Pleiotropic effects of mtor inhibitors : cardiovascular and cancer. Dr Paolo Malvezzi Clinique de Néphrologie CHU Grenoble

Transcription

1 Pleiotropic effects of mtor inhibitors : cardiovascular and cancer Dr Paolo Malvezzi Clinique de Néphrologie CHU Grenoble Tehran August 2016

2 Why this topic? Since last year very little news in the immunosuppressive drug field : No new drug in maintenance It s time to assess the qualities and risks of existing drugs : We now have sufficient experience and hindsight to do so

3 Mechanisms of action of immunosuppressants Basiliximab Steroids Bélatacept 3 3

4 Signal 3 is provided by stimulation of the mtor pathway by IL2 and other cytokines IL2 CD25 PIP 3 PI3K PI-3K PIP 2 PI-3K / Akt pathway signalling influences T-cell proliferation, expansion and migration 1 3 PI3K PI-3K The pathway also controls lymphocyte size and metabolic activity 4,5 AKT1 e1f4e mtor P70SK6 CDK2/ / cycline E P27 KIP Cell cycle progression G1 S phase Translation Protein synthesis IL2, interleukin-2; mtor, mammalian target of rapamycin; PI- 3K, phosphoinositide 3 kinase. Cyclin A 1. Song J et al. Cell Mol Immunol. 2008;5: ; 2. Finlay D, Cantrell D. Ann N Y Acad Sci. 2010;1183: ; 3. Colombetti S et al. J Immunol. 2006;176: ; 4. Fruman DA. Curr Opin Immunol. 2004;16: ; 5. Prlic M, Bevan MJ. Nature. 2009;460:41 42.

5 mtor: An important role in several physiological processes mtor Effects of mtor stimulation Translation Proliferation Angiogenesis Transplant-specific downstream effects of mtor stimulation Used by CMV for replication T cells Endothelial cells Malignancy Effect of mtor inhibition Potential antiviral effect Reduce vascular remodelling and fibrosis Immunosuppression Antimalignancy effects mtor, mammalian target of rapamycin. Immunoregulation Drug-eluting stents Renal cancer Breast cancer Tuberous sclerosis

6 What were the hopes when mtor-inhibitors were launched? To be as effective as CNIs as immunosuppressants but with less nephrotoxicity To protect from chronic allograft nephropathy in the setting or organ transplantation To have antineoplastic effects To have an antiviral effect

7 CARDIOVASCULAR EFFECTS

8 CVD in kidney transplantation is a significant risk factor CVD events continue to be a major cause of death with a functioning graft 1 CVD events are a significant contributor to posttransplant graft loss ² Diabetes is a common PRETRANSPLANT finding and an increasing indication for kidney transplantation, but is a key risk factor for subsequent cardiovascular events 3 Immunosuppressive medication can be modified to reduce the risk of CVD CVD, cardiovascular disease. 1. Pilmore H et al. Transplantation 2010;89: Fellström B et al. Am J Transplant 2005;5: Hjelmesaeth J et al. Kidney Int 2006;69: Holdaas H. Am J Cardiovasc Drugs 2005;5:

9 Death rate (per 100 patient-years) CVD continues to be a major cause of death with a functioning graft Cardiovascular Malignancy Infection Other CVD, cardiovascular disease. Data from the Australia and New Zealand Dialysis and Transplant registry; Pilmore H et al. Transplantation 2010;89:851 7.

10 CVD events (%) Renal allograft impairment increases the risk of some CVD events (ALERT trial; placebo arm) Creatinine <200 mmol/l Creatinine >200 mmol/l *** *** *** *** Myocardial infarction Stroke MACE Cardiac death Noncardiovascular death All-cause mortality ALERT trial : 2102 adult KTR; > 6 months posttransplantation; CsA-based immunosuppresion; increased serum total cholesterol; 1st patient 1996; randomized to either placebo or fluvastatin therapy 40mg/d 2y then 80mg/d; follow-up > 5y. ***p< CVD, cardiovascular disease; MACE, major adverse cardiac event. Fellström B et al. Am J Transplant 2005;5:

