Experimental treatment for graft-vs.-host disease may reduce steroid need

Chronic graft-vs.-host disease (GVHD) is a common complication that develops after a stem-cell transplant when immune cells in the donor tissue attack the recipient's organs and skin with damaging inflammation. Such cases are often treated with infusions of steroid drugs like prednisone, but they do not work for all patients and are toxic with long-term use, prompting a quest for other forms of treatment.

In a new, small study reported at the American Society of Hematology annual meeting, researchers at Dana-Farber Cancer Institute found that adding bortezomib (Velcade) to initial treatment for chronic GVHD achieved a good response rate and allowed significant reduction of steroid medication in some patients.

The single-arm, phase 2 trial was motivated by preclinical studies showing that bortezomib, a proteasome inhibitor drug used to treat multiple myeloma, "inhibits pathways involved in immune cell activation and function," said Alex Herrera, MD, first author of the study. "Given that, we wanted to see bortezomib might be helpful in treating chronic GVHD."

The study enrolled 22 patients who had developed chronic GVHD seven months, on average, following a stem cell transplant as a treatment for blood cancer. The patients included recipients of matched related donors as well as unrelated or mismatched donors. Weekly infusions of bortezomib for 15 weeks were added to the steroid medications typically used for initial treatment of chronic GVHD.

In 20 patients who could be evaluated, the observed response rate at the end of 15 weeks of treatment was 80 percent, with the GVHD resolving completely in two patients and 14 patients (70 percent) achieving a partial response.

The main goal of the experimental therapy was to reduce steroid use. Results showed that 14 patients tolerated a 50 percent or greater decrease in steroid medication over the 15-week treatment period, from a median dose of 50 milligrams to 20 milligrams.

Despite side effects, "most patients completed the study, and I would say the response rate at 15 weeks was reasonable, with a good response in patients who had skin and liver involvement," said Herrera. "We can say we got some people off prednisone, and that's good," he added, "but with this short study without a control group, we are mainly able to say that adding bortezomib was feasible and well-tolerated."

The need for weekly infusions of the drug was a barrier to enrollment for some patients, the researchers said, highlighting the potential benefit of using oral proteasome inhibitors – some of which are now in clinical testing.

John Koreth, MBBS, DPhil, the senior author of the report, said "the feasibility and safety of the drug are quite clear, and there are some signs suggesting this regimen should be looked at further."

Additional authors include Haesook Kim, PhD, Joseph Antin, MD, and Robert Soiffer, MD, all of Dana-Farber.

This study was supported in part by NCI (P01 CA142106) and by Millennium Pharmaceuticals.