Two-Year Data Confirm Viability of Mismatched Donor Transplants With PTCy

The introduction of post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has reshaped how transplant physicians are looking at allogeneic hematopoietic cell transplantation (HCT). Mismatched unrelated donors (MMUDs) are now a more viable graft source than ever, leading to less graft-vs-host disease (GVHD) and relapse and better overall survival for HCT while expanding access for genetically diverse recipients.

Findings from research conducted through CIBMTR (Center for International Blood and Marrow Transplant Research), the research collaboration between NMDP and the Medical College of Wisconsin, underscore the transformation that has taken place. In the phase 2 ACCESS trial (NCT04904588), patients receiving peripheral blood stem cells from MMUDs had a 74.2% overall survival rate at 2 years, according to findings presented at the European Blood and Marrow Transplantation Society Annual Meeting (EBMT) in March.¹ The longer follow-up showed that late-presenting complications such as chronic GVHD and relapse are not greater concerns in this population. These findings even supported use of donors with less than 7/8 HLA (human leukocyte antigen) compatibility, opening up the doors to many patients who would previously have had difficulty finding a matched donor.

“[Previous to this study,] we were treating patients who potentially never would have gotten to transplant,” said Heather Stefanski, MD, PhD, in an interview with Targeted Oncology. “When you think about, in the ecosystem of patients who need a transplant, [now we’re able to serve] a population that potentially never would have been able to have this life-saving cell therapy.”

Stefanski, who is Senior Vice President of Clinical Innovation and Partnerships at NMDP, discussed the organization’s sponsorship of vital research conducted through the CIBMTR including the ACCESS trial and other studies confirming the benefit of PTCy as a safe and effective GVHD prevention strategy in MMUD HCT. She also shared about NMDP exploring further approaches to expand the safety of HCT by reducing infections and other post-HCT complications benefitting all patients receiving HCT.

Targeted Oncology: What is the background for NMDP’s research into MMUD transplantation outcomes?

Heather Stefanski, MD: Before we look forward, let’s start with the ACCESS trial. This is an NMDP-sponsored clinical trial that CIBMTR performed, and the goal of this trial was to understand if peripheral blood stem cells, which are used in the vast majority of current transplants, could be a safe stem cell source for patients with common blood cancers [who] would be receiving a MMUD transplant with GVHD prophylaxis using PTCy. The reason that this was important is because prior to the ACCESS trial, we had done another phase 2 trial, using bone marrow as a stem cell source. That trial determined that it was feasible to perform safe and effective MMUD transplants with PTCy.² The reason we focused on MMUD is that we know that not every patient will have a fully matched unrelated donor, an available matched sibling, or even have a mismatched related [haploidentical] donor. …Prior to using PTCy [to prevent life-threatening GVHD], if you used a mismatched unrelated donor with the standard of care, which is calcineurin inhibitor-based GVHD prevention, the outcomes for patients that receive 7/8 [or] 6/8 matches or less than that were dismal. However, with the demonstration that PTCy could be used safe and effectively in haploidentical transplants, we wanted to test that the same could be done in the MMUD setting. That was the rationale for the 15-MMUD trial [NCT02793544], which used bone marrow. After that proved successful in the MMUD setting, we then embarked on the ACCESS trial.

The ACCESS trial looked at 3 different strata. I'm just going to focus on the adults, but we had a myeloablative arm as well as a reduced intensity arm on this trial. This trial began in 2021, and the purpose was to look at the overall survival in patients that received MMUD transplantation with peripheral blood stem cell grafts and PTCy.

In the results that were presented at EBMT, we were looking at the 2-year outcomes for the ACCESS study.¹ The reason that those are important is because there are certain things that can happen after transplant after the first year. To study this, we also looked at GVHD-free, relapse–free survival [GRFS] among other outcomes. We wanted to make sure that the results still looked good, which they did. In fact, the outcomes still looked essentially the same. What that means is, that in a patient [who] potentially did not have a fully matched donor on the registry, now they will have a [suitably-matched] donor on the registry and they can undergo a transplant safely.

What were you most excited about from the 2-year outcomes?

