Preventing graft-versus-host disease disease after bone marrow transplant -- without toxicity
Dec 11, 2006 - 5:00:00 AM
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Levy and Guinan will first conduct a small safety trial, gradually increasing the amount of BPI given and the duration of treatment. If BPI appears safe, they will quickly mount a randomized, controlled trial in 30 to 40 patients who are undergoing HSCT for cancer or blood diseases. Childrens/Dana-Farber will be the lead center, with four to five additional pediatric and adult sites at prominent medical centers around the country.
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By Children's Hospital Boston,
[RxPG] Unless the donor is an identical twin, patients undergoing bone-marrow transplant (also known as hematopoietic stem cell transplant, or HSCT) must first receive powerful chemotherapy drugs to wipe out their immune system and prevent their bodies from rejecting the donated cells. Research from Childrens Hospital Boston and the Dana-Farber Cancer Institute has helped demonstrate that this punishing regimen increases the risk of graft-versus-host disease (GVHD), in which the donors cells mount an immune response against the patient. But the most recent findings also suggest that the risk for GVHD can be reduced by replacing a natural antibiotic protein, known as bactericidal/permeability increasing protein (BPI), which is depleted when patients undergo chemotherapy.
Now, a multicenter study is about to test this idea in HSCT patients, using a manufactured form of BPI known as rBPI21 (XOMA Ltd.) Unlike other treatments to prevent GVHD, BPI does not suppress the immune system and has shown virtually no toxicity.
Researchers Ofer Levy, MD, PhD, of Childrens Hospital Boston, and Eva Guinan, MD, of Childrens Hospital Boston and Dana-Farber Cancer Institute, will present their most recent findings and discuss the new clinical trial on December 11 at the American Society of Hematology (ASH) Annual Meeting in Orlando, Fla. (abstract # 2856).
The new trial is the culmination of over five years of collaborative research by Levy and Guinan in human patients. Many basic and translational studies, including our own, have provided a strong rationale for a trial of BPI in patients undergoing hematopoietic stem cell transplants, says Levy. Replenishing a natural host defense factor that is deficient due to chemotherapy makes theoretical and practical sense, and we hope that bringing our bench work to patients will reduce the complications they suffer.
GVHD occurs when immune cells from donor attack the recipient, and can lead to multiple organ failure and death. It strikes some 30-60 percent of transplant patients, depending on how closely matched the donor is, and is kept in check only by eliminating otherwise useful donor immune cells or by using powerful immune-suppressing drugs.
Studies in mice had shown that the chemotherapy regimens used in HSCT not only wipe out white blood cells (with the intended effect of suppressing the immune system), but also damage the intestinal lining. This breach of the lining allows endotoxin, which is produced by bacteria living in the intestines, to enter the bloodstream. The endotoxin, in turn, provokes an inflammatory response that mobilizes donor immune cells, helping to trigger GVHD.
Levy, in Childrens Division of Infectious Diseases, had long been studying BPI, which naturally blocks and neutralizes endotoxin.(1) BPI is found in neutrophils, the very white blood cells that are virtually wiped out by pre-transplant chemotherapy. Studies in mice had shown that blocking endotoxin reduces the incidence of GVHD after chemotherapy and HSCT.(2)
Intrigued by these findings, Levy and Guinan began to study endotoxin and BPI in human patients undergoing HSCT with pre-transplant chemotherapy. In 2003 they showed, in a study of 57 children, that patients blood endotoxin levels rise markedly within a week of the transplant.(3) And now, in a study of 30 patient:donor pairs to be presented at the ASH meeting, they show that patients undergoing HSCT also have a sharp drop in BPI levels just as their endotoxin levels are rising and that BPI deficiency is associated with a greater likelihood of GVHD.
BPI is markedly deficient 100 to 1000-fold lower in our transplant patients, says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber. If we can replenish this host defense factor, we might be able to moderate the damaging effects of GVHD.
The multicenter clinical trial, expected to begin within the next few months, will test rBPI21 (opebacan, NEUPREX® [Nasdaq: XOMA]). rBPI21 has been in phase I, II, and III human trials, with evidence of benefit in children and adolescents with serious meningococcal infections, but has not yet been approved by the Food and Drug Administration.
Levy and Guinan will first conduct a small safety trial, gradually increasing the amount of BPI given and the duration of treatment. If BPI appears safe, they will quickly mount a randomized, controlled trial in 30 to 40 patients who are undergoing HSCT for cancer or blood diseases. Childrens/Dana-Farber will be the lead center, with four to five additional pediatric and adult sites at prominent medical centers around the country.
Our ultimate goal is to reduce the downstream complications of stem-cell transplant, says Guinan. BPI would make these transplants significantly less toxic.
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