Cord blood, genetic diversity and the search for a match

Two patients are diagnosed with the same leukemia in the same week. Both need a blood stem cell transplant, and neither has a sibling who matches. One, whose grandparents all came from northern Europe, will very likely find a fully matched unrelated volunteer. The other, whose family roots run through West Africa and the Caribbean, is far less likely to. Nothing about their disease explains the difference. The genetics of the immune system and the makeup of donor registries do.

This piece explains why, and how cord blood and newer transplant methods have narrowed a gap that was once very wide. It is general background, not guidance for any individual patient, whose transplant team weighs much more than matching.

HLA: the tags the immune system reads

Human leukocyte antigens (HLA) are proteins on the surface of most cells. The immune system reads them to tell self from non-self. The genes behind them sit in a cluster on chromosome 6 and are among the most variable in the human genome, with many thousands of known versions, called alleles.

For transplant matching, doctors focus on a handful of these genes. The usual shorthand for an adult donor is "8/8": both copies (one from each parent) of HLA-A, HLA-B, HLA-C and HLA-DRB1, identical between patient and donor at high resolution. Some centers add HLA-DQB1 and talk about 10/10. A "7/8" donor differs at one of the eight positions.

Matching matters because donor immune cells that see the patient's tissues as foreign can attack them. That is graft-versus-host disease (GVHD), which ranges from a mild rash to a life-threatening illness. Closer matching lowers the risk. The National Cancer Institute's overview of stem cell transplants covers the clinical side in plain language.

HLA genes travel together as a block from each parent, so a full brother or sister has about a 1 in 4 chance of being a match. NMDP, the US nonprofit that runs the national registry, says about 70 percent of patients who need a transplant have no fully matched donor in their family. Those patients turn to unrelated adult volunteers, banked cord blood or partially matched relatives.

Why ancestry changes the odds

Two forces push in the same direction.

The first is biology. HLA variety is not spread evenly across human populations. Populations with deep African ancestry carry especially high HLA diversity, a legacy of humanity's long history on that continent. More variety means more possible combinations, which makes any single patient's combination rarer. People of mixed ancestry can inherit pairings that are uncommon in every group they descend from.

The second is who has signed up. Registries in the US and Europe grew first and fastest among people of European descent. A patient's likeliest match is someone with similar ancestry, so when that group is underrepresented on the registry, the odds fall further.

The published numbers are stark. A 2014 study in the New England Journal of Medicine, led by Loren Gragert at NMDP, modeled 21 US racial and ethnic groups. The chance of finding an optimal, fully matched adult donor ranged from about 75 percent for white patients of European descent to about 16 percent for Black patients of South or Central American descent, with other groups in between (PubMed abstract). A later NMDP analysis, presented at the 2022 Tandem Meetings of the transplant societies, found a similar spread and put the chance of an 8/8 matched, available donor at about 29 percent for Black and African American patients.

The word "available" is doing work there. A registered volunteer who cannot be reached, has developed a health problem or decides not to go ahead does not help a patient. Availability also differs between groups, which widens the gap again.

Why cord blood forgives more

Cord blood, collected from the umbilical cord and placenta after a birth, is rich in blood-forming stem cells. Since the first cord blood transplant in Paris in 1988, for a child with Fanconi anemia, it has been used for many of the conditions described in our guide to what cord blood transplants treat.

Its big advantage for matching is that the immune cells in cord blood are immature. Cord blood T cells are mostly naive, meaning they have not yet been primed against much of anything, and for a given degree of mismatch they appear less likely to cause severe GVHD. That is why cord blood matching has traditionally used a looser standard: six points (HLA-A and HLA-B at the broader antigen level, HLA-DRB1 at high resolution), with units mismatched at one or two of those points routinely accepted. Many centers now also look at allele-level matching across more genes when choosing a unit, but the tolerance for mismatch remains wider than for adult donors.

The Gragert study found that very few patients had a perfectly matched cord blood unit. Units mismatched at one or two positions, though, were available for almost all patients under 20 and for more than 80 percent of patients 20 and older, regardless of racial or ethnic background. For people facing poor odds in the adult registry, that was a genuine lifeline.