One was that we didn't see a huge uptick in chronic GVHD, which is what can happen at the 2-year mark. We also didn't see a huge increase in relapse, because that can also happen when we're looking at the 2-year outcomes. One of the most exciting things is that when you look at the type of patients that we were transplanting with this study, over 50% of them were from ethnically diverse backgrounds.³ We were treating a population potentially that never would have gotten to transplant. When you think about, in the ecosystem of patients that need a transplant, now we’re [able to serve] a population that potentially never would have been able to have this life-saving cell therapy.

Do you feel this cohort reflects the population that needs more access to transplant?

Yes, I do. When we look at some of the other outcomes and some of the other measures for these patients, we can measure their social vulnerability index. We can also measure their financial toxicity [or the financial barriers to transplant]. These are in other abstracts that were done previously. But I think this is important, that when we look at the types of patients that we're treating, it's not that these are the wealthy patients [who] are making it to transplant. These patients have higher social vulnerability, and they also have higher financial toxicity, and so potentially never would have gotten to transplant.

Some of the other important things that we've learned from this study is that when we were doing it, we actually expanded the number of patients that we had on our reduced intensity arm. The reason for that is that transplant centers were really begging us [to continue], [in fact] we accrued on this trial very rapidly, and they were begging us to be able to still have a patient on a clinical trial. What this allowed us to do was to compare the outcomes from [patients receiving] 7/8s and [those receiving] less than 7/8s [HLA matching]. Because, as data comes in, physicians potentially might feel comfortable with a 7/8 MMUD transplant, but not necessarily a 6/8 or 5/8.

So, we explored this question in an oral abstract at ASH last December looking at 1-year outcomes. We wanted to be able to expand this [evidence] and then say, “Are there differences in outcomes?” The bottom line is that there really wasn't. What that means is that, as you're looking for a patient, and then looking at all of the donors that are available, if they don't have an 8/8, you can easily go to a 7/8, and if they don't have a 7/8 for whatever reason, you can safely go to [a match that is] even less than that. The dogma had always been that you needed this perfect match, and we've basically shown that that is not the case.

What are your plans to follow up on this dataset?

We are going to continue to monitor these patients. I think one of the other exciting things is that PTCy has changed the way that we're able to do HLA [matching]. However, that doesn't mean that it's not without its faults. Patients can have delayed immune reconstitution. They can have infections. In fact, when we look at our ACCESS patients, two-thirds of them had a grade 2 or higher infection.¹ What that means is that that patient could have to be in the hospital. They need other drugs, etc, and it's problematic. PTCy can also cause hemorrhagic cystitis or blood in the bladder, which results in higher morbidity. It's a very painful complication of transplant, and very hard to treat. Also, [there are] cardiac complications with high-dose PTCy.

In the OPTIMIZE trial [NCT06001385], we want to look at if we can reduce the dose of PTCy by half, going from 50 [mg/kg], which is the standard, to 25 [mg/kg] in patients [who] are receiving MMUD transplant with peripheral blood stem cells, and then looking at what their infection-free survival is. We're very excited about that. Some of those results were presented at EBMT 2026 as well, looking at the infections and seeing that they're lower.⁴ We have to continue to monitor those results, because what we want to understand is, at a year and even a little bit later, what is the GRFS look like in those patients? Because when we're looking at the infection-free survival, that's at day 100, so we'll see some acute GVHD, but we won't see the chronic GVHD or the relapse, potentially. We need to look at those outcomes later, because the standard currently is 50 [mg/kg], but if we continue to see improvements with the 25 mg/kg PTCy, that could become the new standard.

What is the next step you are taking with this research?

We [just opened] the ACCELERATE trial [NCT06859424]. It’s a platform-based protocol, and what it allows us to do is to look at different combinations of PTCy with different agents, with PTCy at 50 [mg/kg] as the standard. We currently have 2 investigative arms on it. One is using ruxolitinib [Jakafi], and the other is using abatacept [Orencia]. [We use] PTCy at 25 [mg/kg] plus abatacept [or] PTCy at 25 [mg/kg] plus ruxolitinib and then having a control arm at 50 [mg/kg].