11 CVD events (%) Graft loss increases the risk of some CVD events (ALERT trial; placebo arm) No graft loss Graft loss ** *** ** * 5 0 Myocardial infarction Stroke MACE Cardiac death Noncardiovascular death All-cause mortality *p<0.02; **p<0.005; ***p< CVD, cardiovascular disease; MACE, major adverse cardiac event. Fellström B et al. Am J Transplant 2005;5:

12 Can mtor inhibitors reduce cardiovascular risk? (1) Reduction in CNI-related complications May improve renal function 1,2 Hypertension less frequent with mtori therapy vs. CNI 3,4 Dyslipidaemia more frequent with mtori therapy 1,5 7 but is dose dependent 7 and can be well managed with statins CNI, calcineurin inhibitor; CV, cardiovascular; LVH, left ventricular hypertrophy; LVMi, left ventricular mass index; mtori, mammalian target of rapamycin inhibitor; PWV, pulse wave velocity. 1. Tedesco Silva H Jr et al. Am J Transplant 2010;10: Budde K et al. Lancet 2011;377: Morales JM et al. Transplant Proc 2005;37: Zeier M, van der Giet M. Transpl Int 2011;24: Webster AC et al. Transplantation 2006;81: Kasiske BL et al. Am J Transplant 2008;8: Walker R et al. Presented at: American Transplant Congress; Apr 30 May 4, 2011; Philadelphia, PA; Abstract 1295.

13 Can mtor inhibitors reduce cardiovascular risk? (2) Potential cardioprotective effects of mtor inhibitors: Preliminary studies using surrogates of CV risk suggest that conversion to mtori therapy may improve CV risk posttransplant 8 10 LVH as assessed by LVMi Arterial stiffness as assessed by pulse wave velocity (PWV) index or augmentation index Animal data suggest that mtor inhibitors may restrict atherosclerosis 11 CNI, calcineurin inhibitor; CV, cardiovascular; LVH, left ventricular hypertrophy; LVMi, left ventricular mass index; mtori, mammalian target of rapamycin inhibitor; PWV, pulse wave velocity. 8. Paoletti E et al. Am J Kidney Dis 2008;52: Seckinger J et al. J Hypertens 2008;26: van der Giet M et al. Am J Transplant 2010;10(suppl 4):506; Abstract Zeier M, van der Giet M. Transpl Int 2011;24:30 42.

14 Patient survival (%) Presence of LVH is a strong determinant of risk of CVD LVH is detected in 74% of patients at start of dialysis 1 LVH in the 5th year after transplant predicted death (RR 2.15) LVH in 5th year (n=38) No LVH in 5th year (n=236) p= Time posttransplant (years) CVD, cardiovascular disease; LVH, left ventricular hypertrophy; RR, relative risk Foley RN et al. Kidney Int 1995;47: Rigatto C et al. J Am Soc Nephrol 2003;14:462 8.

15 Everolimus for regression of left ventricular hypertrophy (1) 30 non diabetic de novo KT patients: 21 men, age years) were randomized 1:2 ratio to EVR plus reduced exposure to CsA vs. standard exposure to CsA + MMF (steroids for all) Paoletti E et al. Transplantation 2012:93:503.

16 Everolimus for regression of left ventricular hypertrophy (2) P= Average behavior of left ventricular mass index (LVMi) in KTRs receiving everolimus (EVL) ([Black Square]) and KTR controls ([white square]) during a 1-year observation period. Variable Beta coefficient P EVL therapy Baseline LVMi (g/m²) Predictors of 1 yr changes in LVMi for 10 RTRs administered EVL and for 20 controls, by multivariate analysis -16- Paoletti E, et al. Transplantation 2012;93:

17 Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients Murbraech K et al. Clin Transplant 2015: 29:

18 Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients: baseline characteristics Murbraech K et al. Clin Transplant 2015: 29:

19 Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients Murbraech K et al. Clin Transplant 2015: 29:

