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Immunosuppression Withdrawal in Liver Transplantation: Lessons we are learning

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Title: Immunosuppression Withdrawal in Liver Transplantation: Lessons we are learning


1
Immunosuppression Withdrawal in Liver
Transplantation Lessons we are learning
George V Mazariegos MD FACS Childrens Hospital
of Pittsburgh Hillman Center for Pediatric
Transplantation Thomas E Starzl Transplantation
Institute University of Pittsburgh
2
Objectives
  • Benefits and risks of immunosuppression
    withdrawal
  • Current Single Center Experience
  • Outcomes and biopsy experience
  • Unanswered questions
  • Ongoing and proposed trials

3
Understanding risks and benefits of drug
withdrawal
4
What we do know Recipients Living with a
Functioning Transplant are increasing
5
Populations such as children may comprise the
most challenging population in drug withdrawal
Soltys et al, American Journal of Transplantation
2007 7 21652171
6
Long term immune Suppression at 5 Year
Anniversary are varied
Ng et al, Pediatrics 2008 122, 1128-1135
7
Extra-Hepatic Morbidity at the 5-Year
Anniversary Ng et al, Pediatrics 2008 122,
1128-1135
of patients

cGFR lt 90 PTLD ? BMI ? choles
?triglyceride

8
Immunosuppression Withdrawal after Liver
Transplantation Overview
  • Assessing benefit and risk
  • Current Single Center Experience
  • Unanswered questions
  • Ongoing and proposed trials

9
Pathways to Tolerance
  • Non-compliance
  • Emergent withdrawal for infection or malignancy
    Hurwitz et al (Pediatr Trans 20048210-213)
  • 50 with EBV/PTLD in 335 pediatric LTx
  • IMS withdrawn for all 19 with PTLD and 19/31 with
    EBV infection
  • 8/50 (16) have remained off IS for mean 4.2 yr
    (2.3 of total population)
  • Physician directed withdrawal

10
Emergent immunosuppression withdrawal in liver
transplantation
Lerut et al An Appraisal of Tolerance in Liver
Transplantation AJT 2006
11
Complete elective immunosuppression withdrawal in
liver transplantation
Lerut et al An Appraisal of Tolerance in Liver
Transplantation AJT 2006
12
Design of immunosuppression withdrawal trials
Demetris et al Monitoring of human liver and
kidney allograft tolerance a tissue/histopatholog
y perspective Transplant International 2008
13
Summary of the Tor Vergata Experience
Orlando et al The Tor Vergata weaning off
immunosuppression protocol in stable HCV liver
transplant patients The updated follow up at 78
months Transplant Immunology 2008
14
Role of Donor Bone Marrow Infusion (5.94 X 10
8cells/kg) in Immunosuppression Withdrawal
October 98- May 01 Adult recipients of
liver allograft gt3 years post-OLTX (7.5-8 yrs
post Tx) gt 12 months without ACR
Typhonopoulos,Tzakis,Weppler et al AJT 2005
5608-613
15
Role of Donor Bone Marrow Infusion in
Immunosuppression Withdrawal
Typhonopoulos,Tzakis,Weppler et al AJT 2005
5608-613
16
FREEDOM FROM REJECTION DURING FIRST YEAR OF THE
STUDY
17
FREEDOM FROM REJECTION AFTER WITHDRAWAL OF ISP
18
Prospective Immunosuppressive Weaning in Liver
Transplant Recipients (pre-2001)
  • 120 LTX assessed for weaning
  • 70 adults and 50 children
  • gt5 years post-LTX
  • gt2 years without rejection
  • Protocol for weaning - evolution
  • Initially AZA and pred weaning followed by 25
    decrease in CsA or Tac q2mo
  • Currently Pred and CsA or Tac weaning followed
    by AZA
  • Rescue with steroids and tacrolimus

