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Belatacept-based immunosuppression spares renal function in kidney recipients

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – Belatacept-based immunosuppression after kidney transplantation allows for better renal function compared to cyclosporine, with similar graft and patient survival, phase III trial results suggest.



In kidney allograft recipients, “the leading causes of death and graft loss are cardiovascular disease and chronic allograft nephropathy, respectively,” Dr. Flavio Vincenti and co-researchers note.



Cyclosporine – perhaps the most commonly used immunosuppressive in kidney recipients — is a calcineurin inhibitor. This class of drugs has a wide range of severe side effects, including nephrotoxicity. Their toxicity is thought to relate to their broad range of nonimmunologic targets, Dr. Vincenti, from the University of California, San Francisco, and colleagues note. Thus, a drug with greater specificity, such as the selective T-cell activation blocker belatacept, would be expected to have fewer toxicities.



In the 3-year international BENEFIT trial, 686 patients were randomized to receive a belatacept- or cyclosporine-based regimen. Belatacept-treated patients were further divided to receive a more or less intensive regimen, based on how long the drug was given at a 10-mg/kg dose versus a 5-mg/kg dose.



All patients received induction therapy with basiliximab, mycophenolate mofetil, and steroids.



At 12 months, the composite endpoint of patient and graft survival was similar in all three groups, hovering around 95%.



The composite renal endpoint – measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m2 at month 12, or mGFR decrease of at least 10 mL/min/1.73 m2 between months 3 and 12 – occurred in 55% in the belatacept groups versus 78% in the cyclosporine group (p < 0.001).



Episodes of acute rejection occurred in 22% of patients on the more intensive regimen, 17% on the less intensive regimen, and 7% in the cyclosporine group. Grade of rejection was also higher with the belatacept regimens.



Commenting on their finding that “the overall impact of acute rejection episodes did not negate the…benefits of belatacept,” the authors suggest that “the immune-selectivity of betalacept may affect the composition of rejection infiltrate differently from cyclosporine, resulting in reduced graft damage.”



Side effects were common and generally similar in each group. There were two cases of post-transplant lymphoproliferative disorder in the belatacept group but none in the cyclosporine group.



In a related study, BENEFIT-EXT, Dr. Antoine Durrbach, from Bicetre Hospital, Paris, and colleagues compared belatacept versus cyclosporine in recipients of kidney transplants from extended criteria cadaveric donors. These donors were 60 years of age or older, or 50 years or older with at least two risk factors (stroke, hypertension, or serum creatinine >1.5 mg/dL), or their kidneys had at least 24 hours of cold ischemia, or their organs were procured after cardiac death.



Recipients of grafts from these donors are “challenging to immunosuppress, as they tend to be older and are at increased risk for cardiovascular events and mortality compared with nonextended criteria donor recipients,” the authors note. Nonetheless, the results of BENEFIT-EXT, which featured 578 randomized patients, were similar to those of BENEFIT.



Both studies are reported in the March issue of the American Journal of Transplantation.



BENEFIT and BENEFIT-EXT were funded by Bristol-Myers Squibb, the developer of belatacept.



Reference:


Am J Transpl 2010;10:535-557.