Dr. Laughlin is Director of the Allogeneic Bone Marrow Transplant Program at Case Western Reserve/University Hospitals of Cleveland Ireland Cancer Center. A recipient of significant grants from The Leukemia & Lymphoma Society, she is recognized as an expert in unrelated umbilical cord blood allogeneic transplantation for patients with hematologic malignancies, inherited immunodeficiencies, and marrow failure syndromes.
Dr. Laughlin is seeking answers to some key questions about the role that umbilical cord blood (UCB) will play in leukemia treatment in the future. Recently, transplantation of umbilical cord blood from unrelated donors has been shown to successfully substitute for marrow in young childhood leukemia patients. This success is leading Dr. Laughlin to explore the critical question of the feasibility of UCB transplants in adults.
The goal of Dr. Laughlin's research is to determine whether umbilical cord blood transplants represent a safe and effective treatment for adults with various types of leukemia and lymphoma. In umbilical cord blood transplants, 150 milliliters (about 2 ounces) of blood harvested from an umbilical cord is injected into a patient whose own bone marrow has been depleted by drug therapy or radiation. Umbilical cord blood is a rich source of immature blood-forming cells known as stem cells. The stem cells grow in the patient's body and direct the production of every kind of blood cell. In this way, the marrow regrows with a healthy population of blood cells.
The same type of regrowth occurs during conventional marrow transplantation, where the stem cells come from the bone marrow of another person. Marrow is taken from the donor (during surgery), and given to the patient through an intravenous line, much like a blood transfusion. The marrow donor and the patient must have a similar tissue type for the donor cells to be successfully transplanted. The tissue type match is determined by six HLA antigens, proteins on the surface of cells that allow the immune system to distinguish the body's own cells from other people's cells. The closer the match between the patient and the donor, the better the chance that the transplant will be successful. If the donor is not a close six-antigen HLA match, graft-versus-host disease (GVHD), a serious and potentially fatal complication of transplantation, may occur.
An Alternative to Bone Marrow Dr. Laughlin is excited about the possibility that umbilical cord blood transplantation is a better alternative to marrow transplantation because the cord blood can be collected at no risk to the donor and HLA antigen matching may be less critical.
"It appears that cord blood transplants can be successful even when the tissue types of the cord blood recipient and the donor are less well-matched than with marrow transplants," she says.
Dr. Laughlin has published results that UCB transplants can be successful with mismatches at two of the six HLA antigen sites. With marrow transplantation, the chances for a successful transplant drop dramatically when the donor and patient share fewer than five or six of six HLA antigens.
"Umbilical cord transplants are successful despite some disparity between the tissue type of the donor and the recipient," says Dr.Laughlin. "We attribute this increased tolerance is likely related to the unique immunology of pregnancy which tolerates immune differences between two individuals (mother and baby) who are not genetically identical. A baby inherits half of his genetic makeup from each parent. A baby's immune system is tolerant of mom's proteins and blood cells, which we know cross the placenta during pregnancy, and the baby's immune system does not reject the non-inherited maternal proteins."
The immunologic tolerance of the UCB donors means that the cord blood cells, when transplanted, cause less of an immune reaction than blood cells obtained from adult marrow donors. This results in a decrease in graft-versus-host disease. In Dr. Laughlin's patients transplanted with UCB, the incidence of graft-versus-host disease is very low. Based on these findings, Dr. Laughlin has been performing umbilical cord blood transplants in adults, who are at an increased risk of developing graft-versus-host disease. In the past, smaller patients have been considered better candidates for cord blood transplant because of the limited supply of stem cells found in cord blood as compared with marrow. But Dr. Laughlin believes patient size is not an obstacle. "Our data suggest that cord blood transplants will work in larger patients," she says.
Dr. Laughlin has reportsed on 68 adults transplanted with umbilical cord blood transplants. "These are adults who ranged in age from 18 to 58 years, with an average age of 30 years, and ranged in weight from 94 to 202 pounds," she says. In general, the patients had one of three types of leukemia: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), or chronic myelogenous leukemia (CML), or severe aplastic anemia. Dr. Laughlin's clinical trials of umbilical cord blood transplantation in adults appear very promising.
"Of the 68 adult umbilical cord blood transplants performed, the majority received UCB grafts matched only at 4 out of 6 HLA antigens," she says, "yet the transplants have been successful. Nineteen of these very high risk patients (26 percent) are alive and doing well with no signs of recurrent leukemia. We have followed these patients now for up to four years post transplant. It also appears that the potentially fatal complication of transplantation, graft-versus-host disease, occurs less frequently and with less severity in adult recipients of umbilical cord transplants."
The immune system reactions which are responsible for graft-versus-host disease also cause a beneficial effect of transplantation known as "graft-versus-leukemia" or GVL. The graft-versus-leukemia immune reaction is a potential benefit to transplantation patients since it prevents relapse from leukemia after transplantation. Cures in leukemia patients treated with donor marrow transplants are largely due to the GVL effect. Dr. Laughlin is now studying cord blood to see whether the GVL effect to fight leukemia and lymphoma is preserved in patients after umbilical cord blood transplantation.
What does the future hold? "It appears thus far that cell dose of the UCB graft is critical to a successful outcome of transplantation in these patients," she says. As these clinical trials of adult umbilical cord blood transplantation continue to progress, Dr. Laughlin and other researchers will be studying techniques to expand the number of cells in UCB grafts by growing them in the laboratory before infusing into patients. Dr. Laughlin and her team will also be studying whether injections of cytokines may also be administered to patients after transplantation to expand the population of stem cells and speed the recovery of healthy blood cells in the UCB patients.
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