This trial is currently ongoing, and the reason that it's beneficial to the community is a number of ways. One of them is the fact that we're going to be able to add new arms in, as opposed to having to redo a whole clinical trial. It’s going to be a 1:1:1 randomization across the control arm of 50 mg/kg PTCy and investigative arms of PTCy 25 mg/kg plus abatacept and PTCy 25 mg/kg plus ruxolitinib—and if we find out that one of the arms is better or it isn't working, we get rid of that arm and we can add in [another arm with other agents]. Instead of a transplant center having to redo trials, they just have to do an amendment on that arm.

The other important thing is that if we find something is the new standard, then that becomes the control, and then we can continue to investigate other agents. We’re very excited about this. Also, we're planning on 60 transplant centers participating in this, so that's double what we did with ACCESS and OPTIMIZE and [we are] still looking at MMUDs and how we can serve different patient populations.

What is your biggest takeaway from what you saw at the EBMT meeting this year?

The key things that we're going to be focused on are with PTCy, what are the best combinations, trying to decrease the dose, and then focusing on how to prevent relapse.Relapse is the most common complication post-transplant. How do we prevent relapse? How do we determine, first of all, who should be going to transplant and [achieving] the best remission, and are there other agents that we should be using as maintenance, or what other things should we be doing upfront?

Other key things are, when you're thinking about transplant and the other complications [such as] infections, what that goes along with is immune reconstitution. Immune reconstitution is critical to both prevent infections as well as prevent relapse. What are the ways that we can determine what that immune reconstitution is going to look like and potentially targeting people up front? I think as we're collecting more samples from our patients and then finding new ways to interrogate those samples and determine, if a patient, for example, has a high likelihood to relapse, you might want to put them on maintenance therapy earlier, or potentially if they are going to have GVHD, can we try to prevent that in a different way?

But I think one of the most exciting things, when I think about from 5 or 10 years ago, is just the number of patients that are able to go to transplant now, and that you do not have to worry about a full 8/8 HLA match.

What is your message to hematologist/oncologists who are counseling patients right now?

Before, when they were looking at a patient, they may say “You're not going to have a donor. You shouldn't go to transplant. Let's just continue down that chemotherapy path.” Whereas I think what's beneficial to patients with high-risk leukemia or even high-risk [myelodysplastic syndrome] and even older patients, when we look at our data and see the trends, over 70-year olds is a huge uptick [in diagnoses], and so these patients can get through transplant safely. If you have them, at least have a transplant consult so they can understand what transplant entails and what that would look like, and if that patient would benefit from transplant.

For more information on how NMDP supports hematology-oncology practices, and the patients they treat, with free HLA typing and other methods to move to transplant more quickly and receive long-term support, from diagnosis through to survivorship, visit https://network.nmdp.org/services-support/hematology-oncology/programs-guidelines.

REFERENCES

1. Al Malki M, Stanek J, Bo-Subait S, et al. Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis after mismatched unrelated donor peripheral blood stem cell transplantation – 2-year outcomes from the NMDP-sponsored ACCESS trial. Presented at: 2026 EBMT Annual Meeting; March 22-25, 2026; Madrid, Spain. OS14-03.

2. Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. National Marrow Donor Program-sponsored multicenter, phase II trial of HLA-mismatched unrelated donor bone marrow transplantation using post-transplant cyclophosphamide. J Clin Oncol. 2021;39(18):1971-1982. doi:10.1200/JCO.20.03502

3. Auletta D, Bo-Subait S, Madbouly D, et al. Addressing ethnically diverse patient representation in hematopoietic cell transplant clinical trials: insights gained through the ACCESS trial. Transplant Cell Ther. 2025;31(suppl):S52-S53. doi:10.1016/j.jtct.2025.01.083

4. Auletta JJ, Corrigan D, Bupp C, et al. Early immune recovery in mismatched unrelated donor peripheral blood stem cell transplantation using reduced-dose post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis: results from the OPTIMIZE trial. Presented at: 2026 EBMT Annual Meeting; March 22-25, 2026; Madrid, Spain. OS05-02.