Unrelated Donor Program: Pediatric Bone Marrow Transplant Program

When a histocompatible, related donor is unavailable, one approach has been to identify unrelated, healthy individuals who are appropriately histocompatible with a recipient and willing to donate bone marrow.

The first marrow transplant from an unrelated donor occurred in 1979. In a review of the initial 462 transplants using unrelated donors, 66% were complete matches, while 34% were partial matches. In those receiving HLA-matched marrow from unrelated donors, 64% developed moderate to severe acute GVHD, and 55% developed chronic GVHD.

More recently, there have been significant advances in HLA typing technology. The genes that are responsible for making the HLA antigens in the body have been identified and are well studied. At UCSF, we routinely evaluate the precise characteristics of each of the six major HLA genes in both the recipient and in all potential donors. The availability at UCSF of this type of high resolution DNA typing and the increase in size of the donor database, has resulted in not only a significant increase in the number of donors but also the ability to choose the "perfect match." With this approach we anticipate that the incidence of moderate to severe acute GVHD will be significantly reduced, and more comparable to patients receiving HLA-matched related grafts.

National Bone Marrow Donor Registry

In 1985, the National Bone Marrow Donor Program (NMDP) was founded with the purpose of encouraging volunteers to donate marrow. The organizational structure of the registry includes a board of directors which is broadly representative, composed of individuals not directly involved with the project but who have expertise in marrow transplantation, medical ethics, blood donor recruitment, and health policy. The board is responsible to the public at large to insure that the program is functioning using proper ethical standards and medical procedures. Legal advice and liability insurance for the board and the program is provided by the American Red Cross. The NMDP is also funded by the National Institutes of Health Heart Lung and Blood Institute (NHLBI).

One of the primary purposes of the NMDP is to maintain a sufficiently large pool of HLA-typed volunteer bone marrow donors who are available for patients with life-threatening diseases. More recently, the NMDP has begun to help coordinate some of the numerous umbilical cord blood registries around the world in order to more efficiently match unrelated donors with patients in need of a transplant. Currently, 100 donor centers and 111 transplant centers are participating in the NMDP, and there are over four million donors registered worldwide (i.e., including international registries). In 20-60% of searches, a number which varies according to the ethnicity of the recipient, a matched or closely-matched donor is found.

Using peripheral blood stem cells (PBSC) in unrelated donor transplants

Stem cells are present in blood, and in some clinical situations cytokine- (G-CSF) recruited PBSC are used in place of marrow for transplantation. G-CSF is a genetically-manufactured drug that is found naturally in small amounts in the body. G-CSF stimulates cells to grow in the bone marrow during which an increased number of CD34-positive bone marrow stem cells enter the blood stream. Most of the experience with transplantation of cytokine-recruited PBSC has involved autologous transplants, but more than 1000 allogeneic PBSC transplants from HLA matched and haplocompatible donors have been performed.

The advantages of a PBSC collection include avoiding a surgical procedure in an operating room (thus eliminating anesthesia risk), immediate recovery from the collection, and obtaining as much as ten times the number of CD34 positive stem cells as in a typical marrow harvest. PBSC transplants have been used both as primary sources of stem cells as well as following relapse from an initial BMT. In this latter case, it is thought that the larger number of T cells present in the PBSC collection, in fact, may be responsible for a graft versus leukemia effect, in which another person's healthy bone marrow kills residual leukemia cells and decreases the chance of relapse in the recipient.

The disadvantage of PBSC transplants is the 4-5 days of G-CSF injections that cause bone pain. In most cases, the pain responds to treatment with Tylenol and/or non-steroidal, non-narcotic analgesics. Approximately 3% of normal donors treated with G-CSF have symptoms sufficiently severe to require discontinuation of the drug.

The other potential risk of allogeneic PBSC transplants is an increased incidence of chronic GVHD compared to bone marrow transplants. However, this may be associated with a lower incidence of leukemic relapse. However, because of this risk, we currently only offer PBSC transplants for patients with cancers including leukemia, MDS or histiocytosis in which some GVHD may be of potential advantage. As part of an NMDP study, we are evaluating the effects of PBSC as either first or second transplants in recipients of an unrelated-donor BMT who as the initial transplant or who have either failed to engraft or have relapsed post initial transplant.

Unrelated Umbilical Cord Blood

The UCSF Pediatric BMT Program has an active protocol for using unrelated cord blood for transplantation as an alternative source of stem cells when a matched unrelated marrow donor is not available. In addition to participating in the National Insititutes of Health (NIH) sponsored national collaborative study of cord blood transplantation in children (COBLT), the UCSF protocol permits the use of cord blood for any eligible patient with any disease for which a BMT is indicated.