SAN DIEGO, Calif--Investigators have demonstrated that umbilical cord blood contains cells capable of instituting long-term, donor-derived hematopoiesis--with a very low probability of producing graft-versus-host disease (GVHD), John E. Wagner, MD, said at a conference sponsored by the University of California, San Diego Cancer Center and the UCSD School of Medicine.
SAN DIEGO, Calif--Investigators have demonstrated that umbilicalcord blood contains cells capable of instituting long-term, donor-derivedhematopoiesis--with a very low probability of producing graft-versus-hostdisease (GVHD), John E. Wagner, MD, said at a conference sponsoredby the University of California, San Diego Cancer Center and theUCSD School of Medicine.
Human umbilical cord and placental blood is known to contain hematopoieticprogenitor cells at a frequency that is equal to or greater thanthat in adult bone marrow. This led to investigations of its useto help "remedy, or at least reduce, some of the risks associatedwith allogeneic bone marrow transplantation (BMT)," saidDr. Wagner, associate professor of pediatrics, University of MinnesotaSchool of Medicine, Minneapolis.
The first successful umbilical cord blood transplant from a siblingdonor was performed in 1988, and since that time, 43 additionaltransplants have been performed worldwide and reported to theInternational Cord Blood Transplant Registry. These patients hada variety of malignant (primarily childhood leukemias) and nonmalignantdisorders. Their median age was 4 years, and median weight, 18.6kg.
The children received high-dose chemoradiation and were infusedwith umbilical cord blood from sibling donors. The majority ofthese transplants (77%) were HLA-identical grafts.
Evidence of hematopoietic recovery was seen in 85% of those transplanted."The range of hematopoietic recovery was exactly the samerange as you would see with BMT; however, the median time to recoverywas 22.5 days, which may be somewhat prolonged as compared withBMT," Dr. Wagner said.
With a median follow-up of 1.6 years, the overall survival ofthe group was 70%, he said. Event-free survival was 49% for thosepatients with malignant diseases, and 76% for those with nonmalignantconditions, although some relapses did occur over time.
Study of these transplant results has allowed researchers to learna great deal about the use of umbilical cord blood in clinicaltransplantation. For example, the use of hematopoietic growthfactors had "no observable effects on the time to neutrophilrecovery," Dr. Wagner said.
The total number of nucleated cells and colony forming cells (CFU-GMs)in the grafts was "quite low, almost 10 times less than whatwe typically give in an allograft from bone marrow," he noted.But the study showed that the number of nucleated cells or CFU-GMcells infused did not correlate with the time to engraftment."We must still be above the limiting number of cells neededfor engraftment," he commented.
Transplantation success rates differed between patients with malignantand nonmalignant diseases. "All patients with malignant diseasehad hematopoietic engraftment, whereas those with nonmalignantdisease had some evidence of graft failure," Dr. Wagner said.
These failures are probably due to the underlying disease and/orthe regimen used to treat the disease. Also, the majority of thosewith nonmalignant diseases had bone marrow failure syndromes and,therefore, would be at higher risk for graft failure even withBMT, he said.
One of the most important findings of the study was the very low2% incidence of GVHD in this group of patients. Limited chronicGVHD was observed in only three recipients, and in all cases thedisease quickly resolved following steroid therapy.
In the past, umbilical cord blood was not thought to be usefulin transplantation because of the belief that maternal cell contaminationwould put recipients at a higher risk for acute GVHD. Since nocases of severe GVHD have been reported, Dr. Wagner believes that"maternal cells are not there, are not functional, or arethere in such low numbers that they don't matter."
He noted that researchers are trying to discover why the incidenceof GVHD was so low in this group of patients (see below).
In response to these positive results, a number of umbilical cordblood banks have been created around the world. The largest isat the New York Blood Center. "We now have the ability touse umbilical cord blood as a source of stem cells for transplantationinto unrelated pediatric and adult recipients," Dr. Wagnercommented.
From a "practical point of view," he said, use of umbilicalcord blood may reduce the time for donor search, especially forethnic groups that are underrepresented in bone marrow registries.Also, there would be no problems with donor attrition, and unlikea bone marrow harvest, there would be no risk involved in thedonation process.
Multi-institutional trials are currently being developed to determinelimitations regarding recipient size and HLA mismatch restrictions,and to see if the incidence of GVHD is also lower in unrelateddonor transplants.
In 1995, investigators have already performed 25 unrelated donortransplants. Preliminary data from nine of these patients showthat only one failed to engraft. "One patient with a 2 HLA-DRmismatch engrafted rapidly and was discharged within a month,"he said.
The possible mechanisms for the low incidence of GVHD seen inumbilical cord blood transplants are as yet unclear, Dr. JohnWagner said in his presentation (see story above).
It may be that the immune system in these cord blood grafts isimmature. However, he pointed out, many normal immune system functionshave been shown to exist in these cells, including T-cell activation,cytolytic T lymphocyte precursor frequency, proliferative response,and natural killer activity.
Dr. Wagner noted that there appears to be a defect in antigen-presentingcell activity and also in the cell's cytotoxic response: "Thesecells respond to alloantigens; they proliferate, they just don'tkill, even when you do a secondary exposure."
There also appears to be potent suppressor cell activity, butthis cell has not yet been identified. This defective cytotoxicresponse could also reduce the complications of unrelated cordblood donor transplants, Dr. Wagner said.