Ramos et al Transplantation 59212, 1995
Mazariegos et al Transplantation 63243,
1997 Mazariegos et al Miami 2002
19
Summary of IS Withdrawal Results (1992 1996)
Protocolized Partial
Rejection Weaning Complete
Drug Wean Held
Withdrawal
Mazariegos et al Transplant Immunology 2007
(17) 114-119
20
Clinically Tolerant Liver Transplant Recipients
Long Term Follow-Up (1992 2006)
Method of Drug Withdrawal
Protocol Emergent Non-Compliance
Mazariegos et al Transplant Immunology 2007
(17) 114-119
21
Mean Drug Change/Day (-/)All Groups
22
Outcome of Weaning Kyoto (Feb 1990- April 2008)

675 Pediatric Ltx
Elective
Non-Elective
Resume IS
Resume IS
85 (12.6) off
6 Rejection
56 Weaning
29 Off
56 Off
1 AIH
23 Graft fibrosis
(Koshiba T et al. Transplant Immunol 20071794)
23
Takatsuki et al Transplantation. 2001
72(3)449-454
Mazariegos et al Transplantation. 1997 63(2)
243-9.
24
Cumulative Lessons Learned
25
Histo-pathological characteristics of tolerant
patients
Demetris et al Monitoring of human liver and
kidney allograft tolerance a tissue/histopatholog
y perspective Transplant International 2008
26
General Patient Characteristics
27
Post-weaning Tissue Sample Characteristics
28
Histopathology Follow-up of Drug-Free UPMC Liver
Allograft Recipients
29
Histopathology Follow-up of Drug-Free UPMC Liver
Allograft Recipients
30
Recipient 5 9.7 Drug-free Years with Acquired
HCV s/p OLTx for Biliary Atresia - HCV-induced
cirrhosis with significant obliterative
arteriopathy and low-grade ductopenia
31
Recipient 9 7.3 Drug-free Years s/p OLTX for
HCV - Recurrent HCV - Negative for Obliterative
Art.
32
Recipient 12 2.0 Drug free Years s/p OLTx for
EHE Mild portal inflammation with low-grade
interface activity TB0.5 ALT60 AST48
ALP101 GGTP93
33
Recipient 12 4.8 Drug free Years s/p OLTx for
EHE Mild portal inflammation with low-grade
interface activity Slightly increased
architectural distortion since previous
biopsy TB0.6 ALT66 AST71 ALP146
GGTP32 LFT 4/2009 completely normal
34
Recipient 13 10.8 Drug-free Years s/p OLTx for
? Unexplained chronic hepatitis Obliterative
arteriopathy
35
Recipient 13 10.8 Drug-free Years s/p OLTx for
? Native kidney
36
  • Recipient 8 17.3 Drug-free years s/p OLTx for 2o
    BC
  • Minimal lymphocytic portal inflammation and mild
    NRH
  • - Bx obtained in 1996 Currently 30 drug-free
    years
  • LFT 5/2007 TB0.3 ALT44 AST24 ALP146

37
Common Findings in Post-Weaning Tissue Samples
  • Low-grade lymphocytic portal inflammation
    with/out interface activity
  • Variable fibrosis
  • NRH changes
  • Recurrent disease
  • HCV
  • NAFLD
  • Inflammation has waxed and waned in recipients
    with serial post-weaning biopsies

38
What is the meaning of graft fibrosis encountered
during drug withdrawal?
Requirement of Protocol Biopsy Before and
After Complete Cessation of Immunosuppression
After Liver Transplantation Yoshitomi et al
Transplantation 200987 606614
39
Reintroduction or the increase ofimmunosuppressio
n because of fibrosis.
40
Trials of Immunosuppression Withdrawal in
Children after Liver Transplantation Overview
  • Why are they needed?
  • Current Single Center Experience
  • Unanswered questions
  • Ongoing Trials
  • Proposed Trials

41
Protocol biopsies in operationally tolerant
patients
  • Develop guidelines for
  • Timing
  • Interpretation
  • Clinical Correlation
  • Impact of graft type
  • Assessment of technical variants, vascular
    complications, recurrent disease and other
    aspects that will impact interpretation