20 Grafts surviving (%) Graft survival is related to 1-year systolic blood pressure Cadaver kidney recipients <130 mmhg (n=5540) (n=4227) (n=4414) (n=2551) (n=1746) (n=696) >180 (n=694) Time posttransplant (years) Opelz G et al. Kidney Int 1998;53:

21 mtori-based regimens may reduce hypertension Blood pressure parameters in randomised trials investigating mtori-based regimens Study name / description Study design n Parameter Legendre et al De novo sirolimus vs CsA 161 Sirolimus with tacrolimus Grinyo et al elimination vs sirolimus + tacrolimus Rapamune Sirolimus with CsA Maintenance elimination at month 3 vs Study 3 sirolimus + CsA Sirolimus with CsA Baboolal elimination at month 3 vs sirolimus + CsA Bertoni et al De novo CNI minimisation with everolimus vs CsA A De novo CNI minimisation with everolimus vs CsA Hypertension (TE), % Mean blood pressure, mmhg Mean arterial pressure, mmhg Hypertension as adverse event, % Mean systolic blood pressure, mmhg Hypertension as adverse event, % Treatment group Outcome Sirolimus 29.6 CsA 47.5 Sirolimus 132/75.6 Tacrolimus 141/80.4 Sirolimus 97.1 CsA Sirolimus 26.2 CsA 40.0 Everolimus 125 CsA 131 Everolimus 29.6 CsA 30.0 p value a ns 0.03 a Diastolic only. CNI, calcineurin inhibitor; CsA, cyclosporin; mtori, mammalian target of rapamycin inhibitor; ns, not significant; TE, treatment emergent. 1. Legendre C et al. Transplant Proc 2003;35(suppl):151S 3S. 2. Grinyo JM et al. Am J Transplant 2004;4: Oberbauer R et al. Transpl Int 2005;18: Baboolal K. Transplantation 2003;75: Bertoni E et al. Transpl Int 2009;22(suppl 2):91; Abstract LB1. 6. Tedesco Silva H Jr et al. Am J Transplant 2010;10:

22 In conclusion mtor inhibitors: Probably reduce CV risk in transplant patients: whether their use raises both graft and/or patient survival is debatable. The beneficial effect is probably true in specific high risk sub-groups.

23 ANTI NEOPLASTIC EFFECTS

24 Risk of cancer post-transplant 1965 to 31 March 2001 Primary CD & LD ANZDATA Registry JAMA, December 20, 2006 Vol 296, No. 23

25 Cancer risk following kidney transplantation AUS +NZ JAMA, December 20, 2006 Vol 296, No. 23

26 Risk factors associated with de novo cancer posttransplantation 26

27 mtor inhibitors may reduce the incidence of post-transplant de novo malignancies De novo malignancies a De novo non-skin solid malignancies a Drug group Transplants, n n % n % CsA / tacrolimus alone 30, Sirolimus / everolimus + CsA / tacrolimus b Sirolimus / everolimus alone c a Within 963 days of transplant; b p< for de novo malignancies and p= for de novo non-skin solid malignancies vs. CsA / tacrolimus alone; c p=0.041 for de novo malignancies and p=0.011 for de novo non-skin solid malignancies vs. CsA / tacrolimus alone mtori, mammalian target of rapamycin inhibitor; CNI, calcineurin inhibitor; CsA, ciclosporin 27 Kauffman HM et al. Transplantation 2005;80:883-9

28 Rapamune Maintenance Regimen (Study 310) Design Discontinued Before randomization n=95 SRL-CsA-ST n=215 Sirolimus > 5 ng/ml + CsA + Steroids ng/ml N=525 3 months + 2 weeks Patients with a history of malignancy within 5 years before transplantation, other than adequately treated BCC or SCC, were excluded. CsA Stopped (25% per week) SRL-ST n=215 Sirolimus* (> 5 ng/ml) CsA ( ng/ml) Steroids -28- Sirolimus* (20-30 ng/ml 1 yr) Steroids (15-25 ng/ml > 1 yr) Johnson RWG et al. Transplantation 2001; 72:

