Home > Medical Information > Treatment Topics > Umbilical Cord Blood Stem Cell Transplantation, basic

Introduction

In the 1970s medical researchers discovered that human umbilical cord blood contained the same kind of stem cells found in bone marrow. (Stem cells get their name from their ability to develop into three types of blood cells: red blood cells, while blood cells and platelets). Because stem cells from bone marrow had already been used successfully to treat patients with life-threatening blood diseases, such as leukemia and immune system disorders, researchers believed that they could also use stem cells from cord blood to save patients.

In 1988, doctors transplanted human umbilical cord blood into a 5-year old boy suffering from Fanconi's anemia. Ten years after the transplant, the boy is alive and seems to be cured of his disease. Based on this and other successful transplants, doctors and medical researchers began to collect, freeze and store cord blood units (CBUs) at cord banks throughout the world. As of October 1998, there were approximately 22,000 CBUs collected and frozen for use worldwide, and approximately 700 unrelated donor and 150 related (sibling) donor cord blood transplants had been performed.

Although today marrow transplants and cord blood transplants are often referred to by the same name -- stem cell transplants -- there are important differences between the two. This article will explain these differences and also discuss the kinds of decisions doctors and their patients must make to determine the best source of stem cells for transplantation. Before considering these issues, however, it is important to understand the challenges patients face in finding a donor.

Finding a Donor

Unfortunately, 70% of patients who need a stem cell transplant do not have a suitable donor in their family. The National Marrow Donor Program (NMDP) helps identify stem cell donors for patients who do not have a related donor.

Stem cell transplants require matching certain tissue traits of the donor and patient. Because these traits are inherited, a patient's most likely match is someone of the same heritage. American Indian and Alaska Native, Asian, Black and African American, Hispanic and Latino, Native Hawaiian and Other Pacific Islander, and multiple-race patients face a greater challenge in finding a match than White patients.

The collection and storage of cord blood is one way to give patients of all racial and ethnic backgrounds greater access to stem cell transplantation. For that reason, beginning in the early to mid-1990s, medical institutions around the world began making a serious effort to collect and store cord blood units for use in transplantation.

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Clinical Results

So far, clinical studies by John E. Wagner and others suggest that unrelated cord blood transplantation is a safe and acceptable alternative to bone marrow transplantation for many patients. However, these studies have also found that, as with bone marrow transplants, patients who receive cord blood from sibling (or related) donors generally have higher survival rates than those who receive cord blood from unrelated donors.

Studies have also found that banked cord blood (from both related and unrelated donors) often contains enough stem cells for transplantation. Physicians need to match the number of stem cells in a cord blood unit with the weight of the patient to be sure the unit is likely to be able to reestablish the patient's immune system. Because there are fewer stem cells in cord blood than in marrow, until recently most cord blood recipients have been children or small adults. There is, therefore, some concern that the number of cells in an average cord blood unit may not be sufficient for engraftment in larger adults. Engraftment occurs when the transplanted stem cells -- the "graft" -- regenerate the blood and marrow and begin to function as the recipient's new immune system.

One positive finding is that cord blood transplant patients appear to suffer less from acute graft-versus-host disease (GVHD) than patients who receive bone marrow transplants. GVHD is a very serious, and sometimes fatal, condition that occurs when the patient's new immune system -- which is made up of stem cells from the donor -- starts attacking the patient's body. GVHD affects the skin and internal organs such as the liver and intestines.

Despite the fact that cord blood recipients appear to suffer less from GVHD, it has not yet been proven that the risk of GVHD is less in all recipients after cord blood transplantation. Because children receive the most cord blood transplants, and because they also experience less GVHD than adults after bone marrow transplants, it may be that the success of cord blood transplants is at least partly attributable to the fact that they are used on more children than adults.

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Understanding HLA Matching

With stem cell transplants, the better the match between the donor and the recipient, the less likely graft-versus-host disease is to develop. It is important, therefore, to understand how doctors determine the best, or most acceptable, match between the donor and the recipient. To understand how they do this, it helps to have a basic understanding of the human immune system.

