Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This interesting multicenter open-label study investigated the interaction between low- and high-dose tacrolimus and use of ACE inhibitors on the development of IF/TA following renal transplantation. The investigators used a 2x2 randomised design to compare low- versus high-dose prolonged release tacrolimus and ACEi/ARB versus other antihypertensive use. Protocol biopsies were taken at baseline, 6 months and 24 months. The largest reduction in 24-month IF/TA came from the use of low-dose tacrolimus, although there was some interaction between the two treatments with the lowest rate of IF/TA seen in the ACEi and low-dose Tac group. Use of ACEi/ARB in conjunction with low-dose tacrolimus also appears to reduce the rejection risk associated with low-dose tac use. Interestingly, post-hoc analysis also demonstrated a significant reduction in the risk of IF/TA with inflammatory infiltrate associated with ACEi/ARB use. Taken together, these results suggest that addition of ACEi/ARB to low-dose tacrolimus early after transplantation is safe and may confer some benefit in the progression of IF/TA and risk of T-cell mediated rejection. It is not clear whether the histopathologists involved in this study were blinded to treatment assignment, raising the risk of measurement bias. Longer-term follow-up will determine whether the early benefits seen translate to differences in graft function and survival.
Expert Review
Reviewer:
Robert M. Langer M.D., Ph.D. Professor of Surgery and Nephrology Ordensklinikum Linz, Austria, Krankenhaus der Elisabethinen
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
Usually in daily practice one can see the negative side effects of combined treatments. In this Canadian multicenter study we can observe a positive, beneficial example of RAS blockade combined with low dose tacrolimus. It may have a practice-changing effect, similar to the power of the Symphony study regarding the minimization of immunosuppression, specifically the effects of CNI. The Symphony study could show that low dose tacrolimus in combination with full dose mycophenolate provides the best results with the available immunosuppressant combinations in means of kidney function. By taking another step forward Cockfield et al. show that ACE inhibitory (ACEi) treatment for hypertension in combination with low-dose tacrolimus can lower the T-cell mediated rejection rate and can mitigate the IF/TA histopathologically, so by blocking the chronic inflammation process it may allow for better long-term function. Today’s efforts to lengthen the half-life of allografts is one of the most challenging questions of transplantation, however quite hard to measure which is the major contributing factor. The above study may be a first step in this direction.
Aims:
To assess the effects of IF/TA prevalence using a reduced tacrolimus dosing strategy and RAS-blocking AHTs.
Interventions:
At randomization, patients were assigned to one of four possible treatments; standard-dose, prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=69), or low- dose prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=68), corresponding to two tacrolimus interventions (low vs standard) and two AHT interventions (ACEi/ARB vs OAHT).
Participants:
281 adult renal transplant recepients. Of these, 235 completed the study.
Outcomes:
This study had two co-primary outcomes: the prevalence of IF/TA at Month 6 and at Month 24. Secondary endpoints included the progression of IF/TA post-transplant, and assessment of renal function, blood pressure and use of antihypertensive agents throughout the study period.
Follow Up:
Up to 24 months
Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small but interesting RCT investigates the use of immune monitoring using NFAT-regulated gene expression (NFAT-RE) in stable kidney transplant recipients. All patients received cyclosporine and MMF with/without steroids, and control patients were monitored using standard trough cyclosporine levels. The authors demonstrate a significant improvement in pulse-wave velocity and GFR with NFAT-RE monitoring, with no obvious excess in adverse events or rejection. The small size of this study means that further evidence would be required to demonstrate safety in terms of rejection and graft survival. It appears, however, that NFAT-RE monitoring may allow minimisation of cyclosporine dose safely in these stable, low risk recipients. It is worth noting that trough cyclosporine levels in the standard monitoring arm increased over the 12-month study period, with a corresponding fall in GFR, which does raise the risk of treatment bias in a non-blinded study such as this.
Expert Review
Reviewer:
Professor Ron Shapiro, Kidney/Pancreas Transplantation, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mt. Sinai, USA.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
This is an extremely interesting trial of utilizing immunologic monitoring to manage immunosuppression in stable renal transplant recipients. Patients were randomized either to routine PK monitoring (i.e. peak and trough levels) or NFAT-regulated gene expression. Patients randomized to NFAT-regulated gene expression had reduced cardiovascular risk, as assessed by pulse wave velocity, fewer infections, and better renal function than the control group. This is a very important trial. Most immunosuppression is, at some level, an educated guess about what patients should be receiving, based on a composite of clinical and laboratory factors, but without any real immunologic monitoring data. This trial utilized immunologic monitoring to titrate immunosuppressive drug dosing. Even with a very small number of patients, the authors were able to demonstrate a benefit of immunologic monitoring. The study utilized an immunosuppressive agent, cyclosporine that is used in a very small minority of transplant recipients. This work should be repeated by other centers, with larger numbers of patients, utilizing tacrolimus-based immunosuppression. If the findings from this initial experience are replicated, this could lead to a sea change in how patients are managed after transplantation.
