The hope of PTCy
Stem cell transplants can be a lifesaving treatment for someone with a blood cancer or blood disorder. But they often require a close genetic match to a donor – whether someone in your family or a stranger on the stem cell register – and not everyone has the same chance of finding a well-matched donor.
Now, an exciting treatment is raising hopes in the stem cell transplant community that using less well genetically matched donors (known as “mismatched donors”) could offer good outcomes from a transplant.
Encouraging results from the latest US clinical trial into the treatment were released last week.[1] So what is post-transplant cyclophosphamide, and how exactly might it change the face of stem cell transplants?
An established medicine – repurposed
Cyclophosphamide (pronounced ‘sigh-kloe-foss-fa-mide’) is a chemotherapy drug that has been used to treat various cancers for decades. It works by damaging the DNA of cancer cells. It also has the effect of slowing down the activity of the immune system, which has led to interest in its use in stem cell transplants.
Studies have shown that giving patients cyclophosphamide after a stem cell transplant can help reduce the risk of graft versus host disease (GvHD), a major and potentially fatal side effect.[2]
GvHD is caused by the immune cells of the donor attacking the healthy tissues of the patient, and is more likely to occur if a patient’s donor is less well genetically matched to them.
Scientists think cyclophosphamide may reduce the risk of GvHD by slowing down the activity of over-eager immune cells, when administered in the days following a transplant.[3]
This type of treatment is called ‘post-transplant cyclophosphamide,’ or ‘PTCy’ (pronounced 'pee-tee-sigh’).
PTCy has the potential to be particularly useful for patients who can’t find a fully matched unrelated donor on a stem cell register and who may have limited alternative options.
How PTCy may help address inequities in stem cell transplants
Patients who don’t have access to a fully matched unrelated donor on a stem cell register or a fully matched sibling donor usually have other treatment options – such as an umbilical cord blood transplant, a transplant from a mismatched relative, or a mismatched unrelated donor. However, a stem cell transplant using a mismatched donor holds more risk of the patient developing GvHD. Because of the genetic complexities of the immune system, UK patients from a minority ethnic background are less likely to be able to find a fully matched unrelated donor on the stem cell registers, compared to UK patients with white northern European ancestry.[4]
At Anthony Nolan we are determined to increase the number of treatment options available to patients and give minority ethnic patients the same chance of good outcomes as all patients.
This is where PTCy comes in. This treatment could help improve outcomes from a mismatched donor transplant, by potentially lessening the risk of GvHD. This could help reduce the equity gap between patients with a fully matched unrelated donor and patients without, by expanding the pool of potential donors to include more mismatched donors.
In the past five years, several studies have provided evidence that PTCy can reduce the risks of GvHD in both related and unrelated donors. Perhaps most pivotally, a 2023 phase three clinical trial from the US of over 400 patients receiving stem cell transplants showed that PTCy reduced rates of GvHD for both related and unrelated donors.[5]
The results of the ACCESS clinical trial
Building on this previous evidence, the recent ACCESS trial recruited 145 patients, all of them receiving a first-time stem cell transplant from a mismatched unrelated donor – a mismatch being defined as a 7/8 donor or less.[1] Note: in the US, transplant centres typically report matching based on four genes rather than five or six, hence why matching is reported out of eight (two sets of four genes, one set from each parent) instead of out of ten or twelve as is done in the UK.
The patients were all given PTCy as part of their treatment, and then the outcomes of the transplant were monitored for the year following their transplant.
The main finding of the study was that PTCy appeared safe for these patients, and that it produced good survival rates (around 80% at the one-year mark).
Importantly, there was no significant difference in survival between patients with different levels of donor matching – the study found that patients with a less than 7/8 donor (i.e. 5/8, 6/8) had the same survival rates and risk of GvHD as patients with a 7/8 donor.[1]
This means that PTCy was able to bring everyone onto a more even playing field in terms of their matching level and how that affects the outcome of their transplant, one year after the procedure.
What does this mean for patients?