42
Unanswered questions
  • Benefits of withdrawal
  • Optimal Population for Withdrawal
  • Optimal Timing of Withdrawal
  • Optimal Immune Monitoring
  • Complications of Withdrawal

43
Distribution of anti-HLA antibodiesin liver
transplant recipients
Donor-specific antibody group A vs. group BC X2
10.55, p0.005 Yates correction
44
DC Flow Cytometry
Off Immunosuppression (A)
Prospective Weaning (B)
pDC
pDC1
0.97
1.57
60.6
55.1
HLA-DR
CD11c
HLA-DR
CD11c
17.6
21.4
pDC2
Rejection (C)
Normal (D)
3.41
1.84
53.2
84.4
HLA-DR
HLA-DR
CD11c
CD11c
26.1
7.26
CD123
Lineage
Lineage
CD123
45
precursor p-DC/precursor m-DC ratios
Tokita et al High PD-L1/CD86 Ratio on
Plasmacytoid Dendritic Cells Correlates With
Elevated T-Regulatory Cells in Liver Transplant
Tolerance Transplantation08
46
PD-L1/CD86 ratios, CD4CD25hi/Foxp3 Treg
frequencies and CD4CD25 cell in tolerant
subjects
47
PD-L1/CD86 ratio frequency of CD4CD25hi T reg in
TOL patients.
48
Background-Pediatric LTx-Drug minimization-MLR
and rejection riskPersistence of enhanced
donor-specific alloreactivity predicts delayed
rejection
Immunoreactivity index (IR)Donor/third party
alloreactivity IRlt1decreased rejection risk,
IRgt1increased rejection risk
Recurrent Rejection, n7 of 20, p0.032 Time to
IRlt1 is 103.85 months, p0.0492
Delayed Rejection, n1 of 17 Time to IRlt1 is
1.70.8 months
Sindhi et al, 2005
49
Objectives
  • Benefits and risks of immunosuppression
    withdrawal
  • Current Single Center Experience
  • Outcomes and biopsy experience
  • Unanswered questions
  • Ongoing and proposed trials

50
ITN Studies
  • Immunosuppression Withdrawal for Stable Pediatric
    Living Donor Liver Transplant RecipientsPrincipal
    Investigator Sandy Feng, University of
    California, San Francisco, CA    
  • Immunosuppression withdrawal in liver transplant
    recipients infected with the hepatitis C
    virusPrincipal Investigator Abraham Shaked,
    University of Pennsylvania, Philidelphia, PA  
  •   Campath 1H induction therapy and
    immunosuppression withdrawal in liver transplant
    recipientsPrincipal Investigator J. Richard
    Thistlethwaite, University of Chicago 

51
Proposed Trials
  • SPLIT iWITH Trial
  • Immunosuppression withdrawal in stable pediatric
    liver recipients gt3 years after transplantation
    (U34 DK083031-01)
  • International Solid Organ Transplant Tolerance
    (ISORTT) Registry
  • Establish a multicenter, international web based
    registry to prospectively follow solid organ
    transplant recipients who have been successfully
    withdrawn from immunosuppression for at least 1
    year
  • Establish natural history for the tolerant and
    (in-tolerant patient)
  • Provide entry for interested patients into
    current or future immune monitoring trials

52
Tolerance Registry Specfic Aims
  • Establish an international web based network of
    transplant centers for the enrollment of
    operationally tolerant solid organ transplant
    recipients
  • Describe the natural history of patients
    withdrawn from immunosuppression
  • Provide patient access to current or future
    mechanistic studies of transplant tolerance

53
Determine the natural history of
immunosuppression withdrawal
  • Survival
  • Time off immunosuppression
  • Organ specific graft function
  • Growth
  • Interval events
  • Acute or chronic rejection
  • Biopsy events
  • Graft loss
  • Reinstitution of immunosuppression

54
Data at enrollment and yearly followup
  • Pre tx diagnosis,organ transplanted, donor type,
    age at transplant, height, weight
  • Donor and recipient blood type/HLA
  • Baseline immunosuppression
  • Rejection history
  • Method of drug withdrawal and indications
  • Date of Drug weaning and withdrawal
  • Biopsy history