Antigens, a kind of protein located on the outer surface of most cells in the body, help the immune system to identify foreign bacteria and viruses. The antigens that transplant doctors look for when matching patients and donors are located on a cell called a leukocyte, giving these antigens the name Human Leukocyte Antigens, or HLA. Every person has six groups of HLA antigens, but three groups (called A, B, and DR) are considered most important in a stem cell transplant. Each of these groups has two antigens, one inherited from the father and one from the mother, making a total of six antigens that determine a donor/recipient match. A perfect match is called a 6/6 HLA match.

Bone marrow transplants are usually not attempted unless the donor and recipient are a 6/6 or 5/6 HLA match. However, with cord blood transplants, doctors and medical researchers generally believe that a 4/6 match is sufficient. Because immune system cells contained in cord blood are less mature, they have not yet "learned" to attack foreign substances, and so would be less likely to attack the recipient's immune system, even though the match isn't perfect. Since matching requirements for cord blood are less strict, patients who are unable to find a 5/6 or 6/6 marrow donor may be able to find a suitably matched cord blood unit.

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What is Known About Cord Blood Transplants

With its more than 30-year history, bone marrow transplants are a well-established, life-saving treatment for a wide range of blood disorders such as leukemia and aplastic anemia, as well as selected immune system deficiencies and genetic disorders. While the history of cord blood transplants is less extensive, there is evidence to suggest that these transplants can cure diseases, too. But with cord blood there are more unknowns, and doctors and their patients must carefully evaluate the situation before deciding on the best treatment.

The following lists explain what is known and not known about cord blood transplants. While these lists are not exhaustive, they do include aspects of cord blood transplants that are critical in the decision-making process:

What We Know About Cord Blood Transplants

• Cord blood contains sufficient numbers of stem cells for engraftment in most recipients weighing less than 50 kilograms (about 110 pounds).
• Collection of cord blood poses no health risk to the mother or infant donor.
• Because it is stored and available for use, cord blood is sometimes more readily available than a potential marrow or blood stem donor, who may be unavailable for donation when it is needed.
• Cord blood is rarely contaminated by viruses often found in marrow, such as cytomegalovirus (CMV) and Epstein-Barr virus.
• Cord blood can cause severe GVHD, but possibly less frequently than in bone marrow transplants.

What We Think We Know about Cord Blood Transplants Based on Clinical Data

• Compared to bone marrow transplants, cord blood transplants may have a lower rate of acute GVHD, at least in cases where a related (sibling) donor is used.
• It appears that the transplant process using cord blood (from the time a search is started to the time donor cells are ready for transplant) is shorter than that for marrow cell donation because the cord blood units are in storage and ready for use.

What We Don't Know about Cord Blood Transplants (because of lack of clinical evidence)

• Whether cord blood is sufficient for engraftment in most adult recipients, although experience suggests that it may be sufficient for a significant proportion of these recipients.
• Whether cord blood transplants pose a different risk of relapse (recurrence of an illness after a remission) compared to unrelated bone marrow transplants.
• Whether focused cord blood collection will be successful in meeting the current challenge of finding a match for American Indian and Alaska Native, Asian, Black and African American, Hispanic and Latino, Native Hawaiian and Other Pacific Islander, and multiple-race patients, thus increasing the number of available transplants for these patients.

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Other Factors in the Decision Process

Besides considering the factors just listed, the doctor, the patient and the patient's family must review the results of both a cord blood and bone marrow transplant for the patient's particular disease. To take one example, young patients (those less than five years of age) with chronic myelogenous leukemia (CML) and Wiskott-Aldrich syndrome do well after unrelated bone marrow transplant, while older patients, regardless of disease, do not. Figures 1 and 2 compare the advantages of bone marrow and cord blood transplants.

Figure 1: Advantages of cord blood over bone marrow transplantation.

Figure 2: Advantages of bone marrow over cord blood transplantation.

The decision to use cord blood may depend on how well a patient is predicted to do after bone marrow transplantation. If a patient is predicted to do well, there might be an argument for using a cord blood transplant only if a search fails to identify an HLA-matched unrelated marrow donor. In contrast, a patient with a high risk of complications from unrelated donor bone marrow transplants might be considered a good candidate to try a cord blood transplant. Other factors, such as urgency and cost, may also affect the decision process.

