Steroid Minimization: Great Idea or Silly Move?

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Milton Potter
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1 Steroid Minimization: Great Idea or Silly Move?

2 Disclosures I have financial relationship(s) within the last 12 months relevant to my presentation with: Astellas Grants ** Bristol Myers Squibb Grants, Speaker** Genzyme Grants, Speaker ** Millennium Grants Novartis Grants ** Roche Grants ** Y Therapeutics Grants Wyeth Grants, Speaker ** My presentation includes discussion of off-label use Noted by **above

Early Steroid Withdrawal: Modern Era Reported 1998 Patients transplanted 1995-1996 Prospective single-center study No induction 7-day steroid taper, Tacrolimus /MMF maintenance 52 patients At 3

3 Early Steroid Withdrawal: Modern Era Reported 1998 Patients transplanted Prospective single-center study No induction 7-day steroid taper, Tacrolimus /MMF maintenance 52 patients At 3 years, 86% of all patients remain steroid-free 1 year 3 year Patient survival 98% 98% Graft survival 95% 92.3% DC Graft 98% 94% Acute rejection 19% 25% DC = death-censored; LD = living donor; DD = deceased donor; CAN = chronic allograft nephropathy.

4 Judging Steroid Free IS Results Costs Acute rejection CAN Benefits CV Risk Target Organ Damage (bone, skin, cataract)

5 Judging Steroid Free IS Results Cost Acute rejection CAN Benefits CV Risk Target Organ Damage (bone, skin, cataract)

6 Study European Multicenter Trials Year F/Up Years Italian Multicenter #Pts AR Rate Cy only 70% Cy Pred 50% Cy Aza Pred 49% ATLAS Dutch Multicenter CARMEN UK Multicenter IL2R Tac 26% Tac MMF 30.5% Tac MMF Steroid 8.2% IL2R Tac MMF 15% Tac MMF Steroid 14% IL2R Tac MMF 16.5% Tac MMF Steroid 16.5% IL2R CyA MMF 29% Cya MMF 43%

7 Study Novartis Multicenter Trial US MulticenterTrials Year F/Up Years #Pts AR Rate IL2R Cy MMF 20% IL2R Cy MMF Steroid 16% Astellas Double Thymo/IL2R Tac MMF 17.8% Blind CSWD Trial Thymo/IL2R/Tac MMF Steroid 10.8% IL2R Cy MMF 36% FREEDOM IL2R Cy MMF 7d Steroid 29.6% IL2R Cy MMF Steroids 19.3% INTAC Trial Hi Risk Thymo Tac MMF 13.1% Hi Risk Campath Tac MMF 12.7% Lo Risk IL2R Tac MMF 21.2% Lo Risk Campath Tac MMF 8.9% TRIMS Thymo Tac MMF 14% Tac MMF Steroids 20%

13 Design: Prospective, Double-Blind, Stratified Randomized PTD 3-7, 3 SCr 30% No HD Steroid Maintenance (CCS) N = 195 N = 386 Stratification: 1. Live vs. deceased donor 2. AA vs. non-aa Steroid Withdrawal (CSWD) 7 Days N = 191

15 Rejection Severity: Banff Grading p-value* CCS CSWD N=195 N=191 BCAR 21 (10.8%) 34 (17.8%) A B A 5 8 2B Missing 0 1 Severe AR** 12 (6.2%) 15 (7.9%) *Based on Fisher s Exact test **Severe AR is Banff s 95 2B or greater, or Banff s 97 2A or greater or antibody treated rejection

16 Rejection Therapy CCS CSWD N=195 N=191 Steroid Treatment Alone 8 28 Antilymphocyte Treatment *Based on Fisher s Exact test **Severe ACR is Banff s 95 2B or greater, or Banff s 97 2A or greater or antibody treated rejection

20 Cincinnati v Astellas Double Blind Trial Acute Rejection Multivariate Analyses 3 Obs Risk Thymo DM CPRA>25 AA DRmm>0 Female Dec Donor Cincy Fuji

21 Thymoglobulin Induction Effect Obs Risk NS 0.11 NS Repeat Tx DGF ppra>50 AA Female Dec Donor No Thymo Thymo

22 INTAC Trial 1

24 KAPLAN MEIER ESTIMATES OF REJECTION 21 Group 6m 12m 24m HR C1H Group 93.8% 6m 90.6% 12m 87.3% 24m HR HR C1H 90.4% 93.8% 86.9% 90.6% 86.9% 87.3% Thymo HR Thymo 90.4% 86.9% 86.9%

