HEALTH-SYSTEM EDITION
CLINICAL PRACTICE

Low-dose antirejection drugs may lessen complications

In an effort to reduce the harmful side effects of long-term immunosuppression and prolong survival of patients, one of the world's renowned transplant surgeons, Thomas Starzl, M.D., of the University of Pittsburgh Medical Center (UPMC), has implemented a new protocol. It utilizes low-dose therapy following transplantation. His goal is to eventually wean patients from the drugs completely.

Starzl is one of the original proponents of high-dose immunosuppression. He began to question the current standard of care after a 10-year investigation of some of his original patients who had undergone a transplant more than 40 years ago. They had either stopped taking the drugs entirely or had reduced their doses to extremely low levels and were surviving just fine. He found that cells from the donor organ were able to survive among the recipient's own cells and were still present all these years later. He hypothesized that the two sets of cells had pitched a battle and eventually, over time, learned to coexist.

According to Starzl, this confrontation may be the key to preventing chronic organ rejection that can occur five to 10 years after transplantation and is often life threatening. He also believes this interaction is impossible in the presence of high doses of immunosuppressants.

Despite the recent success in preventing acute rejection while using traditional protocols, "the caveat is the fact that chronic rejection rates have remained unchanged," said Kristine S. Schonder, Pharm.D. She is an assistant professor at the University of Pittsburgh School of Pharmacy and clinical pharmacist at the Thomas E. Starzl Transplantation Institute. "Unfortunately, the half-life of a transplanted organ still averages around five years due to chronic rejection," she said.

According to Schonder, patients on Starzl's tolerance protocol receive a pretransplant bolus dose of steroids, followed by either a single high dose (5 mg/kg) of antilymphocyte globulin (Thymoglobulin, Sangstat) or a single dose (30 or 60 mg) of alemtuzumab (CamPath, Berlex). After transplant, patients receive tacrolimus (Prograf, Fujisawa) only. "Approximately three to four months after transplant, we attempt to wean the tacrolimus, starting with once-daily dosing, then gradually extending the dosing interval to every other day, three times weekly, two times weekly, and so on," she added.

Since July 2001, more than 550 transplant patients have been treated with the new protocol at the Starzl Transplantation Institute at UPMC. So far, the results are encouraging. There has been 95% kidney graft survival greater than one year posttransplant and none of the three kidney allografts lost was due to acute rejection, said Schonder. Of the other organs for which the protocol was used, she said, only one each of 17 liver and 14 pancreas transplants were lost to acute rejection. Additionally, eight of 11 small bowel recipients still have functioning grafts.

Most transplant centers in the United States utilize a conventional three-drug protocol for posttransplant immunosuppression, consisting of a calcineurin inhibitor, for example, cyclosporine A (Neoral, Novartis), tacrolimus—a purine synthesis inhibitor—for example, mycophenolate mofetil (CellCept, Roche), or azathioprine (Imuran, Prometheus Labs) and a corticosteroid, such as prednisone. Sirolimus (Rapamune, Wyeth), a G-cell cycle inhibitor, is sometimes used in place of the calcineurin inhibitor or purine synthesis inhibitor in renal transplant patients, and may be given to patients not doing well on traditional regimens. A fourth drug, such as antilymphocyte globulin, basiliximab (Simulect, Novartis), or daclizumab (Zenapax, Roche), may be added as induction therapy. The protocols can vary greatly from one transplant center to another, but all can lead to significant complications.

"Unfortunately, we see a significant number of long-term complications," said David J. Taber, Pharm.D., BCPS, clinical pharmacy specialist and assistant professor, Medical University of South Carolina, speaking of his institution's conventional protocol. "Patients receiving the current immunosuppressants are at higher risk of developing everything from hypertension to diabetes to osteoporosis, and, in some cases, certain cancers. Use of the calcineurin inhibitors invariably leads to a significant decline in renal function, and even chronic renal failure. We are hopeful that this new approach will improve long-term graft function while preventing these complications," he added.

The UPMC tolerance protocol is not without its critics, however. Many clinicians believe there are too few organs available to run the risk of acute rejection and that the new technique should be considered only experimental at this point.

"I believe the benefits outweigh the risks," Schonder responded. "Early after we began using the protocol, we saw a slightly greater number of acute rejections. However, as time went by and we became more comfortable with the protocol, the number of early acute rejections decreased. We occasionally see late rejections when patients are attempting to wean tacrolimus, usually indicating that the decrease in tacrolimus dose may be too soon." In any case, she pointed out, the majority of both early and late acute rejections can be quickly reversed by bolus doses of steroids, and patients are able to remain on tacrolimus monotherapy.

Schonder feels the numbers speak for themselves as to the relative low risk of graft loss with regard to the number of organs available for transplant. "The anticipated long-term success of the protocol with lower chronic rejection rates will hopefully, in time, help to ease the constraints on the resources for transplantation," she said.

"The ultimate hope of our transplant team is to achieve true allograft tolerance, whereby patients are able to maintain a functioning transplanted organ with no immunosuppression," said Schonder. "We see evidence of that in patients who have received the protocol by looking at cell markers within the transplant and the blood. At the very least, patients will be maintained on very small doses of immunosuppressants [once-weekly tacrolimus], thereby minimizing long-term complications and nephrotoxicity."

Given the limitations of current treatment regimens, said Taber, "it is important to undertake new and innovative strategies. Although not without risks, this is an exciting new approach to immunosuppression." These types of cutting-edge trials need to be done in order to move forward and improve patient outcomes, he added.

Heidi Belden, Pharm.D.

The AUTHOR is a clinical writer based in Plymouth, Mass.