55
Events after drug withdrawal
  • Biopsy events
  • Rejection
  • Graft loss/retransplantattion
  • Death
  • Date if patient resumed immunosuppression
  • Height weight
  • Current graft status
  • Organ Specific Function studies

56
Current Status
  • Coordinating Center IRB approved
  • Center Specific IRB protocols in preparation
  • Univ of Washington approved
  • Others in process
  • Web site completed
  • www.transplant-tolerance.org
  • Data entry interface in process
  • Preliminary patient enrollment (n18)

57
Participating Centers
  • North America
  • University of California, San Francisco (San
    Francisco, CA) Sandy Feng LIVER
  • Stanford University Medical Center (Stanford,
    CA) Ricardo Castilo, Carlos Esquivel, William
    Bergquist, Kenneth Cox, Minnie Sarwal LIVER,
    KIDNEY
  • Columbia University NY Tom Kato LIVER, INTESTINE
  • Childrens Memorial Hospital (Chicago, IL)
    Estella Alonso LIVER
  • Childrens Hospital (Boston, MA) Heung Bae Kim
    LIVER, INTESTINE
  • University of Michigan Ann Arbor (Ann Arbor, MI)
    John Magee LIVER
  • Washington University (St. Louis, MO) Ross
    Shephard, Michelle Nadler LIVER
  • Mount Sinai (New York City, NY) Kishore Iyer
    LIVER, INTESTINE
  • University of Pittsburgh Medical Center
    (Pittsburgh, PA) LIVER, KIDNEY, INTESTINE
  • University of Washington Medical Center (Seattle,
    WA) Simon Horslen, Jorge Reyes
  • Asia
  • Kyoto University (Kyoto, Japan) Takaaki Koshiba
    LIVER
  • Europe
  • Birmingham Childrens Hospital (Birmingham,
    England) Carla Lloyd LIVER
  • Kings College (London, England) Anil Dahwan
    LIVER
  • Unversidad V Hebron Javier Bueno, MD LIVER
  • Ospedali Diuniti Di Bergamo (Bergamo, Italy)
    Michelle Colledan LIVER
  • ISMETT (Palermo, Italy) Marco Spada LIVER

58
www.transplant-tolerance.org
59
(No Transcript)
60
Results Patient Demographics
61
Results Transplant Details
62
Results Drug History
IS Immunosuppression M/ROW Method/Reason of
Withdrawal 1 Protocol 2 Emergent 3
Noncompliant OWinit Initial Date of Wean Doff
Date completely off Meds Rej Epis Rejection
Episodes (biopsy-based)
63
Take home messages
  • Most patients remain on excessive
    immunosuppression
  • Tolerant grafts exhibit inflammation/non-specific
    hepatitis and fibrosis
  • Relation to destructive immunity needs tobe
    clarified
  • Documentation of quality of life, renal injury,
    and other drug related side effects after drug
    withdrawal needed

64
Take home messages
  • Close monitoring is essential
  • Laboratory assessment is insufficient
  • Linver injury tests will fluctuate
  • Timing of biopsy surveillance to be defined
  • Baseline
  • At any sustained liver injury elevation
  • 1, 3-5 years post weaning
  • Understand caveats of biopsy interpreation
  • Sampling
  • Impact of split grafts or any graft where
    segmental ischemic lesions could interfere with
    interpretation

65
Take home messages
  • Develop optimal weaning populations
    (non-autoimmune disease, low incidence of early
    rejection, ?role of HLA matching, ?impact of
    baseline immunosuppression ? Hepatitis C)
  • Develop benefit risk analysis that will
    incorporate the potential gain of drug withdrawal
    with potential risk (age, co-morbidities, risk of
    intervention, risk of rejection, and re-Tx)

66
Acknowledgements
  • Sandy Feng, MD
  • Takaaki Koshiba, MD
  • SPLIT is supported by NIDDK U01-DK061693-01A
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