Section 1: Immunosuppression – how do we
achieve long-term success?
Dr Mönch
Westpfalz-Klinikum Hospital,
Kaiserslautern, Germany
Christian Moench
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Long-term success
 Excellent patient and graft survival
 Ensure primary graft function
 Avoid side effects
 Avoid rejection
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
ELITE-Symphony trial
CsA
n=390
Low CsA
n=399
low Tac
n=401
Low Sir
n=399
p-value
57.1
59.4
65.4
56.7
<0.001
Rejection*
32.8%
29.5%
17.2%
43.5%
<0.001
Allograft
survival
91.9%
94.3%
96.4%
91.7%
0.02
Patient
survival
96.5%
98.2%
97.2%
96.8%
ns
DGF
33.6%
32.4%
35.7%
21.1%
0.004
cGFR
measurement,
mL/min
DGF: delayed graft function; *acute rejection suspected and treated at Month 12
Ekberg H et al. New Engl J Med 2007; 357:2562–75
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
ELITE-Symphony trial
Event, %
CsA
n=384
Low CsA
n=408
Low Tac
n=403
Low Sir
n=380
Blood or lymphatic
33.3
33.6
36.2
36.1
Gastrointestinal
33.3
32.6
41.4
34.7
Opportunistic infection (eg CMV,
candida, HSV)
26.0
22.8
19.9
20.3
Other infection/infestation (eg
nasophayngitis, pneumonia, UTI)
54.2
50.5
52.4
52.6
Delayed wound healing at Week 2
10.8
11.0
9.4
16.6
Diabetes
6.0
4.2
8.4
6.6
Hyperlipidaemia
14.8
12.5
9.9
15.8
Neurological
13.0
9.8
15.9
9.0
Hypertension
14.3
11.5
12.9
11.8
Cancer
0.5
0.7
1.0
2.1
CMV: cytomegalovirus; HSV: herpes simplex virus; UTI: urinary tract infection
Ekberg H et al. New Engl J Med 2007; 357:2562–75
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus + MMF + steroids
 Reflects the basis for long-term success in kidney
transplantation
 Possibility to modify the regimen for liver
transplantation?
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Liver transplantation – risk
n=12,996 adult patients on the liver-transplant waiting list
MELD: model for end-stage liver disease
Merion RM, Am J Transplant 2005:307–313.
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Immunosuppression
Complications
Infection
Side effects
Toxicity
Patient survival
The step programme was funded and developed by Astellas Pharma Europe Ltd
Rejection
Impaired lab values
Impaired graft function
Graft loss
Patient survival
ADV/12/0034/Eun November 2012
Rejection
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Rejection treatment during first year
Deceased donor, first liver transplants 1996–2005
Collaborative Transplant Study (CTS identification code: L-83112-0807)
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Liver transplantation
 Over-immunosuppression is more dangerous than
under-immunosuppression
 Treatment of choice following liver transplantation:
optimisation!
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Minimisation of immunosuppression in liver
transplantation
 Steroid-free immunosuppression
 Low tacrolimus levels
 Delayed tacrolimus
 Tacrolimus prolonged release
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
No steroids
Randomisation schedule; n=110
Moench C et al. Am J Transplant 2007;7:1616–1623
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
No steroids
Moench C et al. Am J Transplant 2007;7:1616–1623
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
No steroids
Steroid group: n=54; placebo group: n=56
Moench C et al. Am J Transplant 2007;7:1616–1623
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
No steroids
 n=110 patients following OLT*, randomised to steroids (n=54) vs
placebo (n=56)
 One-year patient survival: steroids 88.8% vs placebo 85.7%
(p=ns)
 CMV: steroid 33% vs placebo 25% (p=ns)
 PTDM: steroid 53% vs placebo 30% (p=0.024)
 Hypertension: steroid 52% vs placebo 39% (p=ns)
 Hypercholesterolaemia: steroid 41% vs placebo 10% (p=0.002)
 Hypertriglyceridaemia: steroids 54% vs placebo 32% (p=0.046)
*All patients received steroids for 14 days, and tacrolimus without induction therapy throughout the study
Moench C et al. Am J Transplant 2007;7:1616–1623
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
No steroids
 Follow-up after 5 years
 Patient survival (p=0.236), graft survival (p=0.509), acute rejections
(p=0.409) were comparable
 Steroid-free immunosuppression led to a higher rate of chronic
rejections (p=0.023)
 5 years after OLT, there was no difference in hypertension
(p=0.647), PTDM (P=0.453), hypercholesterolaemia (p=0.412), and
osteoporosis (p=0.624)
 In HCV patients, no differences in patient survival (p=0.096), organ
survival (p=0.424), time free from re-cirrhosis (p=0.647). The rate of
re-cirrhosis was influenced by steroid bolus therapy (p=0.01) but not
by avoiding continuous steroid therapy
HCV: hepatitis C virus; PTDM: post-transplant diabetes mellitus
Weiler N et al. Transplantation 2010;90:1562–6
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
 n=52 patients following OLT (3 month duration)
 Initial dose 10.0 +/- 3.8mg
 Trough levels 8.6 +/-3.7ng/ml
 n=7 BPAR (13%)
 Patient and graft survival 100%
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
Evolution of post-transplant tacrolimus doses and blood trough levels
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus once daily
Charco R et al. Transpl Proc 2011;43:718–723
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus prolonged release
Tacrolimus QD plus MMF and basiliximab induction
Trough level (ng/mL) / dose (mg)
18
Patient SM, 55-years-old
Tacrolimus
trough level
16
14
12
10
8
6
4
Tacrolimus
dose
2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Day post liver transplant
Moench C et al, ATC 2010, Poster 1742
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Tacrolimus prolonged release
Trough level (ng/mL)/dose (mg)
Tacrolimus QD plus MMF and basiliximab induction
Patient MJ, 54-years-old
16
14
12
10
8
6
4
2
0
Tacrolimus
trough level
Tacrolimus
dose
1
2
3
4
5
6
7
8
Day post liver transplant
9
10
11
Moench C et al, ATC 2010, Poster 1742
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
DIAMOND study
A multicentre randomised prospective trial after liver transplantation
Arm 1:
Tacrolimus prolonged release + MMF
Arm 2:
Tacrolimus prolonged release (low
dose) + MMF + basiliximab
Arm 3:
Tacrolimus prolonged release –
(delayed, low dose) + MMF +
basiliximab
All regimens to include corticosteroids (bolus)
ClinicalTrials.gov Identifier: NCT01011205
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
‘Bottom-up’ CNI
 Improved outcome after ‘bottom-up’ immunosupression in
liver transplant recipients with pre-operative renal
impairment
 n=30 patients, n=15 CsA + MMF + steroids
vs n=15 MMF + steroids ‘bottom-up’
 Survival and BPAR were similar, although Banff scores
were higher in the bottom-up versus CSA/MMF/steroid
group (p=0.004)
Schnitzbauer AA et al. Eur Surg Res 2010;45:356–367
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Current immunosuppression for high
MELD recipients
Induction:
Basiliximab
MMF:
1g bid
no steroids
Tacrolimus ‘bottom-up’
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012
Long-term success in liver transplantation
 Most evidence for the combination of tacrolimus + MMF +
steroids
 Steroid-free immunosuppression, delayed tacrolimus, low
CNI trough levels, and the use of prolonged-release
tacrolimus offer essential possibilities for minimisation
 Minimisation results in long-term survival
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/Eun November 2012