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Multi-Center Trial of Drug to Prevent Tumor Growth in Pediatric Liver Transplant Recipients Discounts Drug’s Utility

WASHINGTON, June 1, 2003 Following the first and largest clinical trial of its kind involving pediatric liver transplant patients, physicians say they have abandoned any notion of using the drug they thought might prevent Post-Transplant Lymphoproliferative Disease (PTLD), a complication more common in children whereby certain immune cells proliferate to form tumors, in favorof vigilant screening and a more conservative approach.

Results of the multi-center study are to be presented today at the American Transplant Congress, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation. The scientific sessions are June 1 4 at the Marriott Wardman Park Hotel in Washington, D.C.

PTLD is a complication associated with the Epstein-Barr Virus (EBV), which about 90 percent of the worlds population eventually will be exposed to. But many children and young adults have not yet been exposed to EBV, making children who receive transplants particularly vulnerable because the drugs they take that suppress the immune system to prevent organ rejection also impair the immune systems ability to fight this infection. About two-thirds of pediatric transplant recipients will develop a primary EBV infection within six months following transplantation. The course of this infection ranges from an infection with no outward symptoms to a far more serious outcome, with progression of the virus to PTLD or lymphoma.

Researchers from the University of Pittsburgh School of Medicine and Childrens Hospital of Pittsburgh initiated the trial in 1995 to study the effectiveness of the drug CytoGam for the prevention of PTLD in pediatric liver transplant recipients. In 1999, four other centers joined the study, which eventually enrolled nearly 90 children into the double-blind randomized trial, the largest of its kind involving PTLD in children.

But the drug proved somewhat disappointing, according to results being presented by Michael Green, M.D., M.P.H., professor of pediatrics and surgery, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, and the studys principal investigator.

While the incidence of PTLD two years after transplantation was 8 percent in the children who received the active drug versus 16 percent in the group that received a placebo drug, the researchers say the difference was not statistically significant due to the relatively small study sample. Of the 74 patients whose two-year outcomes have been analyzed to date, three of 37 in the treatment group developed PTLD compared to six of the 37 in the placebo group who developed this complication.

Besides the relatively small sample size, another potential explanation for the failure to achieve a statistically significant difference might have been a shift in clinical practice that occurred with the availability of EBV viral load monitoring methods, potentially confounding the studys results. Although physicians were encouraged not to obtain surveillance EBV viral loads on patients participating in this study, methods became readily available in 1998 and viral loads were increasingly obtained in response to even the most subtle clinical symptoms thought to be suggestive of an early EBV infection. If an elevated EBV viral load was detected, physicians caring for the children frequently reduced the patients immunosuppression by lowering the doses of anti-rejection drugs, a move that has previously been shown to reduce the risk of progression to PTLD.

This strategy may have diminished the risk of PTLD in patients regardless of whether they received CytoGam or placebo and thus impacted on the studys power to identify a statistical difference, reports Dr. Green.

In the current era, with more vigilant screening taking place, there does not appear to be any benefit for the use of the drug CytoGam, or any other drug, for that matter, for the prevention of EBV-associated PTLD in our pediatric liver transplant recipients, he concludes.

At the University of Pittsburgh, the aim is to treat patients before symptoms of EBV develop. The team currently follows a protocol of intensive monitoring during the first six months after transplantation with continued, but less intense, viral load screening after that time. If elevations in the EBV viral load are detected, the preferred approach is to carefully reduce immunosuppression until the viral load falls to a lower threshold or until there are early signs of rejection. This way, the patients immune system is given the chance to effectively deal with the virus without the risk of developing disease.

In addition to the University of Pittsburgh, other centers involved in the trial were Mount Sinai Medical School in New York City, Northwestern University School of Medicine in Chicago, the University of North Carolina in Chapel Hill, N.C., and the University of Chicago.

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