Here’s a scenario: you’ve recently been diagnosed with leukemia and find yourself needing a blood stem cell transplant (or, in scientific parlance, a hematopoietic stem cell transplant, HSCT) as part of your treatment regimen. But since stem cells don’t grow on trees, your doctors will need to source them from somewhere—if you’re lucky enough to have a healthy sibling, they’ll test them for compatibility, but otherwise, they’ll turn to the NMDP (National Marrow Donor Program) Registry: a curated database of people (currently, over 9 million of them) who have signed up to donate blood stem cells if and when they’re needed.
To minimize the chances of your body rejecting the transplanted cells or the transplanted cells attacking your body (a condition called graft-versus host disease), potential donors will need to be matched to your specific immunological parameters. For stem cells, this matching is a good deal more complicated than the A/B/O blood types you might remember from high-school science class; instead, stem cell matching looks at a collection of proteins called HLAs (human leukocyte antigens), of which there are multiple types. If you have a common HLA type, you probably have multiple fully matched potential donors; however, if there isn’t a complete HLA-matched donor, the search will return a collection of potential donors with differing degrees of HLA-matching. At this point, your doctors are faced with a decision which could have real consequences for your health—which mismatched donor should they choose?
Drs. Rohtesh Mehta and Stephanie Lee, of the Fred Hutch Clinical Research Division, think a lot about problems like these. “As far as HLA matching goes, there are five ‘classical’ HLA markers we look at (since each one is encoded on two alleles, a ‘fully’-matched donor is often referred to as ‘10/10 matched’),’ notes Mehta. “There is a sixth HLA marker, called DPB1, which is also considered for matching beyond the 10/10-matching. The age of the donor has also emerged as an important variable influencing outcomes, but overall, it’s still quite unclear how these variables interact and how to prioritize them when choosing between HSCT donors.” Indeed, in lieu of clear, agreed-upon guidelines, the choice of HSCT donor often comes down to individual clinicians’ judgements. To address this need, Mehta, Lee, and colleagues set out to formally test the effect that DP-matching and donor age had on HSCT outcomes. They recently published the results of their study in Blood Advances.
To conduct their study, Mehta and colleagues leveraged a publicly-available dataset from the Center for International Blood and Marrow Transplant Research (CIBMTR), which includes information from thousands of 10/10 matched HSC transplants conducted from 2008 to 2018. The team stratified these records based on donor age (greater or less than 35 years of age) and DPB1 matching—importantly, a mismatched DPB1 comes in two flavors: permissive (which you can think of as ‘sort-of matched’) and non-permissive. They noted that DPB1 matching had no significant effect on overall survival following transplant (though it did significantly affect both the risk of relapse and the risk of non-relapse mortality—which includes immune-related complications like graft-versus-host disease). Meanwhile, donor age showed a quite different result: cases with younger donors had a significantly higher overall survival and lower risk of non-relapse mortality, but donor age didn’t affect the risks of relapse! Overall, their results suggest that—if the goal is to maximize overall survival following transplant—donor age should be prioritized over DPB1 matching. Their findings also point to a model whereby overall survival and the risk of post-transplant relapse are distinct biological processes with their own sets of determinants which must be considered in the context of the patient’s goals.
“While DPB1 matching and donor age have individually been found to influence some of these transplant outcomes,” notes Metha, “our study is the first to comprehensively examine the combined effect of these variables and their effects on outcomes in a large, multi-center dataset. There is certainly lots of work left to do—for example, to test whether the choice of post-transplant prophylaxis [immunosuppressives given after a transplant to reduce the chance of graft-versus-host disease or rejection] matters as well—but overall, we think this is an important step forward in maximizing the benefits and minimizing the risks of HSCT.” Dr. Stephanie Lee adds, “and if you’re reading this, we hope you’d consider joining the NMDP Registry—there is always a need for more young donors, and there’s a real chance that your donation could save someone’s life one day.”
For more information and to join the NMDP Registry, visit their website here.
The publicly available dataset was created with funding from the National Institutes of Health, the National Marrow Donor Program, and the Office of Naval Research.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Effie Petersdorf and Stephanie Lee contributed to this study.
Mehta, R. S., Petersdorf, E. W., Wang, T., Spellman, S. R., & Lee, S. J. (2024). Interplay between donor age and HLA-DP matching in 10/10 HLA-matched unrelated donor HCT. Blood Advances, bloodadvances.2024013677.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accomodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.