50 Years of Progress: Unlocking Stem Cell Transplantation for All Patients

When Anthony Nolan was born in 1971 with Wiskott-Aldrich syndrome, a rare inherited immunodeficiency disorder, his mother Shirley was told a bone marrow transplant was his only chance of survival. Known today as a haematopoietic cell transplant (HCT), the procedure would involve replacing his affected bone marrow with that of a healthy human leukocyte antigen (HLA)–matched donor. But with no siblings, he would need an unrelated donor.

At the time, there was no system for finding potential donors for people like Anthony. Desperate for a match for her son, Shirley set up the world’s first register of people willing to donate their bone marrow to those with blood cancers and serious blood disorders.

Sadly, Anthony died at age 7 while waiting for a donor. But his and Shirley’s legacy remains. Fifty years later, Anthony Nolan, the charity with Anthony’s namesake, currently has over 900,000 people on its register and gives 4 people a day a second chance of life by facilitating life-saving stem cell transplants.

Half a Century of Progress

As risks and complications have been reduced with improved clinical understanding and new therapies, HCT has become available for a growing list of indications, including sickle cell disease and thalassemia, and is increasingly used in older patients. Image Credit: © MAY - stock.adobe.com

Initially an experimental treatment, HCT is now considered a routine, but complex, therapy for thousands of patients each year with otherwise incurable blood cancers and serious blood disorders.¹

As risks and complications have been reduced with improved clinical understanding and new therapies, HCT has become available for a growing list of indications, including sickle cell disease and thalassemia, and is increasingly used in older patients.^2-4 In recent years, our knowledge and understanding of HCT has also become central to emerging cell and gene therapies, such as CAR T-cell therapy; for these therapies, genetically engineered cells are used to treat malignant and non-malignant conditions.^5,6

But there is still work to do. The intense nature of a transplant means many patients still suffer serious short and long-term adverse effects and reduced quality of life after treatment.⁷ On average, 5-year survival post-transplant sits at little over 50%.⁸ What's more, disparities in access to and recovery from transplant—due to age, ethnicity, socioeconomic status and more—mean it’s likely many patient groups may face disproportionately worse outcomes.⁹

Finding Matches for All

HLA-matching is the cornerstone of HCT. However, due to the complexity and diversity of HLA genes, some patients have unique genetic types for whom an ideal donor is highly unlikely to be found. Crucially, research shows patients from minority ethnic backgrounds are more likely to have rare genetic types, making it harder to find them an HLA-matched unrelated donor compared to those with White or Northern European heritage.¹⁰

Organisations across the globe, including Anthony Nolan, are working hard to recruit more people of minority ethnic backgrounds to help address this disparity. Yet studies of HLA and population genetics show recruitment alone will not be enough to find everyone their perfect donor.¹¹ In order to level the playing field, we must find alternative solutions when an HLA-matched donor cannot be found.

Unrelated donor umbilical cord blood has been an important alternative source of haematopoietic stem cells for many years. This blood, which is otherwise discarded after birth, is rich in stem cells and can withstand a lower degree of matching than cells taken from adult donors.¹² Since the first successful transplant with cord blood was completed in 2012, over 300 transplants have taken place in the UK.¹² However, the specialist clinical knowledge required to administer cord blood donations, combined with factors like lower cell dose, mean umbilical cord blood is not a suitable alternative for every patient.^13,14

Recent advances in transplant practice and new strategies to prevent graft-versus-host disease (GVHD), such as post-transplant cyclophosphamide (PTCy), are another important option. Use of PTCy is now allowing patients to receive an allogeneic HCT from an HLA-mismatched donor, either related haploidentical or unrelated, in a way that was not previously possible.¹⁵

Ongoing clinical trials are assessing the safety and efficacy of PTCy in both matched and mismatched unrelated donor transplants.^16,17 While further research is needed to understand the long-term consequences of this approach, results so far show that PTCy is significantly increasing donor options for those without an HLA-matched unrelated donor with very encouraging clinical outcomes.¹⁵

Addressing Socioeconomic Barriers to Access

Beyond finding a donor, other factors such as socioeconomic status, household income, educational level, and regional location may also influence HCT outcomes and survival. For example, recovery from transplant can be a lengthy process, with many patients requiring long stays in hospital and extended periods of recuperation at home. Those on lower incomes may face more pressure to return to work prematurely, which could impact their recovery. They may also be disproportionately impacted by the costs associated with a transplant—with some patients telling us they have considered postponing or even refusing a lifesaving transplant due to the financial implications.

