Making use of mismatched donor marrow.

To beat leukemia, it helps to be lucky. A bone marrow transplant can give a patient a fresh start at producing blood cells free of this cancer, but a successful transplant typically requires that at least five out of six key genetic markers in the donor match those in the recipient.

Unfortunately, most patients don't find a good match even among close relatives willing to donate bone marrow and must hope to get appropriate bone marrow from a tissue bank. Some wait months for a good match, and others die waiting. Some acutely ill patients, having little choice, must accept the best available transplant--blood in which only three or four of the six markers are correct. Having a mismatched donor worsens the recipient's survival odds because the transplanted tissue is often rejected.

A study in the Oct. 22 New England Journal of Medicine brightens the picture for leukemia patients. By giving them a massive dose of stem cells--the marrow cells that harbor blueprints for new, healthy blood cells--researchers in Israel and Italy find they can overwhelm a recipient's remaining immune cells and thwart rejection. The dose of stem cells, collected from blood instead of bone marrow, is up to 10 times greater than a marrow transplant would normally provide.

Even when the donated stem cells are mismatched for three of the six markers, the survival rate of recipients approaches that of patients receiving blood from well-matched, unrelated donors.

In both the marrow and new stem-cell transplant procedures, patients typically receive radiation treatment, chemotherapy, and drugs to suppress immune rejection and ward off disease. Even so, the patients can encounter a cancer recurrence, infection, transplant rejection, or graft-versus-host disease, in which the donor's immune cells attack the patient.

The researchers extracted stem cells from the blood of donors who had been primed with hormones to produce these cells prodigiously. To lessen the risk of graft-versus-host disease, the technique also removes the donor's immune T cells.

Of 43 terminally ill leukemia patients treated with this procedure, 12 survived and were healthy 18 months after the stem-cell transplant, says study coauthor Yair Reisner of the Weizmann Institute in Rehovot, Israel. The other patients died or suffered a relapse of leukemia.

"For patients who don't have matched donors or don't have time to wait, this is a huge step forward," says LeeAnn T. Jensen of the National Heart, Lung, and Blood Institute in Bethesda, Md.

At the core of the mismatch problem are human leukocyte antigens, cell-surface proteins that help direct immune system functions. Genes encoding these proteins are inherited as a unit, one from each parent. Identifying the DNA sequence at three specific locations on each unit provides the six genetic markers used in seeking a match.

Less than a third of patients have a family member who matches five or six markers, but everyone's parents and most siblings match at least three. "It would be very unusual that you wouldn't have a [related] donor for every patient," Reisner says.