Aims:
To compare the monitoring of cyclosporine A (CsA) using nuclear factor of activiated T-cells -regulated gene expression (NFAT-RE), versus standard CsA trough level (C0) monitoring.
Interventions:
Participants were randomly assigned to either standard monitoring (CsA dose adjusted to target a C0 of 80–150 μg/L), or NFAT-RE (CsA adjusted to target a residual NFAT-RE of 15–30%).
Participants:
55 renal allograft recipients from a deceased or living donor ≥6 months prior to study entry, aged ≥18 years with stable renal allograft function, and receiving CsA microemulsion, mycophenolic acid with or without low-dose steroids.
Outcomes:
The primary outcome measured was the change in arterial stiffness, assessed by pulse wave velocity. Secondary outcomes included peripheral and central blood pressure, cardiac augmentation index, biopsy-proven acute rejection, graft loss or death, renal function, safety and tolerability.
Follow Up:
12 months
BACKGROUND:
A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE).
METHODS:
Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months.
RESULTS:
In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P < 0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009).
CONCLUSIONS:
NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.
This manuscript reports the 36-month extension from a phase 2 study randomising stable kidney transplant recipients (6-36 months post-transplant) to either continue CNI or switch to Belatacept. The renal function benefit seen at earlier time-points appears to be maintained, with an acceptable safety profile in both arms. Hazard for acute rejection is increased with Belatacept (HR 2.50), but this does not reach significance due to the small size of the study. In all, these data suggest that a switch to belatacept is safe and may result in small improvements in renal function compared to CNI-based therapy. The results are made difficult to interpret as patients/investigators were given the option to switch to belatacept at month 24. 16 patients (around 18%) in the CNI arm chose to switch, which may lead to an underestimation of any efficacy benefit or additional risk posed by the use of belatacept.
Expert Review
Reviewer:
Dr Claudio Ponticelli, Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
In this multicenter controlled trial, 173 CNI-treated adult kidney transplant recipients with stable graft function were randomly assigned to continue therapy with CNI (89 patients) or to be converted to belatacept (84 patients) at 6-36 months after transplantation. Belatacept-treated patients showed a significantly greater increase in GFR compared to CNI (+1.9 vs 0.07 ml/min). No difference between the two arms was seen in death, graft loss, acute rejection, serious adverse events, serious infection or malignancy. However, viral infection occurred more frequently in belatacept-treated patients. This study confirms that switching patients with stable renal graft function from CNI to belatacept is safe. The fact that the mean GFR at 36 months is better in belatacept-treated patients may represent an important result. However, it is also comforting to note that no attrition of renal function was seen in patients who continued CNI up to 3 years. Of note, the concern that belatacept might increase the risk of posttransplant lymphoproliferative disorder (PTLD) seems to be limited to EBV negative patients. Indeed, no case of PTLD was observed in this trial. In conclusion, the results of this study reinforce the idea that different but equally effective treatments are now available for kidney transplant recipients and that switching from a treatment to another one seems to be feasible and relatively safe, at least in patients with stable renal graft function.
Aims:
To summarise outcomes, specifically the safety and tolerability of belatacept at 36 months post randomization of kidney transplant recipients with low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept.
Interventions:
Participants were randomized to either switch to a belatacept-based immunosuppression (5 mg/kg of belatacept intravenous on days 1, 15, 29, 43, and 57 and every 28 days thereafter) or continue with CNI-based therapy.
Participants:
173 adult stable kidney transplant recipients who were receiving CNI based maintenance immunosuppression.
Outcomes:
The primary outcome measured was safety, specifically adverse events (AEs) and serious AEs. Secondary outcomes measured were estimated glomerular filtration rate, acute rejection, transplant loss, and death.
Follow Up:
36 months
BACKGROUND:
In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.
STUDY DESIGN:
36-month follow-up of the intention-to-treat population.
SETTING & PARTICIPANTS:
CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2).
INTERVENTIONS:
At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).
OUTCOMES:
Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.
MEASUREMENTS:
Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.
RESULTS:
Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9).
LIMITATIONS:
Exploratory post hoc analysis with a small sample size.
CONCLUSIONS:
Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.
Dr Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
The RCT compared the efficacy of two treatment strategies for solid organ transplant recipients with CMV infection. Sixty kidney, liver and heart transplant recipients received ganciclovir-valganciclovir according to the manufacturer’s dosing recommendations (based on Cockcroft-Gault-calculated creatinine clearance and body weight) or according to a pharmacokinetics (PPK) modelling approach which did not include body weight. The primary endpoint was defined as a 40% or higher superiority margin in the number of patients reaching the AUC target of 40–50 µg·h/ml. The sample size was sufficient to provide 80% power. There was no description of how patients were allocated to groups and whether allocation was concealed. The PKK modelling approach led to a significantly higher percentage of AUC values within target range (65.9% versus 19.2%) and the time to reach target AUC was also significantly shorter.
