Summary of Essential Facts
The Bottom Line

Approximately 10,000 umbilical cord blood transplants have been performed since the first transplant was performed twenty years ago.
Cord blood has become a proven source of stem cells for transplantation, and the procedure is no longer considered “experimental.”

These transplants have been done for all of the same diseases, approximately 70 in all, for which bone marrow transplants are performed.
These are particularly leukemias, lymphomas, other malignant blood disorders and congenital blood disorders.

Patients who lack a matched related donor in their family or matched unrelated donor in any of the donor registries, such as the National Marrow Donor Program, can be transplanted with cord blood stem cells.
There must be a very close match between the patient and the donor when using stem cells from bone marrow or peripheral blood. For a transplant using cord blood stem cells, however, the matching need is not as precise so that an adequately matched cord blood unit can be found even though a matched adult unit is not available.

Since cord blood transplants can be performed even when no bone marrow donor can be found, a large majority of the recipients could not have been treated and possibly cured if it were not for the existence of cord bloods.
No patient who needs a stem cell transplant should be informed that it is not feasible because of a lack of a donor unless cord blood registries have been searched.

Although some transplant centers do not have experience with cord blood, there are many transplant centers in the United States and throughout the world where numerous such transplants have been performed.
A list of transplant centers with experience performing cord blood transplants can be found on-line at www.cordbloodforum.org.

Cord blood has become the most frequent source of stem cells for transplantation in children in the United States, and is gaining increased usage in adults.
This is a contrast to the early days of cord blood transplantation when it was only performed as an alternative to bone marrow transplants when an adult matched related or unrelated donor could not be found.

Development of the technique of double cord blood transplantation expands use of cord blood transplant into adults.
It was previously thought that cord blood transplants were of value only for children because of the limited number of stem cells in an umbilical cord blood sample.

Cord blood can be obtained very quickly if a transplant is needed urgently, which is frequently true in patients with malignant blood disorders.
Obtaining stem cells from other sources, including bone marrow, usually takes many weeks.

Computerized searches quickly identify cord blood units in banks throughout the world, which can then be quickly transported for transplant.
Also, because cord blood is rapidly available, transplantation can be scheduled almost entirely according to patient needs rather than donor availability.

Some medical centers use cord blood stem cells almost to the exclusion of bone marrow or peripheral blood transplants because of their proven effectiveness and because they can be obtained rapidly.

Graft-versus-host disease, an adverse effect of stem cell transplantation which causes significant mortality, is less common after cord blood transplantation than after transplants using adult stem cells.
This is particularly true when compared with transplants performed using stem cells that are obtained from the peripheral blood of donors.

Development of Cord Blood Transplantation
Historical and Scientific Information

History of the first umbilical cord blood transplant

The first cord blood transplant was preceded by scientific laboratory studies led by Hal Broxmeyer, Ph.D., of the University of Indiana.

These studies suggested the feasibility of using cord blood as a source of transplantable hematopoietic stem and progenitor cells. During the first laboratory studies, Dr. Broxmeyer and his colleagues evaluated the progenitor cell content of numerous cord blood samples. Stem cells cannot be identified directly so that progenitor cells, which are somewhat more mature than stem cells, are measured instead. Progenitor cells are reflective of the number of actual stem cells in a sample.

Comparison of the number of progenitor cells in single cord blood collections with the number of progenitor cells present in marrow collections that were associated with successful engraftment led them to suggest that cord blood could serve as a source of transplantable and engrafting cells. Subsequent animal experiments confirmed that marrow repopulating cells were present in human cord blood and could be used for transplantation.

It was also determined that the progenitor cells could be left at room temperature for a number of days or shipped for 1 or 2 days with complete viable recovery of the cells. Moreover, the cells could be frozen, stored in cryopreserved form in liquid nitrogen and recovered intact with full proliferative and differentiation capacity. This led the researchers to believe that banking cells could be possible.

In order to prove that cord blood cells could be used for transplantation in humans it was necessary to treat a patient

At that time, Joanne Kurtzberg, M.D., from Duke University was treating a 5-year old patient with a fatal blood disorder known as Fanconi’s Anemia. The patient could only be cured by a transplant, but there were no matched donors in the patient’s family and transplantation from matched unrelated donors was not an option. When the patient’s baby sister was born, the umbilical cord blood was collected and cryopreserved. Tissue (HLA) typing indicated a perfect match between the patient and the baby’s blood.

At the time, the most successful clinical results for treating Fanconi’s Anemia were being reported in Paris by Eliane Gluckman, M.D., and her group at the Hôpital St. Louis. As a result, the transplant team contacted Dr. Gluckman to see if she would be willing to perform the transplantation with the cord blood that had been collected from the patient’s newborn sister. Dr. Gluckman expressed interest and agreed to perform the procedure. The patient was treated with pre-transplant chemotherapy and then the cord blood cells were administered. There followed a tense period of time waiting to see if the cells would engraft. After 18 days, the patient’s blood count began to recover and the transplant was successful. The patient is alive and well 20 years after the transplant and is now married and a father.

A celebration of the 20th anniversary of the first cord blood transplant was carried out at the 6th Annual International Cord Blood Transplantation Symposium which was held on June 6 and 7, 2008 in Los Angeles. The patient who was the first cord blood transplant recipient was in attendance and the work the work of Dr. Broxmeyer, Dr. Kurtzberg and Dr. Gluckman was honored.

Important Concepts in Cord Blood Transplantation

Diseases treatable by cord blood transplantation.
(For more information, go to the National Marrow Donor Program web site: www.marrow.org and click on Physicians/When to transplant.)

