With nearly two-thirds of patients who require hematopoietic (blood) stem cell transplants not having a suitable sibling donor, transplants from alternative donor sources can present a viable solution for a larger number of patients.
At any given time, as many as 7,500 Americans are searching for an unrelated bone marrow donor, despite only 2% of the population being on the national registry.
Human leukocyte antigen (HLA) typing is a method which matches patients and donors for bone marrow or cord blood transplants. While there have been several proposed policy solutions to address the general lack of minority donors in stem cell and organ transplants, other concerns exist in the transplantation process. When allogeneic hematopoietic cell transplantations (allogeneic HCT) cannot be done with stem cells from an HLA-matched sibling (an issue that arises 70% of the time) alternative donor graft sources must be explored.
“Some viable alternative donor options include HLA-matched unrelated donors, partially HLA-mismatched (HLA-haploidentical) donors or umbilical cord stem cell donors,” said Dr. Celalettin Ustun, a hematologic oncologist at Rush University Medical Center.
The first alternative donor graft source to examine is HLA-matched unrelated donors. A 2010 study examined the risk of allogeneic HCT using a matched unrelated donor (MUD) and a matched sibling donor (MSD) and found that the survival rates depended largely on the severity of the disease.
For patients with high-risk diseases or those given bone marrow grafts, there were no statistically significant differences between recipients of an MSD and an MUD in survival. An HLA-matched MUD could still provide a successful transplantation for a patient with a high-risk disease and no MSD available. However, for patients with intermediate-risk diseases, transplantations MUD were associated with lower survival than a MSD.
Another alternative source is an HLA-haploidentical donor, or someone who shares exactly one linked genetic loci with the recipient, but is mismatched for other HLA genes. These donors can still provide successful transplants if they have few mismatches. A 2017 study observed that selection for a single HLA mismatch could act as an alternative curative therapy to fully matched donor transplantation without increasing the risk levels for the patient.
One other graft source alternative is cord blood, a biological product found in the blood vessels of the placenta and the umbilical cord. Cord blood has been shown to decrease common transplantation issues such as graft versus host disease and improve long-term immune recovery. Cord blood has been shown to function well as a graft source despite HLA mismatches between the donor and the recipient, making it more widely available.
“Cord blood comes from newborn babies, who don’t have mature immune systems,” said Dr. Stephanie Lee, Professor and Associate Director at the Clinical Research Division, Fred Hutch. “Many of the problems with graft versus host disease are due to the donor attacking the recipient, so if the donor is a baby, doesn’t have a developed immune system and isn’t used to encountering other antigens, they won’t produce as many T-cells or have B-cells making antibodies and we can use that to our advantage.”
While unrelated adult donors need a 10/10 allele match with a patient to have a successful transplantation, cord blood grafts allow for a mismatched transplantation in at least one HLA locus, making them a more viable option for racial minorities whose genetic variations may not be available in donor registries.
“With cord blood, ethnicity doesn’t matter,” Dr. Ustun said. “The major factor is the number of matching alleles — 9/10 or 10/10 for example.”
However, cord blood comes with its limitations — slow engraftment, storage issues and limited cell dose. The limited number of cells in a cord blood unit can result in greater risk of graft failure, causing rejection issues and extended immunosuppression.
“The cord blood takes a long time to grow in, so if your graft doesn’t grow in quickly it’s easier for infections to come in due to the lack of natural immunity,” Dr. Lee said.
Despite this, cord blood is still being explored as a practical alternative to adult blood due to its rich source of undeveloped hematopoietic stem cells for transplantations as well as the cure for blood cancers, such as sickle-cell disease and Wiskott-Aldrich syndrome.
“To expand the donor pool, in recent years, there have been quite a few success stories — use of expanded cord blood transplants, depletion of cells prior to HCT that can result in graft versus host disease (called alpha-beta depletion), and the use of post-transplant cyclophosphamide to make transplants more successful.” said Dr. Ashish Gupta, Assistant Professor and Pediatric Blood and Marrow Transplant Physician at University of Minnesota. “In my opinion, these along with increasing the awareness and need for participation in donor programs will be extremely beneficial for minorities.”