B Rauer

Three-year Outcomes in de Novo Liver Transplant Patients Receiving Everolimus with Reduced Tacrolimus: Follow-Up Results from a Randomized, Multicenter Study

Background Data are lacking regarding the long-term effect of preemptive conversion to everolimus from calcineurin inhibitors early after liver transplantation to avoid renal deterioration. Methods In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30 to (i) everolimus + reduced exposure tacrolimus (EVR + Reduced TAC), (ii) everolimus + tacrolimus elimination (TAC Elimination), or (iii) standard exposure tacrolimus (TAC Control). Results Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR) during TAC withdrawal. Of 370 patients who completed the 24-month core study on-treatment, 282 (76.2%) entered an additional 12-month extension phase. The composite efficacy failure endpoint (tBPAR, graft loss or death) occurred in 11.5% of EVR+Reduced TAC patients versus 14.6% TAC Controls from randomization to month 36 (difference, ‐3.2%; 95% confidence interval, ‐10.5% to 4.2%; P = 0.334). Treated BPAR occurred in 4.8% versus 9.2% of patients (P = 0.076). From randomization to month 36, mean (SD) estimated glomerular filtration rate decreased by 7.0 (31.3) mL/min per 1.73 m2 in the EVR+Reduced TAC group, and 15.5 (22.7) mL/min per 1.73 m2 in the TAC Control group (P = 0.005). Rates of adverse events, serious adverse events, and discontinuation due to adverse events were similar in both groups during the extension. Conclusions A clinically relevant renal benefit after introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation was maintained to 3 years in patients who continued everolimus therapy to the end of the core study, with comparable efficacy and no late safety concerns.

Methodological challenges in monitoring new treatments for rare diseases: lessons from the cryopyrin-associated periodic syndrome registry

BackgroundThe Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID). Canakinumab is a monoclonal antibody directed against IL-1 beta and approved for CAPS patients but requires post-approval monitoring due to low and short exposures during the licensing process. Creative approaches to observational methodology are needed, harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring.MethodsA web-based registry was set up to collect information on long-term safety and effectiveness of canakinumab for CAPS.ResultsStarting in November 2009, this registry enrolled 241 patients in 43 centers and 13 countries by December 31, 2012. One-third of the enrolled population was aged < 18; the overall population is evenly divided by gender. Enrolment is ongoing for children.ConclusionsInnovative therapies in orphan diseases require post-approval structures to enable in depth understanding of safety and natural history of disease. The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow-up. Broad international practice-based recruitment and web-based data collection are practical.

Sustained Virological Response to Antiviral Therapy in a Randomized Trial of Cyclosporine versus Tacrolimus in Liver Transplant Patients with Recurrent Hepatitis C Infection

BACKGROUND Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection. MATERIAL AND METHODS In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis. RESULTS The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups. CONCLUSIONS Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

Everolimus and reduced calcineurin inhibitor therapy in pediatric liver transplant recipients: Results from a multicenter, prospective study

In a 24‐month, multicenter, single‐arm, prospective study, 56 pediatric liver transplant patients with or without basiliximab induction were converted at 1‐6 months post‐transplant from standard calcineurin inhibitor (CN) therapy (± mycophenolic acid), to everolimus with reduced exposure to CNI (tacrolimus n=50, cyclosporine n=6). Steroid therapy was optional. Recruitment was stopped prematurely due to high rates of PTLD, treatment‐related serious infections leading to hospitalization and premature study drug discontinuation. Subsequently, patients aged <7 years reverted to local standard‐of‐care immunosuppression. Mean tacrolimus concentration was above or near the upper end of the maintenance target range (2‐5 ng/mL) until after month 6 post‐enrollment. The primary variable, mean (SD) change in eGFR from baseline to month 12 (last observation carried forward), was +6.2 (19.5) mL/min/1.73 m2. Two patients experienced treated biopsy‐proven acute rejection. No graft losses or deaths occurred. PTLD occurred in five patients (8.9%) (3/25 [12.0%] patients <2 years, 2/31 aged 2‐18 years [6.5%]). Adverse events, serious adverse events, and discontinuation due to adverse events were reported in 100.0%, 76.8%, and 44.6% of patients, respectively. In conclusion, everolimus with reduced CNI improved renal function while maintaining antirejection potency in pediatric liver transplant patients but safety outcomes suggest that patients were overimmunosuppressed.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

In a 12‐month, multicenter, open‐label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co‐primary efficacy end point (biopsy‐proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co‐primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Everolimus With Reduced Tacrolimus Preserves Long-Term Renal Function in Liver Transplant Recipients: 36 and 48 Months Results From The H2304E1 Study.: Abstract# 2187