Expert Review
Reviewer:
Professor Jan Ijzermans, Erasmus Medical Center, Rotterdam, The Netherlands
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
The paper describes the outcome of a personalized approach to optimize anti-CMV management in transplant recipients for prevention as well as treatment of viral disease. In a two-arm, randomized, open-label, single-center trial organ recipients were either treated with ganciclovir (GCV)-valganciclovir (VGCV) according to normal dosing recommendations based on Cockcroft calculated clearance and body weight (controls), or with GCV-VGCV as calculated by a previously developed population pharmacokinetic model (PPK). The primary endpoint of the study was defined as a pharmacological parameter including the percentage of patients achieving the target therapeutic exposure. Using the PPK model as a tool for Bayesian prediction the authors demonstrate that the target AUC values of the experimental group were superior to those of controls, and that the time to reach these values were significantly shorter as well. A trend toward reduced time to viral clearance was found but no significant difference. However, as stated by the authors, it should be noted that the study was powered on a pharmacodynamic endpoint and not on viral clearance, leading to a smaller number of inclusions. This study is of great interest as it demonstrates the feasibility of a personalized approach to optimize anti-CMV drug exposure in transplant recipients. It should be noted that the primary outcome was defined as a pharmacological parameter and a more effective and earlier viral clearance in these patients still has to be demonstrated. In addition, it will be of interest to investigate whether the efficacy in viral clearance will be the same for prophylaxis as well as treatment of CMV disease as suggested by the pharmacological outcome of this paper. Before wider application of this approach can be realized some issues need to be addressed to facilitate implementation, such as the intensity of the blood sampling collection which is quite intensive. Nevertheless, this study has clearly demonstrated the feasibility of personalized therapeutic drug monitoring and calls for new studies demonstrating the clinical benefits of this approach for CMV management.
Aims:
To investigate whether a Bayesian prediction model can optimize Ganciclovir-Valganciclovir (GCV-VGCV) dosing in solid organ transplant recipients.
Interventions:
Patients were randomized to receive either GCV-VGCV according to the manufacturer’s dosing recommendations (group A), versus adjusted dosing based on target exposures using a Bayesian prediction model (group B).
Participants:
60 kidney, liver, and heart transplant recipients aged ≥18 years of age, treated with GCV or VGCV as either prophylaxis or treatment of cytomegalovirus (CMV) infection.
Outcomes:
The primary outcomes measured were the percentage of patients achieving target area under the curve (AUC) values between 40-50µg.h/ml, exposures on days 30, 60, and 90, and the time needed to achieve target AUC values. Secondary measured outcomes were measurements of time to viral clearance, recurrence of CMV infection, and incidence of late-onset CMV infection.
Follow Up:
6 months
Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).
In this large UK very well done multicentre trial induction with alemtuzumab was compared with induction with basiliximab but with reduced tacrolimus and mycophenolate mofetil and no steroids in the alemtuzumab arm. At 6 months patients were randomised to either continue on tacrolimus or switch to sirolimus based maintenance treatment but that is a second trial within this one major trial. I think I am correct in saying that with 852 participants this is the largest trial in organ transplantation carried out in the UK. The incidence of acute rejection, biopsy proven or clinically diagnosed, was halved in the patients induced with alemtuzumab (7% vs 16%). There was no difference in adverse events, although there is a suggestion that BK viraemia occurred more often with alemtuzumab. Tacrolimus trough levels in the alemtuzumab arm were statistically lower (mean 1.4 ng/ml) in the alemtuzumab arm but this is unlikely to be clinically significant. Overall the results are compatible with the systematic review published by Morgan et al in 2012 (which does point out the value of a good systematic review). Again it is pointed out in the Morgan systematic review that induction with ATG was comparable to induction with alemtuzumab, which of course was not studied in this particular trial. Obviously with time and follow up to one or two years, much more information will be available about renal function and other adverse events and as the authors point out this long term follow up will assess whether the initial effects translate into better long term transplant function and survival.
