For patients undergoing allogeneic hematopoietic stem cell transplant, some potential donors may be better than others. At present, however, little is done to select a suitable donor other than immunologic matching to the intended recipient. Biological characteristics that impact either the efficacy of transplant (i.e. the recipient's risk of relapse), toxicity (i.e. graft-versus-host disease), or both, have not been explored and are not considered in identifying suitable donors.
To this end, Dana-Farber Cancer Institute researchers have recently shown that clonal hematopoiesis (CH) in donors is associated with reduced risk of relapse and improved overall survival in some transplant recipients. CH is an asymptomatic, age-related condition in which somatic (acquired) genetic mutations drive clonal expansions of blood cells that can be detected by next-generation sequencing. In non-transplant populations, patients with CH have evidence of augmented inflammation and a higher risk of death due primarily to an increased risk of cardiovascular disease.
Researchers at Dana-Farber sequenced products from over 1,700 donors for transplants performed at Dana-Farber and Johns Hopkins University. Surprisingly, they found that recipients of donors who had CH with DNMT3A mutations had a reduced risk of relapse after transplant, which translated into improved overall survival compared with recipients of donors without CH. The biological basis of this effect is not yet clear and is the subject of ongoing investigation. Dana-Farber is now leading a large validation effort with samples and funding from the NMDP. The project, which will span over several years, is expected to assess between 20,000 and 30,000 donor samples for CH, and its clinical impact on recipient outcomes.
Expanding from this project, Dana-Farber researchers are leading efforts to understand the impacts of other donor biological features, such as telomere length, in recipients. Telomeres are repetitive DNA sequences that protect the ends of chromosomes from degradation. Telomere length decreases with advancing age, and individuals with prematurely short telomeres often display signs of accelerated aging. As part of the collaboration with NMDP, Dana-Farber researchers are studying whether donor telomere length impacts recipient outcomes.
Results of this work could revolutionize how donors are selected. If the NMDP collaboration leads to validation of the donor clonal hematopoiesis findings, older donors with CH could be included in the unrelated donor pool, whereas individuals over age 35 are currently excluded. Conversely, studies of donor telomere length could identify younger individuals with premature biological aging who should be excluded from donation. The impacts could extend beyond donor selection as well. Once the biology of donor CH's impact on relapse is understood, researchers will be able to explore whether the effect can be replicated beyond donor CH to augment the efficacy of transplant.