In Brief: In HLA-matched transplants, younger donor age was the only factor reliably associated with patient survival. Other secondary selection characteristics included sex, ethnicity, the presence of cytomegalovirus and non-HLA and HLA genetic factors. Several factors are believed to inhibit the proper functioning of stem cells as the donor ages, making the young stem cells in cord blood a beneficial source when HLA-matching is equal.
Success in Stem Cell Transplantations
The key to a high survival rate in any stem cell transplantation is the degree of human leukocyte antigen (HLA)–matching found between the donor’s and the recipient’s cells. Studies show that in unrelated donor hematopoietic stem cell (HSC) transplantations, HLA-mismatching can lower the overall survival rate.1,2
Besides the prioritization of matching HLA markers, researchers have looked at secondary selection characteristics to see if there were effects. Studies have been conducted to see how much weight to give various secondary characteristics, and the data show that the age of the donor at the time of collecting the stem cells is the most significant factor.
Stem cells collected at birth are some of the youngest that can be collected.
In a study published in the Blood for January 2016, the effects of donor characteristics on survival were compared in 10,000 unrelated donor transplantations for hematologic malignancies. It found younger HLA-matched donors had the best survival rates after adjusting for patient, disease and transplant characteristics.
In another study published in the Blood, data from 6,978 unrelated bone marrow transplantations were analyzed. It found younger donors were predictors of less graft-versus-host disease, better overall survival and better disease-free survival in recipients of transplants.
In the most recent study, published in Biology of Blood and Marrow Transplantation in February 2018, researchers analyzed 10,462 fully HLA-matched transplants from more than 450 transplant centers for the association of donor factors and transplant complications. It found that younger transplant cells were the only secondary factor consistently associated with better survival rates. A stand-out finding from this study was the association between age and survival rates was linear, with every additional year of age decreasing the survival rate. This study is the first to look at only transplants with fully matching donors.
In these analyses, other secondary conditions studied included age, sex, ethnicity, and the presence of the cytomegalovirus. In addition, they looked at HLA genetic factors such as low expression loci (including DRB3/4/5,DQB1 and DPB1) and non-HLA genetic factors including natural killer immunoglobin-like receptors (KIR) and ABO type.
The study found that stem cells from older donors were more prone to inflammation, produced more red blood cells and fewer white blood cell and were more likely to have cellular mutations. As stem cells age, a few important factors are believed to inhibit proper function:
- Toxic metabolites accumulate with age, leading to abnormal proliferation and malignant and compromised stem cell renewal;
- Age-related reductions in mitochondrial function are thought to largely occur from accumulation of mutations in mitochondrial DNA;
- Exposure to genotoxic stress factors could cause genetic instability;
- Elevated stress could lead to cellular senescence, where the cells not only no longer divide but also secrete factors that cause inflammation and dysfunction in nearby stem cells;
- Alterations in the epigenome can impinge on stem cells’ cellular processes. In a study of the world’s formerly oldest woman, 450 somatic mutations were found across 115 years of her life. This equates to four mutations per year or about three mutations per division given HSCs renew every 25 weeks to 50 weeks.5
The studies also showed graft-versus-host disease was more common in transplantations when the stem cells were older. The increase in graft-versus-host disease in older donors may be explained by naïve T cells being replaced with memory T cells as the immune system ages.
In a recent study, researchers analyzed data from 10,000 transplantations between 1999 and 2014 with fully HLA-matched stem cells from unrelated donors and discovered that only one secondary factor contributed to survival: the younger the stem cells, the more likely the recipient would survive. This confers with outcomes from earlier trials that did not analyze data from only full HLA matches. Stem cells from cord blood are among the youngest retrievable adult stem cells. Cord blood stem cells have not been exposed to factors that inhibit proper function as with older stem cells from other sources. This makes cord blood a better source when HLA-matching is equal.
1. E. Shaw, Bronwen & R. Logan, Brent & R. Spellman, Stephen & Marsh, ... J. Lee, Stephanie. (2018). Development of an Unrelated Donor Selection Score Predictive of Survival after HCT: Donor Age Matters Most. Biology of Blood and Marrow Transplantation. 10.1016/j. bbmt.2018.02.006.
2. Juhyun Oh, Yang David Lee, Amy Wagers J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. doi:10.1038/nm.3651. 2014; 20(8):87–880.
3. Kollman C, Spellman SR, Zhang MJ, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016; 127(2):260–267.
4. LeeSJ, Klein J, Haagenson M, et al. High Resolution donor recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576–4583.
5. Holstege, H., Pfeiffer, W., Sie, D., Hulsman, M., Nicholas, T.J., Lee, C.C., Ross, T., Lin, J., Miller, M.A., Ylstra, B., et al. (2014). Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 24, 733–742.
6. Broxmeyer, H. E.; Lee, M. R.; Hangoc, G.; Cooper, S.; Prasain, N.; Kim, Y. J.; Mallett, C.; Ye, Z.; Witting, S.; Cornetta, K.; Cheng, L.; Yoder, M. C. Hematopoietic stem/progenitor cells, generation of induced pluripotent stem cells, and isolation of endothelial progenitors from 21–23.5 year cryopreserved cord blood. Blood 117(18): 4773–4777; 2011.
7. Impact of length of cryopreservation and origin of cord blood units on hematologic recovery following cord blood transplantation. Bone Marrow Transplantation (2015), 1–4. Appeared in www.nature.com/bmt.