Despite this, currently in the UK there is no widely accepted method of routinely collecting information about socioeconomic status, and how this may affect quality of life or survival post-transplant.

In the Anthony Nolan study SEQoL, investigators are pioneering methods for collecting patient-reported outcomes data and linking this to socioeconomic factors, with the aim of informing how the transplant community can offer the best support possible to every patient.

Looking to the Future

Since the inception of the world’s first register of unrelated stem cell donors was established 50 years ago, there has been unprecedented progress in outcomes and survival from stem cell transplants. Based on our understanding of his condition, if Anthony Nolan needed a donor today, we estimate he would have as much as a 93% chance of finding a 9/10 or 10/10 HLA-matched donor on our register. But until we see equivalent progress in every patient—regardless of their ethnicity, socioeconomic status and more—there is more work to be done.

REFERENCES

1. Stem Cell Transplant. NHS. Accessed July 20, 2024. https://www.nhs.uk/conditions/stem-cell-transplant/.

2. Sickle Cell Disease. NHS. Accessed July 20, 2024. https://www.nhs.uk/conditions/sickle-cell-disease/treatment/

3. NHS to offer stem cell transplants to cure life-limiting blood disorder. NHS. Accessed July 20, 2024. https://www.england.nhs.uk/2023/11/nhs-to-offer-stem-cell-transplants-to-cure-life-limiting-blood-disorder/

4. Auner HW, Szydlo R, Hoek J, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2015;50(2):209-215.

5. Locke FL, Siddiqi T, Jacobson CA, et al. Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity. Blood. 2024 Jun 27;143(26):2722-2734. doi:10.1182/blood.2023023447.

6. Fabian Müller, Jule Taubmann, Laura Bucci et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med. 2024 Feb 22;390(8):687-700. doi:10.1056/NEJMoa2308917

7. Di Giuseppe G, Thacker N, Schechter T, et al. Anxiety, depression, and mental health-related quality of life in survivors of pediatric allogeneic hematopoietic stem cell transplantation: a systematic review. Bone Marrow Transplant 2020;55:1240-1254. doi:10.1038/s41409-020-0782-z

8. Cusatis R, Litovich C, Feng Z, et al. Current trends and outcomes in cellular therapy activity in the United States, including prospective Patient Reported Outcomes data collection within the CIBMTR registry. Transplant Cell Ther. 2024 Jun 27;S2666-6367(24):00482-2. doi:10.1016/j.jtct.2024.06.021

9. Blue BJ, Brazauskas R, Chen K, et al. Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis. Transplant Cell Ther. 2023 Nov;29(11):709.e1-709.e11.

10. Leen G, Stein JE, Robinson J, et al. The HLA diversity of the Anthony Nolan register. HLA. 2021 Jan;97(1):15-29. doi:10.1111/tan.14127

11. Schmidt AH, Sauter J, Baier DM, et al. Immunogenetics in stem cell donor registry work: The DKMS example (Part 1). Int J Immunogenet. 2020;47:13–23. doi:10.1111/iji.12471

12. Nolan A. What is umbilical cord blood donation. Anthony Nolan. Accessed July 20, 2024. https://www.anthonynolan.org/help-save-a-life/donate-your-umbilical-cord/what-umbilical-cord-donation

13. Cord blood transplants. Anthony Nolan. Accessed July 20, 2024. https://www.anthonynolan.org/patients-and-families/understanding-stem-cell-transplants/cord-blood-transplants#:~:text=Engraftment%20can%20take%20longer%20to,an%20unrelated%20or%20sibling%20transplant

14. Ross AJ, Gillibrand RA. Barriers to Cord Blood Banking: Perspectives of Midwives and Cord Collectors. Stem Cells Transl Med. 2019 Aug 28;8(Suppl_1):S25. doi:10.1002/sctm.12568

15. Shaffer BC, Gooptu M, DeFor TE, et al. Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors. J Clin Oncol. 2024 Jul 17:JCO2400184. doi:10.1200/JCO.24.00184

16. Methods of T Cell Depletion Trial (MoTD) (MoTD). Clinicaltrials.gov. Accessed July 20, 2024. https://clinicaltrials.gov/study/NCT04888741?term=motd&rank=1

17. HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide (ACCESS). Clinicaltrials.gov. Accessed July 20, 2024. https://clinicaltrials.gov/study/NCT04904588?term=ACCESS&intr=Cyclophosphamide%20&rank=1