Be The Match® has a matching stem cell donor for most US patients
A suitable cord blood match (HLA match of 4 out of 6 or better) is available from Be The Match for nearly every US patient under age 20 and for more than 80% of patients age 20 and over, regardless of racial or ethnic background. The challenge at this point is how best to apply the limited resources of the Be The Match organization to find matches for the remaining patients, who are predominantly ethnic minorities and mixed race individuals.
In July 2014 the prestigious New England Journal of Medicine published a study of donor-patient match likelihoods in the US stem cell registries. These registries are operated by the National Marrow Donor Program® (NMDP), aka Be The Match®. The likelihoods of donor-patient matching were calculated based on models of the genetic variations in the US population. The research was led by bioinformatics scientists at NMDP, through its research program CIBMTR® (Center for International Blood and Marrow Transplant Research). This study was an NMDP contract deliverable that first appeared as a White Paper presented to the HRSA Advisory Council in June 2010.
It is important to emphasize that the published cord blood matching takes into account the range of weights among patients of various ages and the range of cell doses in the cord blood inventory. The reason that nearly every patient under age 20 can find a match is that the cell dose of the cord blood units in public banks are adequate for almost all pediatric patients. Moreover, over 80% of adult patients can also find a cord blood unit that is big enough and a close enough match for a cord blood transplant.
However, a close enough match is not necessarily what a transplant physician would consider an optimal match. The ideal donor is always a matching sibling, but only 30% of patients have one. Based on current clinical practice, the best donor from a registry search is an adult donor of bone marrow or peripheral blood who matches at 8 out of 8 HLA types.
The three main factors that enter donor selection are: the type of stem cells, the cell dose, and the degree of donor-patient match. First, adult donors of bone marrow and peripheral blood stem cells are currently preferred over stored units of cord blood stem cells because adult donations are quicker to engraft and replenish the patient's immune system. Second, the cell dose required for a cord blood transplant is a minimum of 25 million Total Nucleated Cells (TNC) per kilogram of patient weight, whereas a cell dose 10 times higher can easily be harvested from adult donors. Third, the current clinical standards require an adult donor to match at 8 out of 8 HLA types (abbreviated as 8/8 match) or at least 7/8, while a cord blood unit is considered to be a match at 6/6, but 5/6 and 4/6 are also acceptable.
The upshot of the various matching considerations is that a matching adult donor is more desirable to transplant physicians, but a matching cord blood unit is easier to obtain.
The first step in a registry search for a matching donor is always to seek an 8/8 adult donor. The NMDP registry holds 11 million potential adult donors, and has access to 22 million donors that can be searched through international registries (but the other international donors were not included in the study just published in NEJM) (Reference: NMDP press release).
The NMDP study looked at how well patients of different racial/ethnic groups fared at finding a match. The patient and donor populations were divided into 21 different racial/ethnic groups, based on how people self-identified when they filled out their paperwork.
The odds of finding an 8/8 adult donor are best for White European patients, at 75%. Most racial/ethnic groups fall in the 30-50% range. The lowest probabilities are among Black patients, where the ability to find an 8/8 adult donor ranges between 16% for Blacks of South or Central American descent, 18% for African descent, and 19% for African American or Caribbean descent.
Oftentimes when a patient needs a matching donor, their family will organize a donor drive among persons of similar racial/ethnic background, through community or religious organizations. This strategy is well-founded, because HLA types are inherited. The study confirms that most patients are more likely to find a donor within their own racial and ethnic group than outside. For example, Koreans and Chinese only pick up another 1% chance of finding an adult donor by looking outside their group. But a group that historically has a high degree of racial admixture, for example Hispanics from South and Central America, can find half again as many donors by looking outside their group (Reference: NEJM Appendix Table S2).
If an 8/8 adult donor cannot be found, the next step in the matching strategy is either to look for a 7/8 adult donor, and then try a cord blood search, or else go straight to a cord blood search. If the transplant physician goes straight to a cord blood search, then the majority of matches identified for the patient will be cord blood units, for every racial group except White Europeans. This is illustrated below by NEJM Appendix Figure S3.
The cord blood inventory is currently 193,00 in the NMDP network (NMDP) or 731,280 worldwide (WMDA). Thanks to the less stringent HLA matching requirements with cord blood, this search strategy raises the fraction of adult African American patients who can find a donor to over 80%.
Going forward, how should NMDP/BeTheMatch® invest their resources to build on this success? The registry is projected to grow 9% each year, but the study authors admit that trying to increase the match rates by recruiting more adult donors has reached a stage of "diminishing returns". Moreover, not all of the registered adult donors will actually be available if called to donate. This limitation varies by ethnic group and was factored into the predictions. The authors calculated that outreach efforts to improve donor availability by 5% would have the same impact as two years of recruitment.
The study concluded that growth of the cord blood inventory holds the most promise to narrow the disparity in transplant access between white Europeans and members of those racial/ethnic groups that are minorities in the US.
There remains the clinical challenge that transplant physicians still consider 8/8 adult donors to be optimal, and by this measure many patients who have a cord blood match do not have an optimal donor. But if ongoing research into ways to make cord blood transplants engraft faster are successful, this search strategy should change. If the engraftment concerns were removed, the fact that a matching cord blood unit is immediately available from the bank, and will not have a change of status or a change of mind, would become a more dominant consideration.
- HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry
Loren Gragert, Mary Eapen, Eric Williams, John Freeman, Stephen Spellman, Robert Baitty, Robert Hartzman, J. Douglas Rizzo, Mary Horowitz, Dennis Confer, and Martin Maiers
N Engl J Med 2014;371:339-48. DOI:10.1056/NEJMsa1311707