Seattle -- In the largest United States study ever conducted of unrelated marrow transplants for leukemia Fred Hutchinson Cancer Research Center researchers showed that using genetic techniques for matching patients with marrow donors can all but eliminate the guesswork involved and may change the standard practice for marrow transplantation donor typing. The study, funded by the National Institutes of Health and the Friends of Allison, Inc., is reported in the Nov. 15 issue of the journal Blood.
"The study has great implications for marrow transplantation worldwide," says lead author Effie Petersdorf, M.D., a clinical investigator in the Human Immunogenetics Program at the Hutchinson Center. "As a result of this information, DNA methods for tissue typing are needed to select prospective volunteer donors."
According to Petersdorf this is good news for the majority of patients who do not have fully matched brothers or sisters and cannot find an unrelated donor matched at all five genes that govern tissue type.
"This is our single most important study in donor matching," says Petersdorf. "This is really preventive medicine. By selecting better-matched donors, we can reduce complications due to graft-versus-host disease and graft failure, which means patients require less medication and have better overall outcome."
"The study shows that if a complete DNA match can't be found, a single mismatch offers the same survival rate as the complete match," Petersdorf says. Current tissue matching for marrow transplants uses what are called serologic tests that compare certain proteins, called human leukocyte antigens (HLA), found on the surface of cells in the patient's body to those found in the donor. If a donor's cells carry the same antigens as the patient, the immune system that grows from the donated marrow is much less likely to recognize the patient's tissues as different and attack them.
It has long been known that mismatches between donors and patients resulted in varying degrees of post-transplant complications. In the worst cases, the donated marrow either failed to take hold and grow, called graft failure, or the donated marrow would not tolerate the patient's tissues, called graft-versus-host disease (GVHD).
Using more precise techniques to analyze differences in the genes that produce HLA proteins, the researchers were able for the first time to define the role of the five proteins used to determine compatibility between patients and their marrow donors.
The research team led by Dr. John Hansen, head of the Program in Human Immunogentics at the Hutchinson Center, compared overall survival of 300 patients who received unrelated marrow transplants for chronic myeloid leukemia (CML) between 1985 and 1998. The study reexamined the tissue matches of these patients and their donors using the more sensitive genetic technique.
The team investigated the five genes that govern tissue typing named HLA-A, B, C, DRB1 and DQB1. Each gene has two variations called alleles, one inherited from the mother, one from the father, for a total of 10 alleles. The former three genes are grouped together as class I antigens and the latter two are called class II markers.
They found that 142 patients had matches at all five of the HLA genes. There were 79 patients with one mismatch, 72 patients with a mismatch for two alleles and 7 patients had more than two mismatches. The results showed that 80 percent of patients matching all five genes (10 out of 10 alleles) survived four or more years.
Just as important, patients who had a single allele mismatch among either the class I or class II genes had statistically the same survival rate as those matched for all five. By contrast, patients mismatched for two class I alleles and patients with a mismatch at a class I and class II alleles had significantly lower survival rates.
Currently, donors are selected from registries based on initial matching of HLA-A, B and DR antigens. The results for the first time revealed that DNA mismatches at the class II genes (HLA-DRB1 and -DQB1) result in GVHD, while mismatches among the class I genes (HLA-A, B, C) were associated with graft failure.
The study enables physicians to select the donor who will offer a patient an 80 percent chance of long-term survival - the same as patients with matched family members.
According to Petersdorf it is unknown whether the same results could be expected from unrelated transplants for other diseases, but notes that the National Marrow Donor Registry is gearing up to conduct a nationwide study that may answer that question.
Previous studies of outcomes for unrelated marrow transplant patients treated for a variety of leukemias showed an overall three-year survival rate between 22 percent and 45 percent. Hansen points out that those studies, however, were done when unrelated transplants were often the last option for very sick patients. "Most patients in those studies waited a long time before choosing transplantation. Consequently, at the time of transplant, many were high-risk patients who had progressed to an advanced stage of the disease," says Hansen.
Chronic Myelogenous Leukemia (CML), also called chronic granulocytic leukemia, is a disease in which too many white blood cells are made in the bone marrow. CML comprises about one-third of the several forms of adult leukemia that strike more than 26,500 people in the U.S. each year, according to National Cancer Institute statistics.
Other members of the research team included Theodore Gooley, Ph.D., Claudio Anasetti, M.D., Paul Martin, M.D., Anajane Smith, Ann Woolfrey, M.D., and Eric Mickelson.
Journal
Blood