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Eligibility Criteria

Should the doctor and patient decide to explore a cord blood transplant as a potential transplant option, the first part of their search for a donor will be identical to that for finding a marrow donor. They will first submit information about the patient, including diagnosis, weight and HLA typing, to the appropriate transplant center. The patient's eligibility for a transplant, however, will vary from center to center. See Choosing a Transplant Center: A Patient's Guide for more information about individual transplant center transplant criteria.

The following eligibility criteria, proposed by transplant doctors participating in the National Heart, Lung and Blood Institute's study on unrelated donor cord blood transplantation, can be used as a general guideline:

1. Patients must have one of the following forms of leukemia or related diseases:
• High-risk acute lymphocytic leukemia (ALL)
• Acute myelocytic leukemia (AML)
• Acute undifferentiated leukemia
• Juvenile myelomonocytic leukemia
• Mylelodysplastic syndrome
• Advanced chronic myleocytic leukemia (that is, with a chronic phase occurring more than a year after diagnosis)
• Chronic myelomonocytic leukemia
• Paroxysmal nocturnal hemoglobinuria
• Advanced lymphoma


2. Or, patients must have one of the following forms of anemia or related diseases:
• "High risk" severe aplastic anemia
• Fanconi's anemia
• Inborn errors of metabolism (e.g., Hurler syndrome, Maroteux-Lamy syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, mannosidosis, fucosidosis)
• Immunodeficiency states (e.g., Wiskott-Aldrich syndrome, SCID, Chediak-Higashi Syndrome, leukocyte adhesion deficiency, X-linked lymphoproliferative disease)
• Familial erythrophagocytic lymphohistiocytosis (FEL)
• Blackfan-Diamond syndrome
• Infantile osteopetrosis
• Kostmann's syndrome
• Congenital amegakaryocytic thrombocytopenia
• Others


3. The donated cord blood must contain more than 1 x 10⁷ nucleated cells per kilogram of the recipient's body weight and must be matched at 4 of the 6 HLA-A, B, and DRB1 antigens. (In other words, there must be an adequate number of stem cells for engraftment in the donor base on the donor's weight, and there must be at least a 4/6 HLA match between the CBU and patient.)



4. The patient's liver, kidney, heart and lung function must be adequate.

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Future Directions

As a result of encouraging early findings, doctors are very interested in learning more about the limitations of cord blood transplants. They are particularly interested in determining maximum patient size, and the maximum degree of difference between the HLA types of the donor and patient. This research will be carried on both by individual transplant centers and those participating in the National Heart, Lung, and Blood Institute's study of cord blood transplants.

In addition to this research, several teams are exploring stem cell expansion, which looks at how stem cells in a cord blood unit can be stimulated to grow additional cells before infusing them into a patient. These studies have only recently begun and are focused on evaluating the safety of the procedure. There is a possibility, for example, that stem cell expansion may damage, rather than aid, the engraftment potential of cord blood.

Finally, studies that compare outcomes after cord blood and marrow transplantation are ongoing. These studies may reveal additional factors that can aid doctors and their patients in making the right decision between cord blood and bone marrow transplants.

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Summary

Clinical studies have demonstrated that stored cord blood is a sufficient source of transplantable stem cells, at least for young patients. Also, in addition to previously known advantages of cord blood (rapid availability and a low rate of virus contamination) studies have found that cord blood transplants may also lead to less GVHD than bone marrow transplants.

Clinical experience also shows that a high stem cell dose (a sufficient number of stem cells based on the patient's body weight) is an important factor in recipient survival, and that cord blood transplants can be successful with as low as a 4/6 HLA match.

Finally, when considering stem cell transplants, doctors and their patients should base their decisions on what is currently known about the successes and limitations of each stem cell source. They should also be aware of continuing studies in the stem cell transplant field and in new technologies such as stem cell expansion.

Information about cord blood transplants in this article is based on published studies. The references to these articles can be found at the end of the advanced level article on Umbilical Cord Blood Transplantation.