• Leukemias and lymphomas
• Multiple myeloma and other plasma cell disorders
• Severe aplastic anemia and other marrow failure states
• Severe combined immunodeficiency (SCID) inherited immune system disorders
• Hemoglobinopathies, including β-thalassemia major and sickle cell disease
• Hurler's syndrome and other inherited metabolic disorders
• Myelodysplastic and myeloproliferative disorders
• Familial erythrophagocytic lymphohistiocytosis and other histiocytic disorders

Importance of Cell Dose and HLA matching.
Cell dose has a critical role in the success of cord blood transplantation. For children, there are generally enough progenitor cells in a single cord blood unit for transplantation. However, there are usually not enough cells in a cord blood unit for transplantation of adult patients. To overcome this problem, most adults are transplanted with two cord blood units rather than one.

HLA matching
Typing is generally performed for six HLA antigens on the patient and on the cord blood. Most cord blood transplants to date have involved using partially mismatched units, that is, four or five of the six HLA antigens are matched. Because of the comparatively limited number of high quality cord blood units that are available world-wide, it is quite unusual to find a six out of six matched unit from a donor that is not related to the patient.

Transplant physicians consider both the number of nucleated cells in the unit and the degree of HLA match when searching for a cord blood for a given patient.

Double cord blood transplants
For many adults, there are not enough stem cells in a single cord blood sample for transplantation. However, transplant physicians have determined that two cord bloods can be used for a single patient, thereby supplying adequate numbers of stem cells for most adults.

Reduced-intensity transplantation
Many patients, especially older patients, those with extensive prior therapy and those with significant other diseases, do not tolerate the pre-transplant chemo-radiotherapy that is necessary for marrow ablation in preparation for a transplant. Accordingly, reduced-intensity pre-transplant regimens have been developed and have been used successfully. This causes fewer side effects and allows for transplantation of patients who could not otherwise tolerate maximum doses.

Graft-versus-host disease
Acute graft-versus-host disease (GVHD) is a frequent and serious complication of stem cell transplantation. It is characterized by an extensive skin rash, liver involvement such as liver test abnormalities and jaundice, and intestinal involvement such as severe diarrhea and failure of intestinal function. Lung toxicity may also occur. The principle risk factor for the development of GVHD in humans is HLA incompatibility between donor and patient. Other factors include older age of the patient, older age of the donor, prior transfusions or pregnancies, late stage of disease and the pre-transplant conditioning regimen.

Chronic GVHD is the major cause of non-relapse morbidity and mortality after hematopoietic stem cell transplantation and generally presents more than 100 days after transplantation. Chronic GVHD can affect any organ or tissue of the body and produces symptoms similar to autoimmune diseases. Skin, oral, liver and lacrimal gland problems are most common. Treatment is generally unsatisfactory.

A unique aspect of cord blood transplantation is the less than expected severity of GVHD. Also, chronic GVHD is more responsive to treatment and associated with a lower mortality after cord blood transplantation than after bone marrow or peripheral blood stem cell transplantation.

Cord Blood Banking
Even though a perfect HLA match is not required, data suggest that a perfect match in cord blood transplantation will produce superior results. However, the limited number of cord blood samples available in cord blood banks world-wide makes the finding of a six out of six HLA match for a patient quite unusual. The only way to improve this is to increase the number of units in cord blood banks, which is occurring but cannot be accomplished quickly.

Public cord blood banks collect units from mothers who are willing to volunteer their child’s cord blood. These units are frozen in cord blood banks, placed on national and international registries, and are available to any person in need of a transplant. There is no cost to the mother donating the cord blood, nor is there any payment to the mother. Although there has been considerable emphasis placed on educating mothers to donate their cord blood, it is unfortunately true that there are few cord blood banks in the United States.

Private cord blood banks charge a significant fee for the collection and storage of cord blood units. These banks reserve the units for use if needed at a later date by the baby or other family members as indicated by the donor who is paying for the storage.

Glossary of Terms

Hematopoietic stem cell transplant, often just referred to as a stem cell transplant, is used to treat patients with life-threatening or fatal blood disorders. Originally, the stem cells for such transplants were obtained from the bone marrow of a donor – hence why the procedure was called bone marrow transplantation. More recently, three sources of stem cells have been used – bone marrow, peripheral blood and umbilical cord blood. As a result, transplants are now called bone marrow transplants, peripheral blood stem cell transplants or cord blood transplants depending on the source of the stem cells. The collective term for all three types of transplants is Hematopoietic Cell Transplantation.

HLA-Matching (Human Leukocyte Antigen Matching) is the process by which the patient is “matched” with the potential donor. At least six markers (antigens) on white blood cells (leukocytes) are tested by DNA techniques to see if the same antigens are present in both the patient and donor. For hematopoietic cell transplants using stem cells from adult donors, all six generally must be matched. For cord blood transplants, four, five and six out of six matches are used. Even though four out of six matches are frequently used, data suggest that better matches will yield improved results. The fact that six out of six matches are not required for cord blood transplants is the central fact that makes them available for patients who cannot find a matched donor in their family or in donor registries of adult volunteers.

Pre-transplant conditioning is the term used for the chemotherapy and radiation therapy that is given to destroy the diseased cells in the patient’s bone marrow. This also suppresses the patient’s immune system so that stem cells from the donor can develop in the patient’s bone marrow. For some patients, especially older adults, a milder form of treatment is used that is termed “reduced-intensity conditioning”. This causes fewer side effects and allows for transplantation of patients who could not otherwise tolerate maximum doses.

Regenerative Medicine is the field which is attempting to use stem cells to treat many common disorders such as diabetes, stroke, spinal cord injury, Parkinson’s disease and Alzheimer’s disease. Such treatments are in the early stages of research and are not as advanced as hematopoietic cell transplantation.