From Medscape Medical News
ATC 2009:
Intensive Belatacept Regimen Improves Patient Survival After Extended-Criteria Donor Kidney TransplantAlice McCarthy
Authors and Disclosures
June 4, 2009 (Boston, Massachusetts) — A phase 3 study of patients who received an extended-criteria donor (ECD) kidney demonstrated that patients treated with a more intensive level of belatacept had better renal function and better cardiovascular and metabolic profiles than those treated with cyclosporine (CsA), and had similar patient and graft survival and a similar rate of acute rejection.
The data, part of the 3-year BENEFIT-EXT trial, were presented here at the American Transplant Congress 2009: The Joint Annual Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation.
Because of the great number of patients waiting for kidney transplantation, ECD transplantation is becoming more commonly used. However, it is associated with reduced survival and poorer renal function in transplant recipients.
"ECD transplant recipients are more vulnerable to the renal toxicity of calcineurin-inhibitor treatment, such as cyclosporine," Antoine Durrbach, MD, from Hôpital du Kremlin-Bicêtre in Paris, France, told conference delegates.
Recipients of ECD kidneys are at elevated risk for graft dysfunction and loss, and they could particularly benefit from a non-nephrotoxic option, such as belatacept, according to the presentation abstract.
"Belatacept is a first-in-class costimulation blocker that inhibits T-cell activation," explained Dr. Durrbach.
First Phase 3 Trial
In a previous phase 2 trial comparing belatacept with cyclosporine (N Engl J Med. 2005;353:770-781), Dr. Durrbach and colleagues noted that belatacept is associated with a similar incidence of acute rejection, superior renal function, less chronic allograft nephropathy, and an improved cardiovascular profile. Two phase 3 studies were then designed to confirm these results, 1 of which is this trial.
"This is the first phase 3 trial with belatacept as the main treatment for extended-criteria donor kidney transplant," Dr. Durrbach told Medscape Transplantation.
The BENEFIT-EXT trial consisted of 543 patients randomized equally to 1 of 3 treatment groups: a more intensive (MI) or less intensive (LI) belatacept regimen, or CsA. The 2 coprimary end points were composite patient/graft survival at 12 months and composite renal function (defined as a measured glomerular filtration rate [GFR] of <60 mL/min per 1.73 m2 at month 12 or a decrease in measured GFR of ≥10 mL/min per 1.73 m2 from month 3 to month 12.
Secondary end points included the incidence of acute rejection, chronic allograft nephropathy, and metabolic outcomes.
At 12 months, patient and graft survival with belatacept was nearly identical to that with CsA (86% in the MI group, 88% in the LI group, and 85% in the CsA group). However, renal function was superior in the MI group, compared with the cyclosporine group; fewer patients in the MI group reached the composite renal end point (71% in the MI group, 76% in the LI group, and 85% in the CsA group; P = .002 for MI vs CsA; P = .06 for LI vs CsA) and the measured GFR at month 12 (52 mL/min per 1.73 m2 in the MI group, 50 mL/min per 1.73 m2 in the LI group, and 45 mL/min per 1.73 m2 in the CsA group; P = .008 for MI vs CsA; P = .10 for LI vs CsA). The incidence of acute rejection was 17%, 18%, and 14%, respectively, in the 3 groups.
Higher Incidence of PTLD
Investigators observed similar rates of infection and malignancy in the belatacept groups and the CsA group. "In this study, the drug was well-tolerated as a once-daily infusion," said Dr. Durrbach.
However, more patients in the belatacept groups experienced a higher incidence of posttransplant lymphoproliferative disorder (PTLD). "We observed 3 cases in the first 12 months and 2 cases during follow-up, but it is important to note that in those cases, they [tested negative for Epstein-Barr virus] at transplantation and, in most of the cases, PTLD involved the central nervous system," he said.
Study investigators also noted better cardiovascular profiles in the belatacept groups than in the CsA group. "Belatacept was associated with lower systolic and diastolic blood pressure, lower non-[high-density lipoprotein cholesterol] and triglyceride levels, and a reduced rate of new-onset diabetes in the MI treatment arm," said Dr. Durrbach.
"In contrast to the standard-criteria donor benefit study (BENEFIT), there was no increase in acute rejection in the extended-criteria donor case (BENEFIT-EXT), so this was a positive finding," cosession moderator Edward H. Cole, MD, from the Division of Nephropathy at the University of Toronto in Ontario, told Medscape Transplantation.
"But the less intensive regimen of belatacept was not really associated with the same kind of substantial improvement in kidney function as the more intensive regimen, so I must confess that the way forward is not yet clear to me from these data. But I do believe it is an interesting drug of a new class."
THe BENEFIT-EXT study was supported by Bristol-Myers Squibb. Dr. Cole has received honoraria from Bristol-Myers Squibb and Novartis. Dr. Durrbach has disclosed no relevant financial relationships.
American Transplant Congress (ATC) 2009: The Joint Annual Meeting of the American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST): Abstract 27. Presented May 31, 2009.
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Authors and Disclosures
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Alice McCarthy
Alice McCarthy is a freelance writer for Medscape.
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Authors and Disclosures
Alice McCarthy
Alice McCarthy is a freelance writer for Medscape.
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