2187 Everolimus With Reduced Tacrolimus Preserves Long-Term Renal Function in Liver Transplant Recipients: 36 and 48 Months Results From The H2304E1 Study. J. Fung, F. Saliba, G. Kaiser, L. De Carlis, H. Metselaar, F. Nevens, C. Duvoux, P. De Simone, L. Fischer, G. Dong, B. Rauer, G. Junge. H2304E1 Study Group, Cleveland. Purpose: Preserving long-term renal function in liver transplant recipients (LTxRs) remains a major concern. This study evaluates if early introduction of everolimus (EVR) with reduced tacrolimus (rTAC) provides long-term renal benefi ts in LTxRs. Methods: Patients who completed the 24 month (M) randomized H2304 study could continue their assigned treatment regimen during the 12M extension study (H2304E1): EVR+rTAC (N=106, EVR C0 3-8 ng/mL; TAC C0 3-5 ng/mL) or TAC-C (N=125, C0 6-10 ng/mL). In the extension phase, patients in the EVR+rTAC arm were studied for 12M followed by an additional 12M follow-up on the same regimen. Key primary endpoint was renal function assessed by estimated GFR (eGFR) using MDRD4. Additionally, evolution of renal function from M24 to M36 was explored using a mixed-effect model for longitudinal data. Results: At M36, the EVR+rTAC arm had lower incidence of composite effi cacy failure (11.5% vs 14.6% in TAC-C, risk difference -3.2%, 97.5% CI: -10.5, 4.2; p=0.334). Renal function (mean eGFR) was superior with EVR+rTAC vs TAC-C (78.7 vs 63.5 mL/min/1.73m2) with a difference of 15.2 mL/min/1.73m2 in favor of the EVR+rTAC arm (p<0.001; all extension patients). Proportion of patients with eGFR <60 mL/min/1.73m2 was signifi cantly lower with EVR+rTAC (28.0% vs 42.6% in TAC-C, p=0.032). From randomization to M36, decline in eGFR by ≥30% was reported for 20.0% of patients in the EVR+rTAC arm vs 28.7% in the TAC-C arm. At M48, mean eGFR in the EVR+rTAC arm was 80.5 mL/min/1.73m2 and the number of patients with eGFR <60 mL/min/1.73m2 decreased to 15%. From M24 to M36, longitudinal data analysis for eGFR showed no change in renal function for the EVR+rTAC arm vs a decrease for TAC-C arm (0.04 vs -0.26 mL/min/1.73m2/month). Fewer patients in the EVR+rTAC vs TAC-C arm experienced renal failure (2 vs 10) and renal impairment (1 vs 3) with none vs 2 patients discontinuing study medication due to these adverse events. Proteinuria (≥3 g/day) was not reported in either arm. Conclusion: Early introduction of EVR to reduce TAC exposure preserves longterm renal function in LTxRs. The 48M data show that a notable renal function was maintained for patients on EVR with rTAC. DISCLOSURE: Fung, J.: Other, Novartis, Advisory Committee, Vital Therapies, Consultant. Saliba, F.: Grant/Research Support, Novartis, Astellas, Roche and Gambro, Speaker’s Bureau, Schering Plough, MSD and Gambro, Other, Novartis, Astellas, Roche, Genzyme, Advisory committee, Viropharma and Vital Therapies, Advisory committee. Kaiser, G.: Grant/Research Support, Novartis, Astellas, Roche and Pfi zer. Metselaar, H.: Grant/Research Support, Astellas, Biotest and Novartis, Speaker’s Bureau, Astellas, Biotest and Novartis. Nevens, F.: Grant/ Research Support, Ipsen, Roche, MSD, Jansen, CAF, Astellas, Ferring, Eumedica, and Boston Scientifi c. Duvoux, C.: Grant/Research Support, Novartis, Astellas and Roche, Speaker’s Bureau, Astellas, Other, Novartis, Data Safety Monitoring board member. De Simone, P.: Other, Novartis, Consultant. Fischer, L.: Grant/Research Support, Novartis, Astellas, Speaker’s Bureau, Gilead Sciences, Other, Novartis, Advisory committee. Dong, G.: Employee, Novartis. Rauer, B.: Employee, Novartis. Junge, G.: Employee, Novartis. Abstract# 2188 Liver Allograft Provides Immunoprotection Against Both Acute Cellular Immunity and Chronic Humoral Injury in Simultaneous Liver-Kidney (SLK) Transplantation. T. Taner, J. Heimbach, M. Stegall. Mayo Clinic, Rochester, MN. In SLK, the liver appears to protect the kidney from antibody-mediated injury (AMR), however its ability to protect against cell-mediated or chronic injury are less clear. The goal of this study was to compare SLK to kidney transplant (KT) recipients by assessing the; 1) incidence of acute cellular (ACR) and AMR (both clinical and subclinical), and 2) chronic changes seen in kidney allograft protocol biopsies up to 5-yr after transplantation. Methods: 68 SLK recipients were matched (age, race and sex) with 128 KT recipients. Demographic, laboratory, protocol kidney