Trial Information

Alemtuzumab Versus Thymoglobulin Induction Therapy in Kidney and Pancreas Transplantation

Anti-Thymocyte Globulin, rabbit (r-ATG, Thymoglobulin®) is a polyclonal antibody against
T-lymphocytes that is used for the prevention and treatment of acute allograft rejection.
r-ATG induction therapy is effective in preventing acute allograft rejection, however the
usual 7-14 day course involves extensive clinical monitoring and is costly. Recent studies
had suggested that smaller cumulative doses are efficacious for induction therapy, and may
have an advantage by decreasing the adverse effects associated with the agent (such as
leukopenia and thrombocytopenia). Our program subsequently modified our r-ATG induction
regimen in November 2001 to give doses on alternate days for at least three doses and has
achieved excellent results. However, this regimen is somewhat complex in that it requires
central venous access for administration, pre-medication administration to prevent
infusion-related reactions, and monitoring of vital signs during each infusion.

Alemtuzumab (Campath®) is a humanized monoclonal antibody to CD52 that is FDA approved for
the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but has also been used for
immunosuppression induction at the time of solid organ transplant and as anti-rejection
therapy. CD52 is present on most lymphocytes, macrophages, monocytes, and NK cells, and
causes antibody-dependent cell lysis following the binding of alemtuzumab to the CD52
surface antigen. Alemtuzumab produces significant lymphocyte depletion similar to r-ATG, so
some investigators began evaluating it as a preconditioning agent in tolerance protocols
(using very low-dose maintenance immunosuppression) in solid organ transplantation. While
these studies showed no significant tolerogenic potential for alemtuzumab, one or two 20-30
mg doses of alemtuzumab produced a similar degree of lymphocyte depletion as r-ATG
administration. Based on these preliminary data in transplant recipients and prior safety
data obtained from safety and efficacy studies of alemtuzumab in patients with rheumatoid
arthritis, some US transplant centers changed from using r-ATG to alemtuzumab as their
primary induction agent. Most of these centers (notably Wisconsin and Northwestern, where
more than 500 kidney and pancreas patients have received alemtuzumab, personal communication
Dixon Kaufman, Northwestern) use one or two doses of alemtuzumab for induction, followed by
a traditional 2-3 drug maintenance immunosuppressive regimen (rather than the low-dose
immunosuppression used in the tolerance protocols).

Knechtle and colleagues from the University of Wisconsin have reported a comparable
incidence of acute rejection and favorable graft survival in 130 patients who received a
single intraoperative 30 mg dose (+/- an additional dose on post-operative day 1) of
alemtuzumab compared with a historical cohort who received r-ATG, OKT3, an IL-2 receptor
antagonist, or no induction. In addition, the group found that there was a dramatically
lower incidence of acute rejection in the patients who experienced delayed graft function in
the alemtuzumab group (9% vs 45% in the control group, p=0.0078).

The use of alemtuzumab as an induction agent in solid organ transplantation is appealing.
Only a single intraoperative dose would be required (compared with between 2 and 6
additional doses of r-ATG post-op), thereby eliminating the necessity for central venous
access and extensive clinical and nurse monitoring. In addition, the cost of therapy would
be less with alemtuzumab than with r-ATG. At WFUBMC, 18 recipients of kidney or
kidney/pancreas transplants who received alemtuzumab have had only a 9% six-month rejection
rate. Our clinical experience suggests that the agents produce similar results; however, a
prospective, randomized study to compare the safety and efficacy of alemtuzumab with r-ATG
has not been reported. Also, although alemtuzumab would offer a significant medication cost
savings over r-ATG, the impact on the overall cost of care has yet to be established. A
comparative study will help us decide if we should make alemtuzumab our new standard of care
at this institution.

The purpose of this study is to evaluate the use of alemtuzumab (Campath-1H) for induction
therapy in kidney and pancreas transplantation compared to our standard of care,
alternate-day r-ATG.