Cord blood has real limits. A unit holds far fewer cells than an adult donation, which matters more as patient size goes up. Blood counts recover more slowly after a cord transplant, leaving a longer window for infections. And there is no going back to the donor for more cells later. Adults have often received two units at once, a "double cord" transplant, and researchers spent decades working on ways to grow more cells from a unit before infusion. One expanded product, Omisirge (omidubicel), was approved by the FDA in April 2023. Our explainer on expanding cord blood stem cells outside the body traces how that work developed.

Half-matched relatives and an old drug used a new way

The largest change in donor availability over the past 15 years came not from registries but from a different way of preventing GVHD.

A haploidentical, or half-matched, donor shares one of the patient's two HLA blocks. Almost every patient has several: biological parents, children, and on average half of their full siblings. For a long time these transplants were seen as too risky, because of severe GVHD and graft failure.

Researchers at Johns Hopkins developed an approach built on post-transplant cyclophosphamide, usually shortened to PTCy. The chemotherapy drug is given a few days after the stem cell infusion, when the donor T cells reacting most strongly against the patient are dividing fast. Those cells take the heaviest hit, while blood-forming stem cells are relatively spared. The method spread widely through the 2010s.

It was then tested head to head against cord blood. In the BMT CTN 1101 trial, published in Blood in 2021 by Ephraim Fuchs and colleagues, 368 adults with leukemia or lymphoma were randomly assigned to a double cord blood transplant or a haploidentical bone marrow transplant using PTCy. Progression-free survival was similar between the groups, but the haploidentical group had lower non-relapse mortality and better overall survival (PubMed abstract).

NMDP has since applied the same idea to unrelated volunteers who match only partly. Its Donor for All research program reports that about 66 percent of patients have an 8/8 matched donor, about 84 percent have one when 7/8 donors are counted, and nearly all patients have a donor when matches from 5/8 to 8/8 are included, with PTCy used to hold down GVHD. NMDP describes outcomes with these partially matched donors in its studies as comparable to fully matched ones. Ongoing trials will show how well that holds across more diseases and patient groups.

Where that leaves cord blood

As half-matched and mismatched transplants with PTCy have grown, many US transplant centers now turn to cord blood less often than they did a decade ago. That does not make it obsolete.

A banked unit is already frozen, tested and typed, so it can be shipped quickly when a patient cannot wait weeks for a volunteer to be found and cleared. It remains an important option for children and for patients without suitable relatives. Some centers with long experience report strong results in specific settings: a 2016 single-center analysis from Seattle, published in the New England Journal of Medicine, found lower relapse after cord blood than after unrelated adult donor transplants in leukemia patients who still had detectable disease going into transplant. Findings like that need confirmation in other centers, but they help explain why public banks keep collecting.

The diversity argument for public banking has not gone away either. An inventory that reflects the whole population gives transplant teams more choices, whatever donor type they end up using. HRSA, the federal agency that runs the national cord blood program, contracts with public banks specifically to build a genetically varied inventory.

What expectant parents can do

Public cord blood donation costs families nothing, and a donated unit is listed on the registry for any patient who needs it. It is not set aside for your own family, which is the key difference from private storage. Our guide to public, private and hybrid cord blood banking compares the models in detail.

If you would like to donate, the steps are straightforward:

1. Ask early. HRSA's Blood Stem Cell site suggests raising it with your doctor or midwife around the 28th to 34th week of pregnancy and asking whether your hospital collects for a public bank.
2. Check the list. NMDP keeps a directory of public cord blood banks and participating hospitals, arranged by state and city.
3. Complete the bank's consent form and health history, usually before delivery.
4. Tell the labor and delivery staff when you arrive that you plan to donate.
5. If you also plan delayed cord clamping, ask the bank how that affects the chance a unit can be stored. Collection happens after the baby is born and the cord is clamped and cut, so your baby's care comes first.

Not every hospital collects, and not every donated unit is banked. Many units are too small to meet transplant standards. Depending on the consent you sign, those may go to research or be discarded. The FDA's consumer page on cord blood banking answers common questions about how banks are regulated.

Parents can help in one more way that has nothing to do with the birth. NMDP's adult registry currently accepts new members aged 18 to 35 through a mailed cheek swab, and members stay listed until 61. A partner, sibling or friend from an underrepresented background who signs up adds exactly the kind of HLA type that patients in the opening example are missing.