Blood and bone marrow transplantation (also known as hematopoietic cell transplantation, or HCT) was developed at Fred Hutch nearly 50 years ago to cure leukemias and other diseases of the immune system. Since then, physicians and researchers have made significant discoveries that have allowed for more options for picking a donor and for less toxic pre-transplant chemotherapies. While these advances improve HCT safety and accessibility, they increase the complexity of decisions that doctors make to reduce the potential risk of serious complications.
A recent study by Dr. Roland Walter's group published in Leukemia sought to deconvolute some of the complex, interrelated factors that can impact HCT success. The authors performed a retrospective, non-randomized investigation of transplant outcomes in relation to donor-recipient immune matching, the graft’s cell source, and the pre-transplant chemotherapy and/or radiation regimens. “With this work, we could clarify the role of different graft sources in AML patients undergoing allogeneic HCT, and most particularly umbilical cord blood,” lead author Dr. Corentin Orvain emphasized.
To reduce risks of immune incompatibility, physicians attempt to pair each recipient with a donor who best matches their immune fingerprint defined by their human leukocyte antigen (HLA) genes, which help the body identify which cells belong to the “self” and which may be intruders. Donors who are closely related to a patient are more likely to be HLA matched and therefore often the best candidates, but unrelated donors can also match just by chance.
Without an exact HLA match, sourcing donors is trickier. To expand the pool of potential donors, doctors turn to haploidentical donors, or blood relations who share just one of their HLA haplotypes with the recipient. Alternatively, physicians can use stem cells obtained from umbilical cords rather than adult patients. The logic behind using umbilical cord blood is that the mother and child are genetically mismatched, yet somehow cord blood passes between them without rejection. Although mismatching in cord blood transplants may be tolerated better than in those using peripheral stem cells, there can be consequences such as reduced viral exposure of cord blood leading to a virus-naïve reconstituted immune system that puts patients at prolonged risk of viral infections.
Another consideration is pre-transplant chemotherapies or radiation treatment. The most intensive conditioning regimens are myeloablative—they kill all the cells in the bone marrow, even the healthy ones. Myeloablative regimens can give the best chance at engraftment, but they can lead to infections or other severe side effects. Reduced intensity or non-myeloablative regimens reduce toxicity and can be tolerated by more patients but may not kill all the cancer cells, increasing the potential of cancer relapse.
Dr. Orvain and his colleagues analyzed data from 1,265 adult patients with acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS)/AML who underwent transplants at Fred Hutch or the University of Washington between 2006 and 2023. By studying this large dataset, the team explored how different transplant factors influenced survival. They found that overall survival and relapse-free survival were highest in patients who received umbilical cord blood or matched donations either from a related or unrelated donor. Adverse, non-relapse complications correlated with increased mortality for patients receiving mismatched or haploidentical grafts. These results agree with the current standard of care that matched donors are preferred.
This improvement in outcomes for those receiving matched or cord blood donation was especially pronounced for patients who had intensive myeloablative conditioning. Patients who received less intensive regimens had higher relapse rates, which may explain why their survival outcomes were worse.
In addition, they investigated how disease status interplays with conditioning intensity and transplant origin by comparing outcomes of patients with measurable residual disease—i.e., detectable cancer cells in the body—to patients without residual disease. For umbilical cord blood transplants, the amount of measurable residual disease and intensity of conditioning regimen seem especially important. “Interestingly, we observed that [umbilical cord blood] was associated with outstanding outcomes in those with pre-HCT measurable residual disease undergoing [myeloablative conditioning],” Dr. Orvain says.
While more research is needed to confirm these findings, the authors believe that their results point toward more choices in donation source depending on patient suitability. Dr. Orvain is especially excited about the potential for cord blood transplants. “Although it seems unlikely that we will randomize graft source in future clinical trials in patients with pre-HCT [measurable residual disease], [umbilical cord blood] might be considered in these patients if multiple graft sources are available,” he says.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Filippo Milano, Megan Othus, Effie Petersdorf, Brenda Sandmaier, Frederick Appelbaum, and Roland Walter contributed to this research.
The spotlighted research was funded by the National Cancer Institute.
Orvain, C., Milano, F., Rodríguez-Arbolí, E., Othus, M., Petersdorf, E., Sandmaier, B., Appelbaum, F., & Walter, R. (2024). Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia. Leukemia. https://doi.org/10.1038/s41375-024-02497-z
Hannah Lewis is a postdoctoral research fellow with Jim Boonyaratanakornkit’s group in the Vaccine and Infectious Disease Division (VIDD). She is developing screens to find rare B cells that produce protective antibodies against human herpesviruses. She obtained her PhD in molecular and cellular biology from the University of Washington.
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