Sept. 6, 2002
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New drug for fatal complication of stem cell transplants

BOSTON -- Sept. 6, 2002 -- A drug extracted from pig intestines reduced the risk of death in patients who experienced a severe and often-fatal complication of stem cell transplants.

In the largest trial of its kind to date, the study confirms results of earlier, small studies. Led by Dr. Paul Richardson and colleagues at Dana-Farber Cancer Institute, the research showed that the experimental drug, defibrotide, reversed severe veno-occlusive disease (VOD) of the liver in more than one-third of the stem cell transplant recipients enrolled in the study.

"Stem cell transplant patients suffering from severe veno-occlusive disease are at a very high risk of death, with a mortality rate in excess of 90 percent," Richardson said in a prepared statement. "The results from this study are compelling, especially given the remarkable safety of the drug in this extremely sick population."

VOD is a type of potentially fatal liver damage that can result from the high doses of chemotherapy given prior to a transplant. The findings, which will be published in the Dec. 15, 2002 issue of Blood, have been posted as a "First Edition Paper" on the journal's web site.

Five to 60 percent of stem cell transplant patients develop VOD, which ranges in severity from mild and reversible to severe and almost always fatal. Stem cell recipients have an elevated risk for VOD due to the high-dose chemotherapy they undergo prior to transplantation and the type of transplant they have, with allogeneic (unrelated donor) transplant recipients being at greater risk than autologous (self donor) patients.

Under a research protocol allowing it to be used on an emergency basis, defibrotide was given to 88 transplant patients who had severe VOD and multi-system organ failure. The drug reversed VOD completely in 32 patients (36 percent), and 31 patients (35 percent) survived at least 100 days after transplant, a milestone used to determine transplant success. Less than 10 percent of these patients typically would have been expected to survive 100 days post-transplant.

Chemotherapy drugs can damage the cells lining the small blood vessels in the liver as well as liver cells. This disrupts the liver's circulation, causing it to swell painfully, resulting in VOD. Patients with VOD usually become jaundiced and bloated, and they are at risk for other organs to fail, such as the kidneys and lungs.

The younger patients in the trial fared better than those who were older, explains senior author Eva C. Guinan, MD, director of the Pediatric Stem Cell Transplant Program at Children's Hospital Boston and a pediatric oncologist at Dana-Farber.

Many of the survivors were younger than 18, including infants as young as 8 months. "We've had some children in the Intensive Care Unit with incredibly severe VOD, who were on ventilators and dialysis, and who are now long-term survivors with excellent function," says Guinan, who is also an associate professor of pediatrics at Harvard Medical School.

VOD is more common in transplant centers that accept sicker patients with a poorer outlook, Richardson says, and less common in centers that include only the best candidates. Some individuals are more susceptible to VOD than others, but it is not possible to always identify those patients ahead of time.

Previously, doctors administered clot-busting drugs like t-PA and heparin to treat VOD, but the drugs caused severe bleeding and were ineffective in patients with multi-system organ failure. In this study, defibrotide, which is a single stranded piece of DNA that is selectively active on the surface of small blood vessels and repairs blood vessel injury, did not cause any serious bleeding and side effects, such as hot flashes, were mild.

Richardson and his colleagues currently are conducting a randomized, prospective trial of defibrotide to verify this study's findings and determine the best dose.

"Given the drug's favorable safety record and promising activity, we plan to next study this drug as a prophylactic agent in patients undergoing transplant. In the future, this may allow us to treat patients who otherwise would be denied transplants because of their high risk of VOD," says Richardson, who is also an instructor at Harvard Medical School.

The study was funded in part by the Orphan Products Development Program of the Food and Drug Administration. Defibrotide is manufactured by Gentium SpA of Como, Italy.