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

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

ITN024: Alemtuzumab / Tacrolimus MonotherapyOutcome of Immunosuppression Withdrawal

27 enrolled

10 initiated withdrawal

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

Thymoglobulin / Sirolimus Monotherapy

Outcome of Immunosuppression Withdrawal

D140 D206 D124

D280 D246 D163

Donckier et al., Transplantation 2009

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

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

Benitez et al., AJT, 2010

Thymoglobulin / Low Dose Tacrolimus Monotherapy Acute Rejection Rates

1

23456789

10

Spontaneous Operational Tolerance

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

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

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

DuringWithdrawal

AfterWithdrawal

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

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