Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes.
ABSTRACT Renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. To assess the effect of belatacept in this high-risk group, we evaluated outcomes of the subpopulation with PD from previously published BENEFIT and BENEFIT-EXT trials.
A post hoc analysis evaluated pooled data from BENEFIT (living donors or standard criteria donors) and BENEFIT-EXT (extended criteria donors). Patients were randomized to receive cyclosporine or a more intensive (MI) or less intensive (LI) belatacept regimen.
Of 1209 intent-to-treat patients, 336 had PD. At 12 months, the belatacept LI arm demonstrated a numerically higher rate of patients surviving with a functioning graft (90.4% MI [103 of 114], 92.8% LI [90 of 97], and 80.8% cyclosporine [101 of 125]), and fewer serious adverse events than cyclosporine or MI patients. Three cases of posttransplant lymphoproliferative disorder were reported in LI patients, one involving the central nervous system. Higher rates (% [95% confidence interval]: 22.8% MI [15.1 to 30.5]; 20.6% LI [12.6 to 28.7]; 14.4% cyclosporine (8.2 to 20.6]) and grades of acute rejection were observed with belatacept. Measured GFR (ml/min per 1.73 m(2), 59.8 MI; 62.5 LI; 45.4 cyclosporine), and cardiovascular risk profile were better for belatacept versus cyclosporine.
In post hoc analysis of patients with PD, patient/graft survival and renal function at 12 months were numerically higher with belatacept versus cyclosporine, but not statistically significant. Further study is necessary to confirm the benefits belatacept may provide in these patients.
Article: Belatacept[Show abstract] [Hide abstract]
ABSTRACT: Belatacept is a second-generation cytotoxic T-lymphocyte-associated antigen-4-Ig fusion protein, which down-regulates T-cell response, and is used in the prophylaxis of organ rejection in adults receiving a kidney transplant. This article reviews the pharmacologic properties of belatacept and its clinical efficacy and tolerability in kidney transplant recipients. In the well designed, phase III trials BENEFIT and BENEFIT-EXT (in patients receiving kidneys from living/standard-criteria or extended-criteria donors, respectively), a belatacept-based treatment regimen was noninferior to a cyclosporine (ciclosporin)-based regimen with regard to patient and graft survival and acute graft rejection rate, and was significantly superior to the cyclo-sporine-based regimen with regard to the rate of renal impairment (in BENEFIT only), at 12 months. Belatacept-based treatment showed long-term efficacy and remained effective after 2, 3, and 4 years with regard to these endpoints. Belatacept was generally well tolerated in patients with kidney transplants from living, standard-criteria, or extended-criteria donors. The most serious adverse events that have been reported with belatacept treatment are post-transplant lymphoproliferative disorder, other malignancies, and serious infections. At month 12, the incidence of new-onset diabetes mellitus after transplant was significantly lower with belatacept than with cyclosporine, and belatacept recipients had significantly lower blood pressure and a significantly smaller increase in certain lipid levels than cyclosporine recipients.BioDrugs 12/2012; 26(6). DOI:10.1007/BF03261898 · 2.12 Impact Factor
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ABSTRACT: INTRODUCTION: Over the past decades, calcineurin inhibitors (CNIs) have become the cornerstone of transplant immunosuppression. CNIs can exert negative effects on chronic allograft function along with cardiovascular (CV) and metabolic adverse effects. Belatacept , a selective co-stimulation blocker of T cells, is the first US FDA (06/2011) and EMEA (06/2011) approved biologic agent for maintenance immunosuppression in renal transplantation. AREAS COVERED: The authors critically reviewed the literature over the last few years comparing belatacept with current standard of maintenance immunosuppression including CNIs in kidney transplantation. EXPERT OPINION: Despite the increased incidence and severity of acute rejection with belatacept in Phase II and III studies, a better preservation of GFR and reduced incidence of chronic allograft nephropathy was observed as compared with CNIs. Patient and graft survivals were similar over 3- and 5-year follow-up post-transplantation. Incidence of adverse events were similar between the groups, but the risk of post-transplant lymphoproliferative disorder, predominantly involving CNS, was higher in Epstein-Barr virus seronegative recipients on belatacept, especially with a more intensive regimen. CV and metabolic end points were more favorable in belatacept versus CNI groups with similar incidences of diabetes after transplantation. Belatacept seems to be a promising drug for the future, but long-term outcomes are awaited.Expert opinion on biological therapy 05/2012; 12(7):965-79. DOI:10.1517/14712598.2012.683522 · 3.65 Impact Factor
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ABSTRACT: Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.Journal of Transplantation 06/2012; 2012:203780. DOI:10.1155/2012/203780