The trial was designed to determine whether the drug bortezomib (trade name Velcade), when added to routine agents (tacrolimus, methotrexate), can improve control of graft-versus-host disease (GVHD) and improve immune system recovery following a transplant from a mismatched-unrelated donor. GVHD is a common and potentially severe side effect of blood-forming stem cell transplants, in which donor immune cells attack normal patient cells and tissues. GVHD is more frequent in patients receiving transplants from mismatched-unrelated donors (in comparison with matched-related donors).
Based on bortezomib's effect in preclinical models, and in multiple myeloma patients who have received donor stem cell transplants, Dana-Farber's John Koreth, MBBS, DPhil, and colleagues theorized that it could help control the overactivity of immune cells responsible for GVHD in stem cell transplant patients.
Bortezomib inhibits the activity of antigen-presenting cells, which help initiate the immune attack in GVHD, and reduces activity of an important protein called nuclear factor-ƒÛB in T cells, which undertake the immune attack. In preclinical studies, bortezomib has been shown to selectively deplete T cells that can target patients' normal cells. Mouse transplant studies have shown that early administration of bortezomib protects against GVHD without reducing the transplanted stem cells' ability to settle in the bone marrow.
The new, Phase 1 clinical trial involved 23 patients who received bortezomib-based therapy (bortezomib, tacrolimus, and methotrexate) after reduced-intensity stem cell transplants from mismatched-unrelated donors. Three dosage levels of bortezomib were tested. In updated results on 35 bortezomib-based mismatched-unrelated patients reported at ASH, GVHD rates and extent of immune system reconstitution were compared with patients who had received sirolimus-based therapy (sirolimus, tacrolimus, and methotrexate) after transplants from matched-related donors, matched-unrelated donors, and mismatched-unrelated donors.
The results show that the bortezomib-based therapy was safe and had little toxicity. Transplanted stem cells took root, or "engrafted" reliably, and the rate of GVHD in the bortezomib-based mismatched-unrelated transplants was comparable to that in sirolimus-based matched-related transplants. Interestingly, immune cell reconstitution was significantly improved in the bortezomib-based patients in the early post-transplant period (3-6 months), compared with the sirolimus-based patients.
"Our results suggest that borezomib is a promising novel immunomodulatory agent in donor stem-cell transplantation," Koreth says. "A Phase 2 trial is now accruing patients to help determine its ultimate effectiveness."
The study's senior author is Dana-Farber's Edwin Alyea, MD. Co-authors are Kristen Stevenson, Haesook Kim, PhD, Michael Garcia, Vincent Ho, MD, Philippe Armand, MD, Corey Cutler, MD, Jerome Ritz, MD, Joseph Antin, MD, and Robert Soiffer, MD, all of Dana-Farber.
The study was supported by Millennium Pharmaceuticals Inc. and the National Institutes of Health.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.
Teresa Herbert | EurekAlert!
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