25 KAPLAN MEIER ESTIMATES OF REJECTION 23 Group 6m 12m 24m LR C1H 98.1% * 97.5% * 91.1% * LR Bas 83.0% *P = < % 78.8% * P < 0.05 * P < 0.0 5

27 Variable 308 Patients Acute Rejection Relative Risk # Pts With Risk Factor P value Repeat Transplant DGF NS Current PRA> NS African American NS HLA DR MM> NS Female Gender NS Live Donor NS Diabetes I Diabetes II Thymo Induction

Retrospective analysis of prospectively collected data (n = 52) 646 renal allograft recipients (transplanted between 1/1/2003 and 8/1/2007) were reviewed for renal allograft biopsy demonstrating ACR

28 Retrospective analysis of prospectively collected data (n = 52) 646 renal allograft recipients (transplanted between 1/1/2003 and 8/1/2007) were reviewed for renal allograft biopsy demonstrating ACR and/or AMR 52 were evaluated for DSA determinations at time of transplantation and at rejection diagnosis De novo DSA were defined as being absent at the time of transplantation, but present at time of rejection diagnosis

29 p < Time from Transplantation (Months) Death-Censored Allograft Survival

30 Predictors of Graft Loss Univariate Analysis Recipient age Recipient gender African-American Race Donor age Donor race Transplant type HLA AB mismatches Current PRA >20% or peak PRA >50% Flow Crossmatch (+ or -) Delayed Graft Function Repeat Transplant Mean baseline SCr >2mg/dL Time to bx Incidence of rejection reversal Repeat rejection Rejection Type DSA Treatment Everly et al. Abstract #1674. ATC 2008 (Toronto, Canada) p-values < 0.15 entered into the MVA

31 Predictors of Graft Loss Multivariate Analysis OR 95% CI p-value DSA Everly et al. Abstract #1674. ATC 2008 (Toronto, Canada)

35 Judging Steroid Free IS Results Cost Acute rejection Chronic rejection/can Benefits CV Risk Target Organ Damage (bone, skin, cataract)

36 Late Graft Loss and Steroid Elimination: The Great Misconception

37 Canadian Multicenter Trial Actuarial Graft Survival % Survival Years Differences in graft survival were statistically significant By Mantel-Cox test statistic ( p = 0.03) Placebo Prednisone

38 Canadian Multicenter Trial Risk factor analyses Weibull stepwise model HLA B mismatching Increased donor age Male recipient Donor death due to CVA Cox proportional hazards estimation Influence of assigned treatment was estimated to be p=0.10

39 Canadian Multicenter Trial Problem: Inadequate therapy in CSWD group Sandimmune monotherapy with inadequate trough levels Mean cyclosporine trough levels 1 yr 110 ng/ml 2 yr 107 ng/ml 3 yr 102 ng/ml Problem: No pathologic data in allograft losses

40 Canadian Multicenter Trial Problem: Inclusion of Repeat Transplant Recipients Accounts for Substantial Proportion of Graft Losses Graft Survival (%) Repeat Transplants: 5 Yr Graft Survival Placebo Prednisone

41 Late Graft Loss and Steroid Elimination The only data that exists is from the Canadian Multicenter trial, which indicates that the risk exists in high risk, but not low risk patients There is no data from randomized, controlled trials indicating that immunologic low risk populations are at increased risk of graft loss to CAN/chronic rejection/ IF/TA

42 Late Graft Loss and Steroid Elimination The assumed relationship between steroid elimination and late graft loss, is therefore hypothetical based on assumed risk related to association of acute rejection and chronic rejection

43 Late Graft Loss and Steroid Elimination If there is no increased risk of acute rejection, there should be no price to pay in terms of late graft loss with steroid elimination

44 CAN and the Astellas Double Blind Trial

46 Canadian Multicenter Trial Actuarial Graft Survival % Survival Years Differences in graft survival were statistically significant By Mantel-Cox test statistic ( p = 0.03) Placebo Prednisone

47 Primary Composite Endpoint Death, graft loss or moderate/severe acute rejection at 6 months and 1 through 5 years Moderate/severe acute rejection defined as Banff 97 grade > 2A Requiring antilymphocyte antibody therapy

52 Chronic Allograft Nephropathy at 5 Years CCS (n=195) CSWD (n=191) P value Biopsy confirmed CAN 8 (4.1%) 19 (9.9%) Biopsy confirmed CAN with pretransplant biopsy showing no chronic changes 2 (1%) 5(2.3%) NS

