Steroid Withdrawal Posttransplant: Yes or No

1
Steroid Withdrawal Posttransplant Yes or No

• E. Steve Woodle, MD, FACS
• Professor of Surgery
• Director, Division of Transplantation
• Department of Surgery
• University of Cincinnati

2
Corticosteroid Elimination Disadvantages

• Acute rejection
• Baseline immunosuppression
• Antibody induction
• Recipient immunologic risk
• Leukopenia-induced dose limitation of
  anti-proliferative agents (sirolimus/MMF/Aza)
• Reduced long-term graft survival
• Increased acute rejection rates
• Loss of non-specific immunosuppression
• Loss of anti-inflammatory effects

Azaazathioprine MMFmycophenolate mofetil
3
Corticosteroid Elimination Advantages

• Reduced Cardiovascular Risk
• Reduced cholesterol
• Reduced triglycerides
• Reduced hypertension
• Reduced weight gain
• Reduced diabetes
• Improved patient survival
• Amelioration of bone disease
• Improved growth in children
• Cosmetic advantages
• Reduced Cushingoid features
• Reduced acne
• Reduced noncompliance
• Replacement in IS regimens by drugs with assays
  for TDM
• Improved wound healing
• Reduced peptic ulceration
• Reduced cataracts

ISimmunosuppression TDMtherapeutic drug
monitoring
4
Immunosuppressive Agents Cardiovascular Risk
Profiles
5
Tacrolimus/MMF-Based Regimens

• University of Chicago Experience
• Protocol initiated following MMF FDA approval
• Early cessation (7 days)
• Rationale
• Ameliorate tacrolimus-associated PTDM
• First step toward programmatic goal to completely
  eliminate steroids in renal transplant recipients
  using modern, more potent immunosuppressive
  regimens

MMFmycophenolate mofetil PTDMposttransplant
diabetes melitus
Grewal HP, et al. Transplant Proc.
1998301378-1379.
6
Clinical Protocol

• Tacrolimus dosing
• PTD 1 0.3 mg/kg/day target 20 -25 ng/ml
• Mycophenolate dosing
• PTD 0 3 gm/day
• PTD 7 2 gm/day
• Corticosteroid dosing
• Standard until DC on PTD 7
• Total dose lt 1500 mg prednisone equivalent
• First patient enrolled 12/26/95
• Most recent serum creatinine 1.7 mg/dL,
• off corticosteroids

PTDposttransplant day
Grewal HP, et al. Transplant Proc.
1998301378-1379.
7
Tacrolimus/MMF Early Corticosteroid Withdrawal
Trials
HLAhuman leukocyte antigen LDliving donor
8
Tacrolimus/MMF Early Corticosteroid Withdrawal
Trials
PTDMposttransplant diabetes mellitus
9
Improved Kidney Function Serum Creatinine
6
5
Serum Creatinine (mg/dL)
4
3
2
1
0
7
14
21
30
90
180
365
545
730
1095
Posttransplant Day
Grewal HP, et al. Transplant Proc.
1998301378-1379.
10
Improved Systolic Blood Pressure
Systolic Blood Pressure (mm Hg)
Pre
30
180
720
1095
Posttransplant Day
Grewal HP, et al. Transplant Proc.
1998301378-1379.
11
No Weight Alterations
Weight (kg)
Posttransplant Day
Grewal HP, et al. Transplant Proc.
1998301378-1379.
12
Argentine Multicenter Corticosteroid Withdrawal
TrialTacrolimus/MMF
Total Cholesterol (mg/dL)
Time (weeks)
13
Tricontinental Corticosteroid Withdrawal Trial
Cyclosporin/MMF

• Europe, Australia, South Africa
• 74 centers in 15 countries
• 500 patients
• Double blind, randomized, prospective multicenter
  trial of 6-month, controlled steroid
  dose-reduction followed by an unblinded 6-month
  follow-up
• First or second cadaveric or live donor
  transplant
• Primary endpoint biopsy-proven rejection at 6
  months

Vanrneterghem Y et al Transplantation
2000701352-1359.
14
Tricontinental Corticosteroid Withdrawal Trial
Cyclosporin/MMF

• Treatment groups
• Group A cyclosporin, MMF, corticosteroids
• Group B cyclosporin, MMF, 1/2 dose
  corticosteroids from Day 1 posttransplant,
  tapering to 0 by three months
• Cyclosporin 5-15 mg/kg/day
• MMF 2000 mg/day
• Polyclonal antibody induction per center if
  desired

