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Umbilical Cord Blood Offers Another Option for Leukemia Patients

Damaris Christensen

Adults with leukemia who need hematopoietic stem cell transplants but do not have bone marrow donors matched for key immune antigens will fare equally well with transplants that use bone marrow grafts that are mismatched for one antigen or that use stem cell–rich blood taken from umbilical cords soon after birth, according to two new studies. These are the first large-scale studies to compare cord blood transplants to current standard therapy in adults with leukemia.

"Cord blood opens the door to provide transplants to thousands of leukemia patients who otherwise would not get a transplant," said Mary J. Laughlin, M.D., of the Case Comprehensive Cancer Center in Cleveland. Only about 30% of leukemia patients who are eligible for transplants have a related bone marrow donor matched for the six most important human leukocyte antigens, or HLAs, which help the immune system recognize and avoid attacking its own cells, she said. Of the rest of the patients, only about 20% get a transplant from an unrelated donor or an HLA-mismatched donor. The closer the HLA match, the greater the likelihood that the transplant will be effective.

Cord blood offers at least two important advantages over bone marrow, said Laughlin, the lead author of one of two studies of cord blood transplants published in the November 25 issue of the New England Journal of Medicine. First, identification and delivery of appropriate units for transplant is much faster with cord blood, and some patients are so sick they cannot afford any delay. Second, matching of HLAs is less important for successful cord blood transplants than for marrow transplants, and this means people are more likely to find acceptable transplants. But because cord blood donations contain about a tenth of the number of hematopoietic stem cells— the precursor cells that will produce all necessary blood cells—as bone marrow donations, many physicians have resisted using cord blood transplants in adults for fear that cord blood units will not contain enough cells to be effective.

In Laughlin's U.S. study, 367 adults who received matched bone marrow transplants fared better than 150 who got umbilical cord transplants mismatched for one or two antigens. However, compared with the 83 bone marrow transplants mismatched for just one antigen, singly or doubly mismatched cord blood transplants led to similar rates of treatment failure, death related to the transplant, and overall death. Singly mismatched bone marrow transplants are the current standard of care, implying that cord blood transplants should also be viewed in this way, Laughlin said. She and her colleagues found no difference in outcome between the 34 patients who got cord blood transplants mismatched for one antigen and the 116 mismatched for two antigens.

Acute graft-versus-host disease—a condition in which the transplanted cells attack the host—was more common after mismatched bone marrow transplantation, while chronic graft-versus-host disease was more common after cord blood transplantation, Laughlin reported. The study included people ages 16 to 60 who had various kinds of leukemias, underwent bone marrow and cord blood transplantation between 1996 and 2001, and were included in the registries of the National Cord Blood Program of the New York Blood Center or the International Bone Marrow Transplant Registry.

In a European study published at the same time, the incidence of chronic graft-versus-host disease, relapse of disease, death related to transplantation, and leukemia-free survival was not significantly different between 98 people who received cord blood transplants and 584 who got HLA- matched bone marrow transplants. Only 6% of the cord blood transplants were fully matched to the recipient, reported Eliane Gluckman, M.D., of the Hôpital Saint-Louis in Paris. About half of the cord blood transplants were mismatched by one antigen, and the rest were mismatched by two or three antigens.

"It shows, at least in our study, that mismatched cord blood is equivalent to matched bone marrow in terms of survival," said Gluckman. Greater disparity in HLAs between a transplant and the recipient often triggers graft-versus-host disease; nevertheless, she said, people who got cord blood transplants were less likely to have acute graft-versus-host disease than those who were given bone marrow transplants. All of the patients in the European study had primary acute leukemia, underwent transplantation between 1998 and 2002, and were enrolled in registries maintained by Eurocord and the European Blood and Marrow Transplant Group.

In both studies, cord blood recipients tended to be younger and sicker than those who got bone marrow transplants. In addition, they received lower doses of nucleated cells, which are used as a marker for stem cells, than did those who got bone marrow transplants. The lower dose of stem cells slows the replacement of the patient's blood cells. This delay in turn increases the risk that a transplant patient will develop potentially deadly infections during recovery (although this did not significantly raise overall mortality rates in either study).

"The results in both settings are not optimal and leave room for improvement," said Joanne Kurtzberg, M.D., of the Duke University Medical Center in Durham, N.C., who was involved with the first cord blood transplant in 1998. But the findings are important and promising, she said, especially for minority patients and those of multiple ethnic backgrounds who have more difficulty finding perfect matches for transplant because they have more diverse HLAs. "Patients lacking matched unrelated bone marrow donors, or without time to search, should not be told they are without options," she said.



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Joanne Kurtzberg

 
That said, many centers may not be prepared for the intensity of supportive care needed after cord blood transplants, said Thomas C. Shea, M.D., an oncologist and transplant specialist at the University of North Carolina, Chapel Hill. People who get cord blood transplants are more vulnerable to infections, so they require more care for longer periods of time, he said.

There is a great deal of research aimed at improving the effectiveness of cord blood transplants and addressing the issue of slower immune recovery. Among the possibilities being explored by research teams are transplanting multiple cord blood donations into a single patient, isolating stem cells from cord blood and increasing their number in vitro before transplant, and using stem cells taken from a family member in combination with a cord blood transplant.

Because other studies found that fewer transplanted immune cells seem to be needed to establish a successful graft when HLA mismatches are minimized, Laughlin said, another plausible method for improving cord blood transplants is to expand the national registries so that more patients can get transplants that are either matched or mismatched for a single antigen. At the request of Congress, the Institute of Medicine is assessing existing cord blood programs, and the group expects to release a report with recommendations for improving the national cord blood banking system this spring.

"The more [cord blood samples] we bank the better will be the match and the availability to patients," Gluckman agreed. However, she noted, the recent studies confirm that cord blood transplantation in adults is already a promising alternative to bone marrow transplantation. Until now, "many transplant centers thought it was not possible to use cord blood cells in adults," she said. "Now, more people will become aware of this possibility."



             
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