Options for People Without a Match

New Options for People Seeking a Donor Match

The Fred Hutch Bone Marrow Transplant Program at Seattle Cancer Care Alliance (SCCA) provides an opportunity for nearly anyone to receive a bone marrow transplant—even without an optimally HLA-matched donor—using minimally mismatched, haploidentical, and cord blood transplants.

“We can do transplants for just about everybody, and we have several ways of getting there,” said Paul J. Martin, MD, a medical oncologist who specializes is treating patients with bone marrow transplantation at SCCA.

Dr. Colleen Delaney describes the ins and outs of cord blood transplants and why they offer so many people hope.Today, because of new sources of stem cells—and new methods for making these cells work safely and effectively—almost all patients who need a bone marrow transplant will have a donor. A study in the New England Journal of Medicine in 2014 verified that lack of a donor is no longer a major limitation to transplants. According to the study, more than 99 percent of white European-Americans and 95 percent of African-Americans who need a transplant will have a suitable match.1 

Researchers at the Hutch were instrumental in developing new adult donor and cord blood options—and they continue to improve these techniques to ensure even better transplant access and outcomes for a diversity of patients.

Transplants with Matched Unrelated Donors

At one time, only 30 percent of those who needed a transplant could find a suitable match (based on HLA typing)—because they had a matched sibling available to donate. That left 70 percent with no chance at a transplant at all.

Over time, advances in the field allowed another 30 to 35 percent to find a match among unrelated donors. This option has its roots at the Hutch, the first place to have an unrelated donor program—a list of about 200 people, including Hutch employees, willing to donate to a stranger. That program eventually developed into the National Marrow Donor Program. Its Be The Match Registry, the largest and most diverse marrow registry, now has more than 10.5 million potential donors. By partnering with other registries, Be The Match gives doctors and patients access to a total of more than 22.5 million donors around the world.

Many of those without an “optimal,” or perfect, HLA match, either from a sibling or from the registry of volunteer donors, can now proceed with a transplant using “minimally mismatched” unrelated donor cells. An optimal match usually means matching on eight of eight HLA markers while a minimal mismatch is usually defined as seven of eight HLA markers. Using new methods to limit potential complications, transplants using a seven-of-eight HLA-matched donor now allow many more patients to move ahead with a transplant that improves their chance for survival. 

Even when patients expand the search outside their family to all registered donors worldwide, it can be difficult to find a suitable match. Until recently, about 35 to 40 percent of people who needed a transplant still had no match. It was a problem in need of a major solution, and researchers went to work.

Newer Options

Today, there are two additional sources of donor cells available: haploidentical (half-matched) family members and cord blood.

Haploidentical Transplants

An HLA-haploidentical donor shares a haplotype with the transplant recipient. This means that the donor and recipient have the same set of closely linked HLA genes on one of the two Number 6 chromosomes they inherited from their parents. Rather than being a perfect match for each other, they are a half-match. 

Parents are always a half-match for their children and vice versa. Siblings have a 50 percent chance of being a half-match for each other. (They have a 25 percent chance of being a perfect match and a 25 percent chance of not matching at all.)

Like transplants with minimally mismatched donors, haploidentical transplants are not ideal, but they allow many patients to find a suitable donor and proceed quickly with a potentially life-saving transplant.

Cord Blood Transplants

Cord blood is collected at the time of a baby’s birth with no risk to the infant or mother. After the umbilical cord is cut, a needle is inserted into the vein of the umbilical cord, and the leftover blood from the placenta and umbilical cord is collected and stored for future use. 

The blood-forming stem cells from cord blood are more versatile than those from bone marrow or peripheral blood when used for a transplant, simply because the immune cells in cord blood are naïve. They aren’t yet educated against foreign invaders, such as bacteria and viruses. So there’s less likelihood of an adverse interaction between the transplanted cells and the recipient’s tissues. As a result, the donor and recipient don’t need to be such a close match for the transplant to be successful. 

A match in four of six HLA markers in cord blood is usually considered acceptable. Importantly, this means that cord blood donors can be identified for almost all patients in need of a transplant, even if the patient cannot find a suitable match otherwise.

Improving the Odds

Haploidentical and cord blood options have changed the world of transplantation, greatly improving the odds of finding suitable donors for people who need a transplant.

“Today, in fact, practically all of our patients find a donor. We have new procedures and clinical studies that can be done safely with many different stem cell sources. Thus, we no longer have to turn away someone who needs a transplant for lack of a donor,” said Ann E. Woolfrey, MD, who directs the unrelated donor program at Fred Hutch.

The new options are important because they mean that patients no longer need to delay transplantation while waiting for a perfect or near-perfect donor match. People who need transplants are usually very ill, and rapid access to the procedure can save lives. At the Fred Hutch Bone Marrow Transplant Program at SCCA, we employ all the new sources of donor cells, and our researchers are always developing new techniques to achieve even better outcomes with these new donor options.

Better Transplant Outcomes

“Many centers across the country are finding that outcomes of transplants using haploidentical or cord blood donors are very similar to outcomes of transplants using matched donors,” said Paul V. O’Donnell, MD, PhD, a researcher in the Clinical Research Division at The Hutch and previous medical director of the Adult Blood and Marrow Transplant Service at SCCA. “The rates of acute or chronic graft-versus-host disease (GVHD) are surprisingly less than or similar to the rates with matched donors using current protocols.”

GVHD results when an incomplete match between the donor and recipient causes the donor immune system to attack the recipient’s (host’s) tissues.

Preventing GVHD in Haploidentical Transplants

Haploidentical transplants rely on advances in drug therapies to prevent GVHD. One preventive therapy uses a high dose of the chemotherapy drug cyclophosphamide given on days three and four post-transplant, followed by standard immunosuppressive treatments starting on day five. This protocol may seem counterintuitive, said Dr. O’Donnell, because high-dose chemotherapy is typically given earlier in the transplant process, during the conditioning phase (to destroy the malfunctioning cells in the recipient’s body). But doctors have found that giving cyclophosphamide after a haploidentical transplant helps prevent GVHD because cyclophosphamide kills certain donor immune cells (T-cells) that would otherwise cause GVHD.

Combining and Expanding Units of Cord Blood

For cord blood transplants, SCCA doctors now routinely combine two units of cord blood (from different donors) to extend this option to adults. Each unit of cord blood has a very limited number of stem cells. So cord blood transplants were once used only in pediatric patients—who, because of their smaller size, don’t need to receive as many stem cells as adults do. By combining units, we can now treat many adults this way.

Still, it takes longer to restore blood counts after a transplant with cord blood than with marrow or peripheral blood from an adult. That’s why the Hutch’s Colleen Delaney, MD, developed a technique that expands the number of cells in a unit of cord blood 150-fold. She is working on increasing that number to treat adults more effectively. Studies show that expanding one of the two units of cord blood in the lab pre-transplant increases the rate of post-transplant engraftment (when the recipient’s body resumes producing blood cells and develops an immune system again).

1. Loren Gragert et al, “HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry,” New England Journal of Medicine 371 (2014): 339-348.