Abstract and Introduction
Abstract
The lymphocyte-depleting antibody alemtuzumab was evaluated in a prospective randomized multicenter trial in deceased donor kidney transplantation.
The 65 patients in the study group received induction with alemtuzumab followed by delayed tacrolimus monotherapy, while the 66 patients in the control group were started on tacrolimus in combination with mycophenolate mofetil and steroids. Tacrolimus levels of 8-12 ng/mL for the first 6 months and 5-8 ng/mL thereafter were aimed for in both groups.
At 12 months the biopsy-proven rejection rate was 20% in the study group and 32% in the control group (p = 0.09). Patient survival at 1 year was 98% for both groups. Graft survival was 96% for the study group versus 90% for the control group (p = 0.18).
Graft function was identical in both groups. Adverse events were similar in both groups apart for more CMV infections in the study group. At the end of the first year 82% of the patients in the study group were steroid-free and 71% continued on tacrolimus monotherapy.
These results suggest that alemtuzumab induction together with tacrolimus monotherapy is at least as efficient in renal transplantation as is a tacrolimus-based triple-drug regimen with a similar safety profile but more CMV infections.
Introduction
The many adverse events associated with the administration of immunosuppressive drugs prompted a search for new protocols for posttransplant immunosuppression that employ no steroids and lower dosages of or no calcineurin inhibitors (CNI), but that would be equally effective with regard to graft survival and possibly encourage the development of unresponsiveness to the graft. The combination of mycophenolate mofetil plus sirolimus, however, has been reported to produce significantly worse results as compared with CNI-containing regimens.
Several experimental studies have shown that lymphocyte depletion at the time of transplantation is associated with a limited T-cell response with subsequent development of tolerance in some models but not routinely in nonhuman primates. Although peripheral depletion is a widely accepted induction strategy in renal transplantation, it was found to be insufficient to prevent rejection if induction was not followed by maintenance immunosuppression.
It was first reported by Calne et al. that alemtuzumab (Campath-1H), a humanized monoclonal antibody to CD52 that causes profound depletion of most immunocompetent cells including T- and B-lymphocytes, monocytes and NK cells, was effective in the prophylaxis of rejection when given together with cyclosporine monotherapy starting 3 days after transplantation. The rationale behind this strategy of leaving a time window with no immunosuppression was to provide an opportunity for immunological engagement. It was shown that T cells with a memory-like function were the most resistant to alemtuzumab depletion, while at least in vitro being more sensitive to tacrolimus than to cyclosporine. This was the reason why we decided to design a protocol that would be similar to that for the initial Campath trial but would replace cyclosporine with tacrolimus. A prospective randomized, controlled, multicenter trial was initiated to assess the efficacy and safety of alemtuzumab induction with tacrolimus monotherapy as compared to a tacrolimus, mycophenolate mofetil and steroid triple-drug regimen.