The selection of suitable donors is crucial for the long-term recovery of patients after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Primarily, the transplantation from a matched sibling donor (MSD) is considered the "first choice" [2]. It is associated with a low risk of non-relapse mortality (NRM) and rejection reactions such as acute graft-versus-host disease (GvHD) [3].
Thanks to improved matching strategies, optimized pre-treatments, and newer options for GvHD prophylaxis, matched unrelated donors (MUDs) or mismatched unrelated donors (MMUDs), with minor HLA differences, can also be considered. Stem cell transplantations from haploidentical family donors whose HLA characteristics only partially match are also possible [2]. In addition to HLA characteristics, additional donor attributes are gaining importance in donor selection. More than five years ago, a study based on more than 10,000 patients and their HLA-compatible, unrelated stem cell donors investigated the influence of biological gender, age, and blood type. The study showed that only the age of the donor was significantly associated with survival. The study found that the 2-year survival rate decreased by around three percent for every ten years of donor age [4]. Further studies followed with the aim of creating a reliable, data-based decision-making basis for selecting optimal stem cell donors.
Young age alongside HLA matching is a decisive factor for success
The latest retrospective registry study published by Prof. Schetelig et al. in October 2025 in the journal Leukemia now confirms that the age of the donor plays a major role in the success of transplantation, even more so than previously assumed [1]. The results showed that patients over the age of 50 with myeloid cancers have better survival chances with allogeneic stem cell transplantation if the stem cells come from young, HLA-compatible, unrelated donors than from older, HLA-identical siblings. "Further studies need to be conducted to understand the underlying biology and differences in immune reconstitution," said Schetelig. The findings could influence clinical practice, where MSD is currently often preferred over MUD regardless of age.
The study examined 3,460 patients aged 50 and older with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and MDS/MPN who had received their first allogeneic HSCT. Patients received either a donation from an MSD (1,235) aged 50 years or older or a MUD aged between 18 and 35 years (2,225). After multivariable adjustment, the MUD group showed a significant risk reduction compared to the MSD group [1]:
- 14% in event-free survival (EFS), p = 0.003
- 18% in overall survival (OS), p < 0.001
- 16% in relapse risk, p = 0.018
The greater the age difference between two donors, the greater the impact on survival.
Gender and CMV status also play a role
In addition to age, the study by Schetelig et al. [1] also examined gender and cytomegalovirus (CMV) status. An advantageous constellation was defined as one in which the CMV serostatus of the donor and patient matched and no female donor donated to a male patient. The results showed that in favorable combinations, the EFS and OS of patients with HLA-compatible young unrelated donors was significantly better than with older sibling donors. When young unrelated donors had an unfavorable constellation, the survival chances for patients were as good as with older sibling donors [1]. "This means that unrelated donors can be selected without any disadvantages," Schetelig concluded.
New findings from the HAMLET study: haploidentical versus mismatched
The as-yet-unpublished HAMLET study (HAploidentical versus Mismatched UnreLatEd Donor Transplantation) by DKMS, the results of which Prof. Schetelig presented once again at the poster session of the Annual Meeting of the German, Austrian and Swiss Societies for Hematology and Medical Oncology (DGHO), addressed the question of which factors are decisive for the selection of donors. The study found no relevant difference between haploidentical family donors and unrelated donors with a mismatch (MMUD, 9/10 mismatch) [5]. The prospective study focused on patients with AML/MDS and acute lymphoblastic leukemia (ALL) who had neither HLA-identical sibling donors nor HLA-compatible unrelated donors. The study data also showed an age effect for non-fully compatible donors: patients with younger donors had a better 2-year survival rate. "The influence of other HLA and non-HLA factors needs to be further investigated to enable the selection of the best donor for a transplant recipient," Schetelig emphasizes.
Despite numerous studies on the subject, Schetelig believes that these are insufficient to adequately reflect the selection decision in practice. "In everyday clinical practice, the main focus is on the urgency of the transplant and the availability of donors. Against this background, the degree of kinship can still be a major factor." The aim of current research is also to better understand why stem cells from young donors are advantageous. Is it the fitness of the stem cells or the transfer of the young immune system? The fact is: "When donating stem cells, a young donor age can be crucial," emphasizes Schetelig. "Young people can save lives by registering as stem cell donors."
Further information on registration can be found on the DKMS website https://www.dkms.org/ .
References:
- Schetelig J, et al. Leukemia 2025; 39(10):2523–2532. doi: 10.1038/s41375-025-02724-1
- German Onkopedia Guideline „Spenderauswahl", as of January 2021, available at: https://www.onkopedia.com/de/onkopedia/guidelines/spenderauswahl/@@guideline/html/index.html
- Salvatore D, et al. Haematologica 2018; 103(8):1317–1328. doi: 10.3324/haematol.2018.189258
- Shaw BE, et al. Biol Blood Marrow Transplant 2018;24(5):1049–1056. doi: 10.1016/j.bbmt.2018.02.006
- Stölzel F, et al., präsentiert auf dem DGHO 2025, Köln 24-27.Oktober, P492.