Data from the US suggest that if matching levels of 5/8 or above were used, almost all US patients, regardless of their ethnicity, would have access to an unrelated donor.[6] Initial analysis by Anthony Nolan suggests the same could be true for patients in the UK. Paired with the ACCESS results, this could mean effectively everyone, regardless of their ethnicity, could have access to a potential unrelated donor thanks to PTCy.
This is emphasised by the fact that over half (59%) of the participants in the ACCESS trial reported belonging to a non-white ethnicity.[1]
Overall this study presents PTCy as a potential way to improve patient equity in stem cell transplants from unrelated donors, by widening the option of mismatched unrelated donors for patients from a minority ethnic background.
Other potential benefits of PTCy
PTCy could also help clinicians select younger donors for their patients, through expanding the number of donor options for every patient. The median age of the stem cell donors seen in the ACCESS trial was 25, and no donors were over the age of 35. This is important as there is plenty of evidence, including from Anthony Nolan, that younger donors provide better outcomes for patients.
Another potential benefit of PTCy could be helping patients find a donor and receive a stem cell transplant more quickly. The most common reason that people need a transplant is to treat an aggressive blood cancer like leukaemia – so avoiding long waits to find a donor can be very important.
Is PTCy safe?
One of the main results from ACCESS is that PTCy was found to be safe for patients one year on. However, we still need to learn more about how to reduce side effects and potential risks of these treatments, to improve outcomes even further.
In the ACCESS trial, side effects previously known to be associated with cyclophosphamide showed up, including organ toxicity and an increased risk of infections (due to the suppression of the immune system).[1] Future studies will need to fully profile these side effects and any long-term harm caused by PTCy, so that doctors can appropriately weigh up its risks against benefits of a potentially lifesaving stem cell transplant.
What next?
Some UK transplant centres already use PTCy for certain patients, usually when doing transplants with a mismatched related (haploidentical) donor. In the UK, the Methods of T cell Depletion (MoTD) clinical trial, is now looking at using PTCy with 10/10 and 9/10 matched unrelated donors and how effective PTCy is compared to the current methods used in the UK for preventing GvHD. The results will be released in the next few years.[7] We expect to see PTCy being used for more patients in the UK who receive a transplant from a mismatched donor in the coming years.
We will campaign for the results of these trials to influence healthcare practice in the UK, with the aim of improving equity for all UK patients waiting for a stem cell transplant.
Our strategy to improve equity for patients means we will continue working to expand our stem cell register and cord blood bank; support the development of new cell & gene therapies that can provide more treatment options for patients; engage in research into targeted recruitment strategies to improve representation of different tissue types on global registers; and advocate for the uptake of treatments like PTCy that have the potential to address inequities in stem cell transplantation for all patients.
References
[1] ACCESS trial results: Al Malki et al (2025) Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis After Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation. J Clin Oncol. 2025 Jun 16:JCO2500856. doi: 10.1200/JCO-25-00856.
[2] Shaffer et al (2024) 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 Oct;42(28):3277-3286. doi: 10.1200/JCO.24.00184.
[3] Nunes & Kanakry (2019) Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding. Front Immunol. 2019 Nov 29;10:2668. doi: 10.3389/fimmu.2019.02668.
[4] Leen et al (2020) The HLA diversity of the Anthony Nolan register, HLA Immune Response Genetics, doi: 10.1111/tan.14127
[5] Bolaños-Meade et al (2023) Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. doi: 10.1056
[6] Chowdhury et al (2022) 337 - Unrelated Donor Registry HLA Match Likelihoods in the Mismatched Setting. Transplantation and Cellular Therapy, 28(3), doi: 10.1016/S2666-6367(22)00497-3.
[7] Chakraverty et al (2024) Multicentre adaptive randomised trial of GvHD prophylaxis following unrelated donor stem cell transplantation comparing Thymoglobulin versus calcineurin inhibitor-based or sirolimus-based post-transplant cyclophosphamide (Methods of T cell Depletion, MoTD trial). BMJ Open. 2025 Jan 28;15(1):e086223. doi: 10.1136/bmjopen-2024-086223.