53 Astellas Trial: CAN Data Problems Not a predefined end point- post hoc analysis No protocol biopsies No central pathology review Lack of pretransplant/postreperfusion biopsies

54 Calculated Creatinine Clearance 100 CCS CSWD 80 ml/min Post-transplant Month

56 Multivariate Analysis: Risk Factors For Graft Loss RISK FACTORS Relative Risk p-value* CCS vs. CSWD With CAN vs. Without CAN <0.001 AA vs. Non-AA With AR vs. Without AR Living Donor vs. Deceased Donor *Based on Cox Proportional Hazard model

57 Causes of Death Cause of Death CCS (n=195) CSWD (n=191) All Deaths 13 (6.7%) 11 (5.8%) P value Infection 6 (3.1%)

58 Graft Survival Astellas US Trial Canadian Trial Survival (%) CCS CSWD % S u r v i v a l CCS CSWD Years

59 Judging Steroid Free IS Results Price Acute rejection CAN Advantages CV Risk Target Organ Damage (bone, skin, cataract)

61 Corticosteroid Dosing > Day 7 Long-term steroids PTD mg/kg/d PTD mg/kg/d PTD mg/kg/d PTD mg/kg/d PTD mg/kg/d PTD > mg/d Corticosteroid cessation PTD >7 placebo

62 NODAT Cause of Death CCS (n=97) CSWD (n=112) P value Experienced hyperglycemia 21 (24.4%) 35 (32.7%) NS % on therapy at assessment 18 (20.9%) 23 (21.5%) NS % on insulin > 30 days 10 (11.6%) 4 (3.7%) % on oral hypoglycemics 8 (9.3%) 19 (17.8%) 0.10 *NODAT=new onset diabetes after transplant **Based on Fisher s Exact test ***Hyperglycemia is defined as fasting glucose 126 mg/dl on at least one occasion or required therapy

63 Hgb-A 1 C Patients with NODAT H g A1C ( % ) CCS CSWD p = p = p = p = p = p = Post-transplant Month

64 Hyperlipidemia Therapy at 5 Years CCS CSWD p-value N=136 N=140 Required Therapy 100 (73.5%) 87 (62.1%) 0.053

65 Triglycerides: Mean Change From Baseline m g /d L p = p = p = p = p = 0. p = CCS CSWD Post-transplant Month

66 Cholesterol Mean Change From Baseline * * * * * p<0.05 CCS CSWD 40 mg/dl Post-transplant Month

67 Hypertension During 5 Years CCS N = 195 CSWD N = 191 p-value* Experienced HTN 182 (93.3%) 179 (93.7%) Severity of HTN Mild 126 (69.2%) 120 (67.0%) Moderate 46 (25.3%) 46 (25.7%) Severe 10 (5.5%) 13 (7.3%) Treatment for HTN 181 (92.8%) 173 (90.6%) Mean # of Medications** *Based on Fisher s Exact test **Based on t-test

70 Judging Steroid Free IS Results Price Acute rejection CAN Advantages CV Risk Target Organ Damage (bone, skin, cataract)

73 Bone Complications During 5 Years p-value CCS CSWD N=195 N=191 Fractures or Avascular Necrosis 22 (11.3%) 10 (5.2%) 0.041

74 A Randomized, Prospective, Multicenter Comparative Study Evaluating A Thymoglobulin-based Early Corticosteroid Cessation Regimen in Renal Transplantation (TRIMS TM ) TRIMS Study Group

75 Corticosteroid Related Adverse Events ECSWD (n=103) CCST (n=48) Cataracts 0 0 Avascular Necrosis 0 1 (2.1%) Fractures 1 (1.0%) 0 Osteopenia/Osteoporosis 6 (5.8%) 5 (10.4%)

76 Patient Survival Kaplan Meier Estimates CSWD CS P< Time (Months)

77 Cardiovascular Event-Free Survival Kaplan Meier Estimates 1.0 CSWD CS These curves start to diverge at about 3 years posttransplant 0.2 P< Time (Months)

78 Death Censored Graft Survival: Acute rejection versus None Death Censored Allograft Survival (%) p P<0.001 No Acute Rejection (N = 514) All Acute Rejection (N = 116) Time (Months)

79 Death Censored Graft Survival: Early rejection versus Late rejection versus None All curves: p<0.001 Early vs Late: p<0.014 Early vs None: p<0.004 Late vs None: p<0.001