MMFmycophenolate mofetil
Vanrneterghem Y et al. Transplantation
2000701352-1359.
15
Influence of Induction Therapy
Control
CSWD
Vanrneterghem Y et al. Transplantation
2000701352-1359.
16
Primary vs Repeat Transplants
Rejection Incidence ()
Control
CSWD
Primary Tx
Repeat Tx
Vanrneterghem Y et al. Transplantation
2000701352-1359.
17
Corticosteroid Withdrawal Trial Cyclosporin/MMF

• Multicenter, prospective, randomized,
  double-blind trial
• Inclusion criteria serum creatinine lt2.4 mg/dL
  or CrCl gt50 ml/min
• Primary renal transplant recipients
• No acute rejection by 90 days posttransplant
• Cyclosporin 5-15 mg/kg/day and MMF 2 g/day
• Randomization at 3 months posttransplant
• Prednisone (10-15 mg/day) taper with cessation at
  8 weeks
• Long-term maintenance at 10 mg/day

Steroid Withdrawal Study Group. Transplantation.
1999681865-1874.
18
Corticosteroid Withdrawal Trial Results

• 500 patients to be randomized for 80 statistical
  power for equivalence of primary endpoint
• Enrollment halted by Data Safety Monitoring
  Board after 266 patients
• At time of enrollment cessation, rejection rates
  were 15 in the withdrawal group and 5 in the
  maintenance group (P.004 by log rank)

Steroid Withdrawal Study Group. Transplantation.
1999681865-1874.
19
Biopsy-Proven Rejection Racial Effects
Cumulative Incidence
M/C
W/C
M/AA
D/AA
Posttransplant Month
AA African American Ccaucasian Mmaintenance
Wwithdrawal Steroid Withdrawal Study Group.
Transplantation. 1999681865-1874.
20
Early CSWD Under Modern Immunosuppression
Multivariate Analysis of Risk Factors For Acute
Rejection

• E. Steve Woodle MD, Rita R. Alloway PharmD,
• JW Alexander MD ScD, G. Sethu PhD, Michael J.
  Hanaway MD, Joseph F. Buell MD, V. Ram Peddi MD,
• Prabir Roy Chaudhry MD PhD, Michael Cardi MD,
• M. Roy First MD, Jennifer Trofe PharmD

University of Cincinnati
21
Methods

• 164 patients from 5 IRB approved trials of CSWD
  or CSAV
• Two trials entered only high risk patients
• High immunologic risk
• DGF
• Immunosuppression
• Thymoglobulin, IL-2R Ab induction, no induction
• Calcineurin inhibitor
• MMF (2 g/day)
• Sirolimus (target levels 8-12 ng/ml)
• All rejections biopsy proven using Banff criteria
• Univariate analyses Chi square
• Multivariate analysis logistic regression

CSAV corticosteroid avoidance
CSWDcorticosteroid withdrawal DGFdelayed graft
function
Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
22
Immunosuppression
of Patients
Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
23
Acute Rejection

• Median Follow-up 545 days
• Overall Acute Rejection Incidence 23
• All rejections during entire follow-up
• Includes accelerated rejections
• Moderate acute rejection 8

Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
24
Patient Demographics
of Patients
LRD
Diabetes
Male
DR MM
DGF
AA
Curr PRA gt25
Hist PRA gt50
Repeat Tx
Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
25
Acute Rejection at 1 Year
Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
26
Acute Rejection at 1 Year
Sethu G, et al. Transplantation. 200478(Suppl
1)170-171.
27
Cincinnati Trial of CSAV/CS Free
Immunosuppression with Simultaneous Calcineurin
Inhibitor Minimization
Exclusion Criteria

• Serious unresolved infections
• lt18 years of age
• Risk of early death
• Malignancy
• Pregnant or lactating females
• History of oxalosis
• Cholesterol gt300 mg/dL or triglycerides gt400
  mg/dL

Alexander JW, et al. Am. J Transplantation.
20033498.
28
Study Design

• Thymoglobulin induction
• Creatinine lt4 mg/dL, based on CD3 monitoring, max
  5 doses
• Sirolimus target 8-12 ng/ml
• MMF 2 g/day
• No maintenance corticosteroids
• No rejection corticosteroids Phase III
• Three Phases Cyclosporin dosing
• Phase I target 200 ng/ml
• Phase II target 100 ng/ml
• Phase III 3 mg/kg/day, reduced if gt100 ng/ml

