 62% 6% 0.001
Ad hoc / per protocol analysis
Overall 83% 31% 0.008
Months 0 - 3 50% 23% ns
Months 4 - 12 83% 8% < 0.001
Benitez et al., AJT, 2010
![Page 11: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/11.jpg)
Benitez et al., AJT, 2010
Thymoglobulin / Low Dose Tacrolimus Monotherapy Acute Rejection Rates
1
23456789
10
![Page 12: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/12.jpg)
Spontaneous Operational Tolerance
![Page 13: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/13.jpg)
ITN030: Tacrolimus ± Mycophenolate
Month
1 - 3
Month
4 - 12
Month
13 - 24Withdrawal
Corticosteroidsd/c by end of month 3
Tacrolimus8 - 12 ng/mL
5 - 10 ng/mL
Withdrawal
MMFIf started, d/c 3 mos before withdrawal
Eligibility
![Page 14: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/14.jpg)
Prospective Study of Immunosuppression Withdrawal
Immunosuppression withdrawal
6-9 months
Withdrawal FailureRejection(Non-TOL)
57
Stable liver function
(TOL)40
97 stable liver Recipient
>3 years
Liver Transplantation
12 month follow-up
•PBMC immunophenotyping•PBMC/Whole blood/Liver tissue gene expression
6-9 months weaning
12 months follow-up
Participating centers: Hospital Clinic Barcelona, University Tor Vergata Rome, University Hospitals Leuven
![Page 15: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/15.jpg)
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.
![Page 16: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/16.jpg)
12 of 20 Participants Met the Primary Endpoint:Off Immunosuppression for 30.0 – 50.7 Months
![Page 17: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/17.jpg)
8 of 20 Participants Did Not Meet the Primary Endpoint
I/E Violation
DuringWithdrawal
AfterWithdrawal
![Page 18: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/18.jpg)
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
![Page 19: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/19.jpg)
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
![Page 20: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/20.jpg)
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
![Page 21: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/21.jpg)
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
![Page 22: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/22.jpg)
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
![Page 23: 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,](https://reader030.fdocuments.us/reader030/viewer/2022032803/56649e315503460f94b21ef1/html5/thumbnails/23.jpg)
Acknowledgements for ITN029
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
Site Coordinators Sharon Blaschka Therese Hess Jonah Zaretsky
ITN CTG Nadia Tchao Peter Sayre Nariman Nasser Ross Jamison Doug Norman
NIAID Nancy Bridges Melissa DePaulis
Rho David Ikle Katie Poole
Alberto Sanchez-Fueyo