80 Early and Late AR Differentially Affects Long term GS in Living and Deceased Donor Transplants

81 Conclusions The risk/benefit equation of steroid free immunosuppression has shifted considerably Acute rejection The risk of acute rejection with T cell depleting induction therapy in steroid free regimens is very low or nonexistent No increased risk exists in immunologic low risk populations The acute rejection risk, when present, is primarily for low grade, steroid sensitive lesions

82 Conclusions The risk/benefit equation of steroid free immunosuppression has shifted considerably Late graft loss Long term graft survival and functional data show no differences out to five years CAN data from Astellas study serious limitations Counterbalanced by increased graft loss to infectious death and other causes in control group Best available histologic data demonstrate no differences in chronic lesions between steroid free and steroid treated populations

83 Conclusions The risk/benefit equation of steroid free immunosuppression has shifted considerably CV Risk Considerable data exists indicating reduction in cardiovascular risk factors with steroid free immunosuppression Triglycerides > diabetes > hypertension / cholesterol Nonrandomized data indicates that CV events are greater in steroid treated patients, but it does not become evident until at least five years

84 Conclusions The risk/benefit equation of steroid free immunosuppression has shifted considerably Target organ damage Bone disease/fractures Cataracts Most other effects have not been measured, eg, dermal thinning

85 Conclusions The preponderance of data now indicates that minimization of maintenance steroid elimination, is associated with A low risk of acute rejection, almost exclusively in high risk populations Acute rejection risk can be minimized by T cell depleting induction therapy No apparent long term graft survival risk CV risk benefits

87 US Trials CV Risk Study Novartis Multicenter Trial Astellas Double Blind CSWD Trial Group Thymo/IL2R TacMMF Thymo/IL2R/TacMMF Steroid FREEDOM INTAC Trial Univ. Minnesota Northwestern

88 Study Treatments Induction ECSWD Thymoglobulin 1.5 mg/kg x 4 doses (Total dose = 6mg/kg) CCST No Antibody Induction Corticosteroids Day 0 Day 1 Day 2 Day 3 Day 4 Methylprednisolone 500mg IV Prednisone 1mg/kg Prednisone 0.5 mg/kg Prednisone 0.5 mg/kg Prednisone 0.25 mg/kg Methylprednisolone 500mg IV Prednisone 1mg/kg Prednisone 0.5 mg/kg Prednisone Taper (Min. 5mg/day for > 90 days) Tacrolimus 0.1 mg/kg/day BID (Day 1), then per institutional standards Mycophenolate Mofetil 1 gm PO/IV Day 0 1 gm PO BID Day 1-4, then per institutional standards ECSWD = Early CorticoSteroid WithDrawal, CCST = Chronic CorticoSteroid Therapy

89 Kaplan-Meier estimate by treatment: Time to biopsy-proven acute rejection, graft loss or death ECSWD CCST p= by log-rank

90 Kaplan-Meier Estimates by Treatment: Time to biopsy-proven acute rejection ECSWD CCST p= by log-rank

91 Disclosures

92 Disclosures

93 Early Steroid Withdrawal University of Minnesota Reported 2005 Patients transplanted Prospective, consecutive, nonrandomized, single center 5 day thymoglobulin induction, 5 day steroid taper, CsA/MMF maintenance (or tacrolimus/sirolimus) 589 patients all with a minimum follow up of 1 year (1 5 years) At follow up, 86% of all patients remain steroid free 1 year 5 year Patient survival 97% 91% Graft survival 95% 84% DC Graft 98% 92% AR LD 11% 15% AR DD 16% 20% (4-yr) CAN LD 2% 13% CAN DD 6% 10% (4-yr) DC = death censored; LD = living donor; DD = deceased donor; CAN = chronic allograft nephropathy. Matas AJ, et al. Am J Transplant. 2005;5:

94 Study Selection and Evaluation Early CS elimination (within 7 days) Randomized Multicenter

SELECTED ABSTRACTS. All (n) % 3-year GS 88% 82% 86% 85% 88% 80% % 3-year DC-GS 95% 87% 94% 89% 96% 80%

SELECTED ABSTRACTS. All (n) % 3-year GS 88% 82% 86% 85% 88% 80% % 3-year DC-GS 95% 87% 94% 89% 96% 80% SELECTED ABSTRACTS The following are summaries of selected posters presented at the American Transplant Congress on May 5 9, 2007, in San Humar A, Gillingham KJ, Payne WD, et al. Review of >1000 kidney