The disorder, chronic granulomatous disease (CGD), leaves individuals vulnerable to life-threatening infections and inflammatory growths, or granulomas, which can damage the lungs, liver and other organs.

Although it is too soon to claim that the patients have been cured, the data so far suggest that for patients in whom the transplant was successful, the immune system is functioning significantly better than before treatment, the investigators say.

"Non-myeloablative stem cell transplantation has previously shown promise in leukemia and kidney cancer patients," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), "but this is the first clinical trial of this strategy in a series of patients who have an inherited immune disorder."

The low-intensity stem cell transplantation procedure, which uses no radiation, is less risky than conventional stem cell transplantation because only some rather than all of the patient's bone marrow cells are wiped out before the individual receives the transplant. As a result, the transplanted patients have a mixture of their own and their sibling's immune cells.

Results of the CGD study, led by Mitchell E. Horwitz, M.D., and Harry L. Malech, M.D., of NIAID's Laboratory of Host Defenses, appear in the March 22 issue of The New England Journal of Medicine (NEJM).

CGD affects more than 1,000 people in the United States and an estimated 25,000 people worldwide. It is caused by several different gene mutations that prevent white blood cells called neutrophils from making oxygen compounds that kill bacteria and fungi.

Based on studies of people with various types of the mutation, the researchers project that restoring just 10 percent of neutrophils to proper function may stave off recurrent CGD infections.

Recent advances in treating CGD based on an immune-based therapy and antibiotics have extended infection-free intervals and survival time in CGD patients. But many people with the disorder still suffer recurrent bouts of potentially deadly infections as well as a compromised quality of life.

Both the infections and the drugs taken to control them can damage vital organs over time. In the United States, between 2 and 5 percent of those affected by CGD die each year.

During the past two decades, the NIAID group has made several important contributions to understanding the genetics and underlying pathology of CGD, and they and others have developed various treatment strategies to reduce the frequency of infections in people with the disorder.

In the NEJM study, the NIAID group attempted to move their efforts one giant step forward. "We wanted to determine," says Dr. Malech, "if there are ways to permanently restore proper immune cell functioning without attempting to correct the underlying genetic defect."

Dr. Horwitz notes, "We will not know whether this treatment is a potential cure until we follow these patients for several more years. But we are encouraged by the freedom from infection and markedly improved quality of life that have come to the patients who have been successfully transplanted."

Conventional stem cell transplants require that the recipients' bone marrow be knocked out with highly toxic drugs before the transplant procedure to reduce the chances that the graft will be rejected. Because that early step carries a significant risk of serious complications and death, such transplants are most often considered a last-resort option for the sickest CGD patients.

To improve the odds of survival, Dr. Horwitz took the non-myeloablative stem cell transplantation strategy that his colleague A. John Barrett, M.D., from the National Heart, Lung and Blood Institute (NHLBI), pioneered in kidney cancer and leukemia patients and tailored it to CGD patients.

Although conditioning regimens associated with low-intensity stem cell transplants are less toxic than those of conventional stem cell transplants, the risk of graft-versus-host disease (GVHD) after the transplant is similar for the two procedures.

Donor T cells present in the stem cell graft are known to cause GVHD. To rid the graft of T cells, Dr. Horwitz turned to the stem cell processing expertise of Elizabeth J. Read, M.D., and her colleagues in the NIH Clinical Center Department of Transfusion Medicine.

But T cells are necessary to help fight infection and facilitate transplantation of the donor stem cells. So Dr. Horwitz gradually began reintroducing donor T cells into the patients beginning about one month after the transplant. Their goal in this study was to achieve a stable presence of transplanted donor cells.

"In developing this strategy, we were walking a fine line between the deleterious and beneficial effects of donor T cells," explains Dr. Horwitz. "Without the re-infusion of donor T cells, 70 to 80 percent of the grafts would be rejected," he says. "We had to gradually add back donor T cells over time, enough to prevent rejection but not so much as to cause graft-versus-host disease."

The study enrolled 10 people with severe CGD between the ages of 5 and 36. Six of the study patients had complete engraftment of donor stem cells, and another two had partial engraftment.

Overall, the transplant worked best in the five children who were 12 years old or younger, only one of whom experienced a mild case of GVHD. Three adults enrolled in the study died. One death was related to GVHD, one was caused by an infection, and the third was due to complications of a second transplantation after the first was immunologically rejected.

In the median 18 months of follow-up, the investigators have observed only one serious infection characteristic of a patient with CGD disease. In addition, they have seen resolution of pre-existing granulomas. Complete immune reconstitution after stem cell transplantation, Dr. Horwitz notes, can take more than one year.

Despite fewer side effects, the new approach to stem cell transplantation still carries considerable risks, the investigators concede. In the future, they will fine-tune the procedure to further reduce the risks.

Dr. Horwitz is planning a new trial that will focus on younger patients with severe CGD. They will be infused with fewer sibling T cells in an attempt to achieve a permanent mixture of sibling and patient blood cells, which data from the current trial indicates will increase the chances of improving immune function and avoiding GVHD.

In an NEJM editorial about the research, R. Alan B. Ezekowitz, M.D., Ch.B., D.Phil., of Massachusetts General Hospital, concludes, "It seems that we are at the threshold of real advances in therapies for inherited disorders....These new techniques may allow the cure of a wide range of inherited disorders in the next decade." - By Laurie K. Doepel

References:

ME Horwitz et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. The New England Journal of Medicine 344:881-88 (2001).

RAB Ezekowitz. What is the best way to treat inherited disorders? The New England Journal of Medicine 344:926-27 (2001).

[Contact: Laurie K. Doepel]

22-Mar-2001