Transcript Weaning of immunosuppression in adult and pediatric liver allograft

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 Monotherapy
Month
Tx
0-3
Month
4 - 12
Month
12 - 24
Corticosteroids
Alemtuzumab
30 mg
days 0 & 4
Tacrolimus
8 - 12
ng/mL
5 - 10
ng/mL
Withdrawal
ITN024: Alemtuzumab / Tacrolimus Monotherapy
Outcome of Immunosuppression Withdrawal
 27 enrolled
 10 initiated
withdrawal
Thymoglobulin / Sirolimus Monotherapy
Tx
Corticosteroids
ATG
SRL
Month
1
Month Month
2
3
Month
4-6
Discontinue by
end of Month 1
3.75 mg/kg
days 1-5
8-12 ng/mL
Donckier et al., Transplantation 2009
Withdrawal to discontinue
SRL between months 4 - 6
Thymoglobulin / Sirolimus Monotherapy
Outcome of Immunosuppression Withdrawal
D280
D140
Donckier et al., Transplantation 2009
D246
D206
D163
D124
Thymoglobulin / Low Dose Tacrolimus Monotherapy vs.
Standard Tacrolimus
ATG 9mg/kg
Tac 5 – 12 ng/mL
Months 0 - 3
Assess for IS
withdrawal;
10 qualified
Benitez et al., AJT, 2010
Tac 10–15ng/mL
Months 0 - 3
Tac 7–12ng/mL
Months 4 - 12
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
Thymoglobulin / Low Dose Tacrolimus Monotherapy
Acute Rejection Rates
1
2
3
4
5
6
7
8
9
10
Benitez et al., AJT, 2010
Spontaneous Operational
Tolerance
ITN030: Tacrolimus ± Mycophenolate
Month Month Month
Withdrawal
1 - 3 4 - 12 13 - 24
Corticosteroids
Tacrolimus
MMF
d/c by
end of
month 3
8 - 12
ng/mL
5 - 10
ng/mL
If started, d/c 3 mos
before withdrawal
Eligibility
Withdrawal
Prospective Study of Immunosuppression Withdrawal
97 stable liver
Recipient
>3 years
Liver
Transplantation
Immunosuppression
6-9
months
withdrawal
weaning
6-9 months
12 months
12
month follow-up
follow-up
Withdrawal Failure
Rejection
(Non-TOL)
57
Stable liver
function
(TOL)
40
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 CTG
 Nadia Tchao
 Peter Sayre
 Nariman Nasser
 Ross Jamison
 Doug Norman
Rho
 David Ikle
 Katie Poole
 ITN TADA Group
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Vicki Seyfert-Margolis
Deborah Phippard
Mark Mueller
Adam Asare
Jason (Zhugong) Liu
Mary Carmelle-Philogene
Zhong Gao
Larry Turka
 A. Jake Demetris
 Alberto Sanchez-Fueyo
NIAID
 Nancy Bridges
 Melissa DePaulis