biopsy (4 mo, 1-, 2and 5-yr) and donor-specifi c HLA antibody (DSA) (baseline, 4 mo, 1-yr and yearly thereafter) data were reviewed. Maintenance immunosuppression dose was lower in KT. 232 kidney biopsies in SLK (median 3, range 1-9) and 487 in KT (median 4, range 1-9) were reviewed; incidence of events analyzed by Kaplan-Meier. Mean follow up was 67 months (±40) in both groups. Results: Patient survival was 89.7 vs 85.2%, kidney graft survival was 82.4 vs 70.3%, in SLK and KT, respectively. Four kidney grafts were lost to rejection in KT (2 ACR, 1 AMR, 1 both), none in SLK. The median eGFR at 1and 5-yr were 53 and 53 in SLK; 52 and 48 in KT. Humoral alloimmunity: DSA (MFI>2000) was present at transplant in 14 SLK (10 with +XM, 14.7%) and 7 KT (all with +XM, 5.5%). One patient in each group had persistent class II DSA post-transplant. De novo DSA, predominantly class II, was found in 11 SLK and 9 KT recipients. Patients with de novo DSA were more likely to be non-compliant (5/11 in SLK and 6/9 in KT), and have liver graft dysfunction in SLK (6/11). 5-yr cumulative incidence of AMR was similar in SLK (7.4%) and KT (9.4%). Cellular immunity: ACR was signifi cantly rarer in SLK (7.4%) than in KT (28.9%) (P=0.001).Most of the ACR were subclinical (80% in SLK and 69% in KT). Chronic changes at 5-yr were similar in SLK vs KT (interstitial fi brosis 27.9 vs 22.7%; arteriolar hyalinosis 13.2 vs 14.1%). Importantly, chronic glomerulopathy (usually associated with humoral injury) was more common in KT at 5-yr (8.6% vs 1.5%, P=0.06). Conclusions: Compared to KT, SLK appears to be associated with lower rates of ACR and fewer chronic changes associated with 2188 Liver Allograft Provides Immunoprotection Against Both Acute Cellular Immunity and Chronic Humoral Injury in Simultaneous Liver-Kidney (SLK) Transplantation. T. Taner, J. Heimbach, M. Stegall. Mayo Clinic, Rochester, MN. In SLK, the liver appears to protect the kidney from antibody-mediated injury (AMR), however its ability to protect against cell-mediated or chronic injury are less clear. The goal of this study was to compare SLK to kidney transplant (KT) recipients by assessing the; 1) incidence of acute cellular (ACR) and AMR (both clinical and subclinical), and 2) chronic changes seen in kidney allograft protocol biopsies up to 5-yr after transplantation. Methods: 68 SLK recipients were matched (age, race and sex) with 128 KT recipients. Demographic, laboratory, protocol kidney biopsy (4 mo, 1-, 2and 5-yr) and donor-specifi c HLA antibody (DSA) (baseline, 4 mo, 1-yr and yearly thereafter) data were reviewed. Maintenance immunosuppression dose was lower in KT. 232 kidney biopsies in SLK (median 3, range 1-9) and 487 in KT (median 4, range 1-9) were reviewed; incidence of events analyzed by Kaplan-Meier. Mean follow up was 67 months (±40) in both groups. Results: Patient survival was 89.7 vs 85.2%, kidney graft survival was 82.4 vs 70.3%, in SLK and KT, respectively. Four kidney grafts were lost to rejection in KT (2 ACR, 1 AMR, 1 both), none in SLK. The median eGFR at 1and 5-yr were 53 and 53 in SLK; 52 and 48 in KT. Humoral alloimmunity: DSA (MFI>2000) was present at transplant in 14 SLK (10 with +XM, 14.7%) and 7 KT (all with +XM, 5.5%). One patient in each group had persistent class II DSA post-transplant. De novo DSA, predominantly class II, was found in 11 SLK and 9 KT recipients. Patients with de novo DSA were more likely to be non-compliant (5/11 in SLK and 6/9 in KT), and have liver graft dysfunction in SLK (6/11). 5-yr cumulative incidence of AMR was similar in SLK (7.4%) and KT (9.4%). Cellular immunity: ACR was signifi cantly rarer in SLK (7.4%) than in KT (28.9%) (P=0.001).Most of the ACR were subclinical (80% in SLK and 69% in KT). Chronic changes at 5-yr were similar in SLK vs KT (interstitial fi brosis 27.9 vs 22.7%; arteriolar hyalinosis 13.2 vs 14.1%). Importantly, chronic glomerulopathy (usually associated with humoral injury) was more common in KT at 5-yr (8.6% vs 1.5%, P=0.06). Conclusions: Compared to KT, SLK appears to be associated with lower rates of ACR and fewer chronic changes associated with DSA, although SLK recipients had a higher prevalence of DSA pretransplant and were maintained on lower doses of immunosuppression; suggesting that in SLK, the liver appears to provide immunoprotection against both acute cellular immunity and chronic humoral injury.