Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease ( GVHD ) after hematopoietic-cell transplantation.

Researchers at the Stanford University Medical Center tested this strategy in humans.

The findings are published in the New England Journal of Medicine ( NEJM ).

Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation ( 80 cGy each ) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor.

Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation.

Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission.

In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation ( 200 cGy ).

The research found that a regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.

The new method tested at Stanford appears to retain the desired result of the transplantation - killing the cancerous cells - without inducing the acute form of graft-versus-host disease. " It allows you to throw out the one effect but not the other," said Samuel Strober, senior author of the study.

Among the 37 study participants included in the National Institutes of Health-funded clinical trial, there was more than a tenfold reduction in the incidence of acute graft-versus-host disease. Only 5 percent, or just two patients, experienced the acute form of the disease.

" You would have expected something in the order of 30 to 60 percent incidence of severe graft-versus-host disease in these patients, according to conventional methods," said Strober. " And it didn't look like there was a price to be paid for this major reduction," he added, explaining that the patients did not have any higher rate of infections or relapse.

The majority of patients who were in partial remission went into complete remission, and those who were in complete remission didn't relapse over the course of the three-year study.

The treatment was not as effective in stemming the less-serious, chronic form of graft-versus-host disease. The study found no apparent difference in the typical rates of the chronic form of the condition among the patients who survived more than 100 days after transplantation.

Acute graft-versus-host disease occurs within 100 days of transplantation and involves the donor immune cells attacking the host's skin, intestines and liver. It is lethal in up to 40 percent of the cases. Chronic graft-versus-host disease is characterized by such long-term problems as dryness of the eyes and mouth, skin rashes, stiff joints, weight loss caused by intestinal scarring, and more infections due to a weakened immune system.

Robertson Parkman, an immunologist who was not involved in the study, said that the new procedure " is definitely a significant improvement " over the existing methods. He did, however, find it a bit problematic that the patients continue to show some chronic graft-versus-host disease. " Reducing acute graft-versus-host disease is a good thing, but this approach may not be as much of a total panacea as we'd like it to be," said Parkman, at Children's Hospital Los Angeles.

The Stanford researchers said that more research is needed, and they hope to begin testing their method with other cancer centers soon.

Source: Stanford University Medical Center, 2005


XagenaMedicine2005