To the Editor:
Dr. van den Hoogen and Dr. Pipeleers raise important issues related to important endpoints of clinical trials in transplantation (1). Indeed at 1 year patients treated with belatacept exhibited more favorable metabolic and cardiovascular profiles as compared to cyclosporine-treated patients. At 3 years, these benefits persisted but because of the drop out of patients in the comparator arm (i.e. cyclosporine) or data not being collected, statistical significance could not be demonstrated. However another important determinant of cardiovascular disease, the glomerular filtration rate (GFR) continued to be superior in patients on belatacept, with a lower percentage of patients with chronic kidney disease stages 4 and 5 as compared to cyclosporine-treated patients. Furthermore in an abstract presented at ESOT in 2011, Fellstrom et al. using the validated methodology from the ALERT trial, predicted substantial reduction in mortality (approximately 18–30%) and greater than 20% decrease in major adverse cardiac events (MACE) in the belatacept treated patients in the phase III trials (2). So I would disagree with the statement of the authors that cardiovascular risk factors in belatacept treated patients were not sustained.
The issue of posttransplant lymphoproliferative disorder (PTLD) is of course serious but the additional cases of PTLD that developed late in the LI group (the approved regimen) were in Epstein-Barr virus (EBV) recipients. The phase III trials clearly showed that EBV− patients were at prohibitive risk for PTLD and is the reason that belatacept should be administered only to patients’ known to be EBV+.
Novel therapeutics in transplantation are going to be increasingly challenging especially agents such as belatacept that represent a paradigm shift in immunosuppression therapy: slightly higher rate of rejection, chronic IV administration, sustained improvement in GFR and the promise of increasing graft half-life. As mentioned in a recent editorial in American Journal of Transplantation, there is much yet to learn of how to improve the efficacy and safety of belatacept, as has happened following the introduction of previous novel transplant drugs (3). Belatacept and likely future novel therapies may be associated with greater risk early on, but could ultimately deliver better outcome. This is an approach we should embrace as we manage the care of transplant recipients for the long term.