29 Sirolimus therapy in de novo KTx and de novo posttransplant malignancies (1) RMR study: On-therapy RMR study: ITT Analysis of any skin carcinoma. (A) Kaplan-Meier plot of time to first skin carcinoma. (B) Cumulative number of skin carcinomas Analysis of any skin carcinoma. (A) Kaplan-Meier plot of time to first skin carcinoma. (B) Cumulative number of skin carcinomas. Campistol JM et al. JASN 2006;17:

30 Sirolimus therapy in de novo KTx and de novo posttransplant malignancies (2) Kaplan-Meier plots of time to non-skin malignancies. (A) On-therapy. (B) Intention-to-treat Campistol JM et al. JASN 2006;17:

31 CONCEPT study Open label randomized prospective multicentric French study evaluating conversion from CsA to sirolimus 3 months after kidney transplantation MMF+ SRL group (n = 95) Daclizumab + Mycophenolate mofetil + Ciclosporine + STÉROIDS Week12 Randomization (n = 192) Transplantation (n = 235) MMF + CsA group (n = 97) Non-randomization criteria at 3 months Acute rejection Creatinine clearance < 40 ml/mn Proteinuria > 1 g/d MMF dose < 1.5 g/d Sirolimus (SRL) STEROID WITHDRAWAL AT 8 MONTHS Ciclosporine (CsA) 31 Lebranchu et al. AJT, 2012

32 CONCEPT study: 60 Month Results % Cancers 13,2 5 6,3 0 SRL CsA 32 Lebranchu Y et al. AJT, 2012

33 The CONVERT study : SRL conversion vs. CNI continuation Pre-randomization: Steroids MMF or AZA CsA or Tacrolimus Screening 2:1 Randomization SRL conversion Day 1: Stop CNI; SRL, mg x 1 Day 2: SRL 4-8 mg/day Days 5-7: Adjust to 8-20 ng/ml MMF or AZA: Continue or stop Continue steroids CNI continuation Continue CsA or TAC (can switch CsA TAC) MMF or AZA: continue or stop Continue steroids Routine follow-up per protocol SRL target trough concentrations based on chromatographic methods -33- Schena et al. Transplantation 2009

34 Significantly lower malignancy rates with sirolimus at 18 months (CONVERT study) 10 p < ,6 CNI (n = 555) SRL (n = 275) Rate, % 5 0 p = ,7 2,0 1,1 p = ,5 0,5 0,0 p < ,0 Total Skin PTLD All others -34- Schena et al. Transplantation 2009

35 mtori and Kaposi sarcoma Kaposi s sarcoma lesions in patient receiving MMF, CsA and steroids 1 month postconversion to sirolimus

36 Sirolimus conversion for Kaposi s sarcoma in renal transplant recipients 36 Campistol JM et al. Transplantation 2004; 77:

37 Incidence per person years (Inc) and standardized incidence ratios (SIR) taking account of age, gender and geographical region Opelz et al.nephrol Dial Transplant (2016) 0: 1 8

38 Immunosuppression with m-tor inhibitor and incidence of post-transplant cancer in kidney transplant recipients Opelz et al.nephrol Dial Transplant (2016) 0: 1 8

39 Immunosuppression with m-tor inhibitor and incidence of post-transplant cancer in kidney transplant recipients Basal cell carcinoma Squamous cell carcinoma Opelz et al.nephrol Dial Transplant (2016) 0: 1 8

40 Immunosuppressive balance and risk of cancer mtori HCV (HCC) HPV (Skin cancer) EBV (PTLD) Infection mtori Tumor Cell Growth All immunosuppressive drugs Immune System Metastasis mtori mtori Angiogenesis IS Cancer mtori Cancer-Free Malignancy 40

41 In conclusion mtor inhibitors: Reduce non-melanoma skin cancer risk in transplant patients especially basocellular carcinomas, probably not solid cancer risk. This action needs to be proven against tacrolimus based IS.

42 THANK YOU Valverde G. La Anatomia, Giunti Ed. 1586