New Drug Therapy To Combat Graft-vs.-Host Disease In Stem-Cell Patients Shows Significant Reduction In Deaths

Gastrointestinal graft-vs.-host disease is a common and potentially deadly side effect for patients who undergo an allogeneic stem-cell transplant to treat certain blood cancers. Now, new research from Fred Hutchinson Cancer Research Center shows that adding a widely used topical corticosteroid to the standard treatment for GVHD kept the disease in remission and significantly reduces deaths one year after therapy.

A reformulation of beclomethasone dipropionate (BDP) into two different pills specifically releasing the drug into the stomach and mid-small intestine prevented relapse of gastrointestinal GVHD and allowed those patients to be on a shorter treatment course of high-dose prednisone. Mortality was reduced by 46 percent a year following the start of treatment in a multi-center Phase III clinical trial, according to findings published today in the online edition of the journal Blood. The lead author is David M. Hockenbery, M.D., a member of the Clinical Research Division at the Hutchinson Center and a professor of medicine/gastroenterology at the University of Washington School of Medicine.

BDP is an anti-inflammatory drug long used to treat a variety of diseases such as asthma and ulcerative colitis.

About 60 percent of patients who receive an allogeneic stem-cell transplant to treat blood cancers such as acute and chronic myelogenous leukemia, acute lymphocytic leukemia and non-Hodgkin's lymphoma develop gastrointestinal GVHD as a major side effect of being infused with donor stem cells. Those 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 drug is a two-edged sword, Hockenbery said. On the one hand it is designed to suppress the donor cells so GVHD can be controlled. But suppressing the immune system also makes patients susceptible to potentially fatal infections.

In the clinical trial, 129 patients were randomized into two groups. One group received a short course of standard prednisone therapy and oral BDP for 50 days. The other group received a placebo in place of the oral BPD for the same period. At day 10, the prednisone dose was quickly tapered in patients whose symptoms had responded. Fewer patients randomized to BDP had a subsequent flare-up of GVHD. After completion of the 50-day treatment period, patients were followed for an additional 30 days to see if the treatment effect would last. Patients randomized to BDP had a significantly more durable response rate compared to those in the placebo group. At one year after treatment, mortality rates had been reduced 46 percent compared to the placebo group.

"Oral BDP 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," Hockenbery said. "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 idea to reformulate BDP into an oral form for stem-cell-transplant patients belongs to George B. McDonald, M.D., one of the study co-authors and a colleague of Hockenbery's at the Hutchinson Center. McDonald, also a member of the Center's Clinical Research Division and a professor of medicine/gastroenterology at UW, initiated the early trials of oral BDP with funding from a U.S. Food & Drug Administration Orphan Products Development Grant. The goal was to target corticosteroid therapy to the areas of the GI tract affected by GVHD. The anti-inflammatory actions of the two BDP- containing pills would then be focused on the intestinal lining from top to bottom to suppress GVHD, thus avoiding excessive corticosteroid medication in the bloodstream.

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 recipients.

The pivotal clinical trial was funded by an Orphan Products Development Grant of the U.S. Food & Drug Administration and by Enteron Pharmaceuticals Inc., a wholly-owned subsidiary of DOR BioPharma Inc. Fifteen other centers in the U.S. and France participated in the study.

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