Alexander JW, et al. Am. J Transplantation.
20033498.
29
Results
49/55 pts followed for 2 yrs on sirolimus
monotherapy
Mean Follow-up 528 days Patient
Survival 97.4 Graft Survival 96.8 (death
censored) Acute Rejection 15 Steroid
Free 88.2 CIN Free 89
Alexander JW, et al. Am. J Transplantation.
20033498.
30
Cyclosporin Trough Levels
Cyclosporin (ng/ml)
Posttransplant Day
Alexander JW, et al. Am. J Transplantation.
20033498.
31
Sirolimus Trough Levels
Sirolimus (ng/ml)
Posttransplant Day
Alexander JW, et al. Am. J Transplantation.
20033498.
32
MMF Dosing
MMF (mg/day)
Posttransplant Day
Alexander JW, et al. Am. J Transplantation.
20033498.
33
Early Corticosteroid Cessation in De Novo Renal
Transplant Recipients

• Multicenter, pen-label, non-comparative, pilot
  study
• 77 patients total enrolled at 8 US centers
• 12 month treatment phase
• Basiliximab, tacrolimus, and sirolimus

Woodle ES, et al. Am. J Transplantation.
20048300.
34
Inclusion/Exclusion Criteria

• Exclusion Criteria
• Repeat kidney transplant
• African Americans
• Current PRA gt50
• Multiple organ transplant recipient
• WBC lt3000/uL
• Platelet count lt100,000/uL
• Fasting triglycerides gt400mg/dL (4.6 mmol/L)
• Fasting cholesterol gt300 mg/dL (7.8 mmol/L)
• Preexisting condition requiring corticosteroids
  posttransplant

• Inclusion Criteria
• Age gt18 years
• Primary renal transplant recipient
• Cadaveric donor
• Living unrelated donor
• Living related, mismatched donor

Woodle ES, et al. Am. J Transplantation.
20048300.
35
Immunosuppressive Regimen

• Basiliximab induction
• 20 mg IV PTD 0, 4
• Tacrolimus
• 0.05 mg/kg/day, start within 24 hours
• Target levels 6-9 ng/ml PTD 1-30, 4-8 ng/ml
  PTD 31-365
• Sirolimus
• 15 mg PTD 1, 10 mg PTD 2 and 3, 6 mg PTD 4 on,
  adjust to target levels
• Target levels 8-12 ng/ml
• Corticosteroid
• PTD 0 250 mg solumedrol
• PTD 1 250 mg solumedrol
• PTD 2 125 mg solumedrol
• PTD 3 65 mg prednisone
• PTD 4 30 mg prednisone

Woodle ES, et al. Am. J Transplantation.
20048300.
36
Immunosuppressive Regimen

• Delayed Graft Function
• Delay introduction of tacrolimus until
• Serum creatinine falls gt 20 from baseline, or
• PTD 14
• Corticosteroids
• Per center practice after PTD 2
• Sirolimus
• 10 mg/day until level determined

Woodle ES, et al. Am. J Transplantation.
20048300.
37
Results

• Study Discontinuation n 14 (19.7)
• Study event n 11
• Lack of efficacy n 1
• Protocol violation n 2
• Patient Survival 100
• Graft Survival 100
• Corticosteroid Use at 6 months 14

Woodle ES, et al. Am. J Transplantation.
20048300.
38
Acute Rejection
Rejection Rate ()
Presumed and Bx Proven Rejection After CSWD
Posttransplant Day
Woodle ES, et al. Am. J Transplantation.
20048300.
39
Immunosuppressive Dose
Sirolimus Dose
Sirolimus Trough Levels
mg/day
ng/mL
Tacrolimus Trough Levels
Tacrolimus Dose
mg/day
ng/ml

Posttransplant Day
Woodle ES, et al. Am. J Transplantation.
20048300.
40
Lipids
Woodle ES, et al. Am. J Transplantation.
20048300.
41
Hypertension, Hyperlipidemia, and Diabetes Therapy
42
Conclusions

• This pilot experience with early CSWD under
  basiliximab, tacrolimus, and sirolimus
  demonstrates
• Low incidence of acute rejection
• Rejection episodes mild in severity
• Excellent patient and graft survival
• Excellent renal function
• Mitigation of hypercholesterolemia associated
  with sirolimus
• Improved hypertension relative to historical
  experience