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New Drug Shows Early Promise in Fight Against GVHD A new drug on the transplant scene is raising hopes that another weapon to fight graft-versus-host disease (GVHD) may be on the horizon. In a small Phase I clinical trial, conducted at the Fred Hutchinson Cancer Research Center in 1999-2000, 17 patients with severe or life-threatening acute GVHD all experienced improvement in their GVHD symptoms after being given the investigational drug visilizumab (Nuvion®). Results of the study were published in the April 15, 2002 issue of the journal Blood. The 17 patients had previously failed steroid therapy-the standard treatment for acute GVHD. All but one had severe grades of acute GVHD affecting the gut, and approximately half of the patients also had GVHD of the skin and liver. Following one or more injections with visilizumab, all patients had at least a partial improvement in their GVHD symptoms. In seven patients, the symptoms of acute GVHD completely resolved. Seven patients remained alive 260 to 490 days after treatment, and at least six are currently still alive.1 Approximately 50 percent of patients who are transplanted with bone marrow or blood stem cells from a matched related donor develop acute GVHD during the first three months after transplant. The percentage is higher among patients transplanted with marrow or blood stem cells from a mismatched or unrelated donor. Roughly half of the patients who develop acute GVHD can be helped by steroid therapy. But for those who do not respond to steroid therapy, there are very few treatment options. The cells that cause acute GVHD are called T-cells. T-cells are a type of white blood cell that can recognize which cells belong in a person's body and which do not. When a donor's T-cells are transplanted into a patient, they often perceive the patient's organs and tissues as foreign cells, begin to multiply, and unleash an immune system attack to destroy them. The usual targets of this immune system attack are the patient's skin, liver, stomach and/or intestines. Visilizumab, which is being developed by Protein Design Labs (Fremont CA), targets active T-cells and causes many of them to self-destruct. "Although the number of patients treated with visilizumab was small, survival rates following this treatment compare favorably to the recent experience with other drugs," says Paul A. Carpenter MD, who headed the Phase I study. "Antithymocyte globulins have often been used to treat acute GVHD that has failed to respond to steriods, but fewer than 20 percent of such patients typically survive more than six months after treatment." However, as with other therapies that eliminate donor T-cells, patients treated with visilizumab have an increased risk of developing Epstein Barr virus post-transplant lymphoproliferative disorder (EBV-PTLD)-a potentially fatal disease. Patients in the study who were given another monoclonal antibody called rituximab (Rituxan®) when active Epstein Barr virus was detected early in their bloodstream, did not develop EBV-PTLD. A Phase II clinical trial, which will further assess the effectiveness of visilizumab in patients with acute GVHD, who do not respond to steroid therapy, is opening at several transplant centers. Eighty patients are expected to enroll in the trial. The trial will measure survival rates six months after treatment and determine the incidence of EBV lymphoproliferative disorder. A second clinical trial will offer visilizumab therapy to patients with acute GVHD who have not failed traditional steroid therapy. Thirty-four patients are expected to enroll in the study at several transplant centers in the U.S. Patients will receive a short course of steroid therapy followed by a single dose of visilizumab. The study is designed to evaluate how well patients tolerate the visilizumab, how much of the drug can safely be given to GVHD patients, and its effectiveness in treating acute GVHD. "We have been extremely encouraged by the complete response rates we have observed when visilizumab was administered to patients with very severe refractory acute GVHD," says Carpenter. "It's now important to test our initial study results in a larger clinical study at multiple treatment centers, in order to gain greater confidence in the effectiveness and safety of this approach." For more information about these trials phone 800-772-0482.
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