World first genome wide study of which people make the best stem cell donors

Patient stem cell donor, Francis Judd, aged 26, is an example of the sort of donor the study wants to find. NHS Blood & Transplant

23 August 2024

A world-first study to identify which genes make some people stem cell super donors has begun by NHS Blood and Transplant and University of Bristol researchers.

Scientists do not currently know why some people are able to give far more than others. The more stem cells in a donation, the more likely the stem cell transplant will successfully save or improve a life.

The GeSTy study will use genetic testing to examine the DNA of frozen samples from up to 5,000 past donors held by the NHS Blood and Transplant registry and the Anthony Nolan registry, to try and identify which genes influence how many stem cells people are able to donate. (1) GeSTy is the first genome wide study of stem cell donor yields.

The results should enable doctors to develop a scoring system to make better choices about which people should be selected to donate. High stem cell yields are associated with faster recovery times and better patient outcomes. (2)(3)

The study is not focused on particular genes identified in advance. It will use a technique called genome wide association analysis so that scientists can look for the ‘signals’ of any genes that are associated with higher yields. (4)

Donor stem cell yields can vary 40-fold. (5) The existing research shows factors such as age, sex, weight, and ethnicity predict stem cell yield to some degree. (6)

For example, bigger people, and men, generally give higher yields. But these factors only explain about 25% of the variation. The GeSty study is aimed at finding out which genes influence the other 75% of variation.

The study should also help make sure donors are picked who can at least meet the minimum stem cell threshold. Around 40% of donors do not give a high enough stem cell yield on the first donation. They may be asked to go through more injections of a growth factor to boost stem cell donation or to donate bone marrow, which requires surgery and general anaesthetic. Five per cent of people are not able give a high enough yield at all.

The study is estimated to complete by 2027. The leads are Dr James Griffin, Medical Director of Cell, Apheresis and Gene Therapy Therapies at NHS Blood and Transplant, Dr Andrew Mumford, Professor of Haematology at the University of Bristol, and Dr Rachel Peck, Clinical Research Fellow Cell at NHSBT. The study is funded by NHS Blood and Transplant.

Francis Judd, aged 26, is an example of the sort of donor the study wants to find.

His stem cell donation last June contained the third highest number of stem cells of any donor through NHS Blood and Transplant during 2023.

His donation of 1.1 billion stem cells was around twice as many stem cells than the average donor to NHSBT that year and around 20 times more than the person whose donation contained the fewest stem cells.

Francis, a software engineer living in Clapham, said: “It was the third time I’d been called as a potential match and the way I thought about it, it would be of negligible impact on me but someone else really needs it, so why not do it.

“It was a cool thing to do.

“I am glad I was able to donate a lot of stem cells for whoever needed them. It does sound like a beneficial study because the people who receive stem cells are very vulnerable and need to have good treatment.”

Dr Rachel Peck, Clinical Research Fellow at NHS Blood and Transplant, one of the study leads, said: “NHS Blood and Transplant is carrying out this study because there can be big stem yield variations between fairly identical people. We think genes are likely to play a big part in that. There are around 7-8 genes we suspect play a part but the study will be ‘gene agnostic’; we’ll see if there are effects from genes we have not studied before. It’s likely to be your combination of genes rather than one or two which make the difference and the more stem cells you can give, the more likely the transplant will be a success.”

Dr James Griffin, Medical Director of Cell, Apheresis and Gene Therapies at NHS Blood and Transplant, one of the study leads, said: “This is world leading research led by NHS Blood and Transplant in collaboration with Anthony Nolan and the University of Bristol, the first genome wide study of stem cell donor yields. The data can be translated into new ways to prioritise donors and save and improve even more lives. The wider use of genomic matching at NHSBT will improve patient and donor matching, which will particularly help reduce health inequalities.”

Dr Andrew Mumford, Professor of Haematology at the University of Bristol, one of the study leads, said: “It’s a privilege to have helped with the technical design of this study which recognises the importance of the genetic characteristics of donors in determining stem cell yield. The study findings will increase the repertoire of genetic factors that are increasingly at to forefront of how we deliver care within the NHS.”

Further information

The DNA testing will be done using a new DNA-based testing array developed by the Blood transfusion Genomics Consortium, an international partnership of which NHS Blood and Transplant is a member. Haematopoietic Stem Cell Transplant (HSCT) is a lifesaving treatment for acute leukaemia, solid tumours and some inherited disorders that was performed in more than 1600 adults and 300 children in the UK during 2021.
Higher doses of CD34+ cells predict faster engraftment of platelets and neutrophils in hematopoietic stem cell transplant recipients, reduce transplant related mortality and prolong disease free survival. (Ramalingam TR, Vaidhyanathan L, Muthu A, Prabhakar V, Ramakrishnan B, Raj R, et al. Simple predictors of peripheral blood stem cell yield in healthy donors: A retrospective analysis in a tertiary care hospital. Journal of Applied Hematology. 2021;12(1):31-6 / Pulsipher MA, Chitphakdithai P, Logan BR, Leitman SF, Anderlini P, Klein JP, et al. Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose. Blood. 2009;114(13):2606-16.).
For most HSCT indications the optimum stem cell dose is >5 million CD34+ cells/kg of recipient. Although standardised G-CSF mobilisation protocols yield a median of approximately 600 million CD34+ cells
The study is estimated to complete by 2027. The leads are Dr James Griffin, Medical Director of Cell, Apheresis and Gene Therapy Therapies at NHS Blood and Transplant, Dr Andrew Mumford, Professor of Haematology at the University of Bristol, and Dr Rachel Peck, Clinical Research Fellow Cell at NHSBT. The study is funded by NHS Blood and Transplant.
There is over a forty fold variation between donors resulting in only 63% of UK donors achieving their target after one apheresis collection procedure.19% required second apheresis and the remaining 18% gave a sub-optimal yield despite this (Holig K. G-CSF in Healthy Allogeneic Stem Cell Donors. Transfus Med Hemother. 2013;40(4):225-35.).
Vasu S, Leitman SF, Tisdale JF, Hsieh MM, Childs RW, Barrett AJ, et al. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. 2008;112(5):2092-100. Piccirillo N, Putzulu R, Metafuni E, Massini G, Fatone F, Corbingi A, et al. Peripheral Blood Allogeneic Stem Cell Mobilization: Can We Predict a Suboptimal Mobilization? Transfus Med Rev. 2023;37(2):150725.