Expert Review
Reviewer:
Professor Stuart J. Knechtle, Duke University School of Medicine, Durham, North Carolina, USA
Conflicts of Interest:
None
Clinical Impact Rating
5
Review:
The C3 study compared alemtuzumab to simulect induction immunosuppression for kidney transplantation utilizing all donor kidney types (living donor, standard deceased donor, and non-heart-beating donors) and included 426 patients in each group. As such, it is the largest randomized controlled trial to date of alemtuzumab in solid organ transplantation and the most inclusive with respect to patient diversity and the quality of the kidneys transplanted. The alemtuzumab group received lower maintenance immunosuppression than the control group yet achieved a lower rejection rate and was not associated with more antibody-mediated rejection or infection as has been reported in smaller studies. The data from the C3 study supports the value of the experimental regimen including alemtuzumab induction with few reservations. The long-term results of the follow up study comparing sirolimus to tacrolimus maintenance after 6 months should reveal whether there is any long-term benefit of lymphocyte depletion given its greater success in the short-term with respect to lowering the rejection rate without compromising protective immunity. Interest in the outcome of phase 2 of the study is heightened by the success of phase 1 that justifies its complex, non-traditional design.
Aims:
To investigate the safety and efficacy of kidney transplant recipients treated with alemtuzumab with reduced calcineurin inhibitor (CNI) exposure or non-depleting antibody induction (basiliximab) with standard CNI exposure.
Interventions:
Patients were administered with either alemtuzumab based induction treatment (30mg immediately after reperfusion and 24h later) followed by tacrolimus (target trough concentration 5-7ng/mL) and mycophenolic acid (360mg twice daily without steroids) or basiliximab based induction treatment which consisted of 20mg on days 0 and 4, followed by tacrolimus (target trough concentrations 5-12ng/mL), mycophenolic acid (540-720mg twice daily) and oral prednisolone.
Participants:
852 adults scheduled to receive kidney transplants within 24h.
Outcomes:
The primary outcome was the incidence of biopsy proven acute rejection, including cellular and anti-body mediated rejection.
Follow Up:
Up to 12 months post-transplant.
BACKGROUND:
Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants.
METHODS:
For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088.
FINDINGS:
Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25).
INTERPRETATION:
Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival.
FUNDING:
UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This long term follow up of the BENEFIT-EXT donor study which included patients who at 3 years following entrance to the trial remained on their assigned treatment. This was around two thirds of the patients who were on belatacept and somewhat less of the patients who were on cyclosporine. Follow-up to 5 years meant further patients were lost to the study but these were evenly distributed between the three arms. The significant findings were that renal function was superior in both belatacept arms and that there were less cardiovascular risk factors seen in the belatacept arms. However PTLD was more frequent with belatacept but only in EBV negative recipients. Thus continued treatment with belatacept to 5 years continued to show no additional safety concerns and furthermore the need for regular intravenous infusions did not appear to be a negative influence on patients continuing in the long term follow-up. There was some potential for bias in that only patients who were doing well, and thus remained on the assigned treatment, were eligible for the long term extension. This is discussed at some length by the authors as a weakness of the study but one that obviously was not in their control. In summary, in recipients of extended criteria kidneys, long term use of belatacept has an acceptable safety profile with a number of benefits especially improved renal function.
Expert Review
Reviewer:
Professor Hans Schlitt, "Direktor Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Germany
Conflicts of Interest:
None
Clinical Impact Rating
4
Review:
This publication reports data of the 5-year data of a randomized study comparing “standard” CNI-based immunosuppression vs. CNI-free, belatacept-based immunosuppression in patients undergoing kidney transplantation with extended criteria donor organs. In the core study a markedly better renal function had been observed in the belatacept group – with the “less intensive” belatacept group showing the best results. Almost all patients, who had remained on assigned treatment over 3 years entered the extension study and, of these, 90% completed the 5-year follow-up. The publication demonstrates that all observations of the core study remained valid after 5 years. In fact, the benefit on renal function in the belatacept groups was increased even further with no safety concern during the extension phase. Although about 40% of the core study patients (both in study and control groups) had not remained on assigned medication, and thus were not entered in the extension study, the data suggest a clear benefit of belatacept-based therapy in the long-term. The study is of particular interest because graft damage by CNI is a major problem after kidney transplantation, particularly in the long-term, and because more and more extended criteria (i.e., suboptimal) donor organs are being used for transplantation.
Aims:
This long term extension trial (LTE) aimed to evaluate the long term safety and tolerability of belatacept in patients that had completed 36 months of treatment in the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-Extended criteria donors (BENEFIT-EXT).
Interventions:
The randomised groups of patients were administered with either an intensive or less intensive belatacept regime, or cyclosporine. All patients received basiliximab induction, mycophenolate mofetil, and corticosteroids.
Participants:
304 de novo adult recipients of extended criteria donor renal allografts. The LTE population was a subset of the original intention to treat population.
Outcomes:
The primary outcome of this LTE was to assess the safety and tolerability of belatacept with prolonged exposure, the frequency of adverse events, serious adverse events and deaths. Secondary outcomes included the mean change in serum lipids from baseline to 5 years, and calculated glomerular filtration rate.
Follow Up:
Up to 5 years.
Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.
CET Conclusion