Controlling gastrointestinal GVHD

Phase III clinical trial on drug therapy to combat graft-vs.-host disease in stem-cell patients shows promise

Dr. George McDonald (left), research nurse Michelle Bouvier and Dr. David Hockenbery

Anyone who has had an allogeneic stem-cell transplant knows the potential problems that can come with it. About 60 percent of patients who receive such a transplant develop gastrointestinal GVHD after being infused with donor stem cells. But Hutchinson Center researchers have made strides against GVHD and recently found that adding a widely used drug to the standard regimen can help keep the disease in remission.

An anti-inflammatory medicine long used to treat a variety of diseases such as asthma and ulcerative colitis can knock GVHD off course. Because GVHD attacks the inside surface that lines the gastrointestinal tract, researchers looked for a way to protect the stomach and intestine from top to bottom. To do that, researchers reformulated the drug beclomethasone dipropionate (BPD) into two different pills, one that releases immediately in the stomach, and another that activates later in the small intestine. Doing so protected the inside lining of these organs, while minimizing the amount of steroid released into the bloodstream. Using that method, investigators were able to prevent a relapse of gastrointestinal GVHD and reduce the amount of time patients were treated with high-dose prednisone, which carries the risk of serious side effects such as fatal infections and weakness.

Allogeneic stem-cell transplants are used to treat blood cancers such as acute and chronic myelogenous leukemia, acute lymphocytic leukemia and non-Hodgkin's lymphoma. Patients who show gastrointestinal symptoms of the disease usually receive a two to four-week course of high-dose systemic prednisone therapy that is then tapered slowly. However, that treatment is a double-edged sword. On one hand, it is designed to suppress the donor cells so GVHD can be controlled. But suppressing the immune system also makes patients more susceptible to potentially fatal infections, so the less time spent on a high-dose treatment, the better.

During the clinical trial, the new treatment significantly reduced the flare-ups of GVHD. After the 50-day treatment period, patients were followed for an additional 30 days to see if the treatment effect would last. The results, published in the journal Blood, showed that patients who had received BPD had a significantly better response rate compared to those in the placebo group.

"Oral BPD provides much more tailored and targeted control of gastrointestinal GVHD and it allows patients to move away from the side effects of standard prednisone therapy. All of this improves the chances that patients will have a successful outcome," said Hutchinson Center's Dr. David Hockenbery, lead author of the paper. "I think this is a very convincing clinical trial because by targeting topical therapy to the areas most affected, we were able to keep symptoms at bay while minimizing systemic immune suppression."

The FDA is expected to decide whether to approve use of the oral form of the drug by July. If approved, it would be only the second drug approved by the FDA for treatment of GVHD in stem-cell transplant patients.