Cancer Drug Found Effective in Preventing Rejection in 1st Large, Multicenter Trial

CINCINNATI—A large, multicenter trial led by University of Cincinnati (UC) faculty has provided the first head-to-head comparison of the three most common agents used in the early post-transplant period to prevent rejection following kidney transplantation.

The study, co-first authored by E. Steve Woodle, MD, director of UC’s transplant surgery division, and William A. Altemeier chair and professor of surgery, is published online ahead of print May 19, 2011, in the New England Journal of Medicine. Woodle co-first authored the study with a former UC transplant surgeon, Michael Hanaway, MD, associate professor of surgery at the University of Alabama at Birmingham.

This study, referred to as the INTAC trial, followed 474 patients undergoing kidney transplantation in 30 U.S. transplant centers.

In induction therapy, transplant recipients are given anti-lymphocyte antibodies in the early period following transplantation—the therapy begins the process of immunosuppression and reduces the risk of rejection. Patients receive the treatment for the first few days to several weeks after transplantation, in coordination with other standard post-transplant medication.

Between 1998 and 2007, 78 percent of kidney transplant recipients in the United State received antibody induction therapy—the most commonly used therapies being rabbit antithymocyte globulin, a lymphocyte-depleting polyclonal antibody, and basiliximab, a non-lymphocyte-depleting monoclonal antibody targeting the interleukin-2 receptor.

In the INTAC trial, researchers compared the efficacy and safety of these commonly used antibody induction agents with that of alemtuzumab, an antibody approved for cancer treatment by the FDA, but which has also been used in treating transplant recipients. 
Patients enrolled in the INTAC trial were first classified as being at a low or high risk of transplant rejection (high-risk patients included more African-American patients and patients already sensitized to transplantation from a previous transplant). Low-risk patients were randomly assigned to receive either basiliximab or alemtuzumab. High-risk patients were randomized into receiving rabbit antithymocyte globulin or alemtuzumab.

All patients were treated with an early glucocorticoid withdrawal regimen. Previous UC research shows that early steroid withdrawal results in reduced rates of rejection and increased graft survival in transplant patients. "Antibody indication therapy is generally considered important for achieving optimal results with steroid withdrawal,” writes Woodle.

Results showed the incidents of acute rejection were significantly lower in low-risk patients with alemtuzumab than with basiliximab. Rejection rates in high-risk patients were similar with alemtuzumab and antithymocyte globulin.

"Each of the three major antibody induction agents has advantages and disadvantages,” says Woodle. "This three-year study provides an evidence base for clinicians to be able to weigh those advantages and disadvantages in patients about to undergo kidney transplantation.”

He says the study also provides the first direct comparison of the two major T-cell depleting agents in high-risk kidney transplant recipients: "These results provide strong evidence that, with potent T-cell depleting induction treatment, even high-immunologic-risk patients can undergo early steroid withdrawal and still achieve excellent patient and graft survival rates.”

But alemtuzumab was not without risks, says Woodle. "Alemtuzumab patients demonstrated a trend toward more late rejection and more humoral rejection, which will need to be studied carefully in future trials.”

The study was sponsored by Astellas Pharma Inc. Woodle reports no financial interest in Astellas and has been a paid consultant for Genzyme and Novartis, manufacturers of Thymoglobulin and Simulect (basiliximab).