Photomicrograph of bone marrow aspirate showing myeloblasts of AML: © David A Litman – stock.adobe.com
Historically, finding a fully matched unrelated donor has been a significant challenge, particularly for patients from racially and ethnically diverse backgrounds. A White patient has about a 75% chance of finding a fully matched unrelated donor in the US NMDP Registry, while a person of any other ethnicity (Black, Hispanic, Asian, Pacific Islander, or Native American) has a chance closer to 30 to 40%.
NMDP-led research, particularly the Donor for All initiative, aims to overcome these disparities. The ACCESS trial, for example, has significantly expanded access to curative therapy for patients who historically had limited or no donor options by demonstrating the safety and efficacy of mismatched unrelated donors.1,2
With novel approaches like posttransplant cyclophosphamide (PTCy) and using 7/8 or fewer HLA-matched donors, the probability of finding a donor increases to 75% to 95% for any ethnicity, effectively meaning every patient can have a “match.”
In an interview with Targeted Oncology, Steven Devine, MD, chief medical officer at NMDP and senior scientific director at the Center for International Blood and Marrow Transplant Research (CIBMTR), discussed the ACCELERATE trial, which builds off the previous successes of the Donor for All initiative and continues the mission to expand access to life-saving cell therapies for blood cancers and disorders.
Targeted Oncology: What is the purpose of the ACCELERATE trial?
Steven Devine, MD: The broad overview is that allogeneic blood or marrow transplantation is curative for many advanced hematologic malignancies like acute leukemia, but graft-vs-host disease has been a long-standing barrier to allowing access to transplantation for more patients, particularly patients who might not have a perfect match. There is a disparity in access to fully matched transplants that affects racially and ethnically diverse patients more than non-Hispanic Whites.
Our group has been testing a drug called cyclophosphamide that’s been around since the 1950s, but it was repurposed in the early 2000s to prevent graft-vs-host disease, or GVHD, and it’s been a game-changer. It’s reduced the rates of graft-vs-host disease for patients, regardless of whether their donor is matched or less than fully matched. That’s allowed access to transplantation for patients who are historically excluded, but it does cause problems. While graft-vs-host disease has been reduced, it still leads to infections and other [adverse] effects for patients.
What ACCELERATE is trying to do is actually make transplant safer and more accessible to all patients by taking the benefits of the cyclophosphamide, which is prevention of graft-vs-host disease, but trying to make it safer through combinations with other potentially less toxic drugs.
Could you describe the study design?
The study uses a what’s called a platform study design, which, per se, is not unique in that the clinical trial design has been around a long time, particularly in oncology. But it’s never been applied to transplantation for the prevention of graft-vs-host disease. The idea of using that platform design to more efficiently test strategies that might make transplants safer.
How does ACCELERATE build off past trials like ACCESS?
The ACCESS trial is key to understanding why we’re moving to the ACCELERATE trial. ACCESS, I think, was a great success. It enrolled 300 patients, including 32 pediatric [patients]. We have the results back in all the adult patients. And lo and behold, using the posttransplant cyclophosphamide, the outcomes in terms of overall survival and prevention of severe forms of graft-vs-host disease [in patients with mismatched donors] were very similar to what we would expect would fully matched transplants, which really means that we have provided access to curative transplant for all patients, regardless of their ancestry.
The problem was that roughly two-thirds of patients on the ACCESS trial experienced a serious infection in the first 100 days, and that obviously causes [adverse] effects and the use of more antibiotics. What we’re now trying to do is to see if we can get the good aspects of cyclophosphamide, which is preventing GVHD, but lower the [adverse] effects and have fewer infections and less need for steroids, which can cause all their other problems as well.
ACCESS, though, will form the backbone. We think ACCESS is now the standard of care for patients undergoing mismatched, unrelated donor transplants, and so that will serve as the control group for the ACCELERATE study, and then the combinations of the reduced-dose posttransplant cyclophosphamide will be then compared to that control group.
What are you most excited to learn from this study?
I’m really interested in learning if we can have our cake and eat it too. Patients can get all the benefit from the posttransplant cyclophosphamide, in terms of not having a high risk of graft-vs-host disease, but if it can be safer, so that they don’t have as many infections, and they have a better overall quality of life because they’re not on steroids or other drugs to prevent [adverse] effects. The great thing about ACCELERATE is it’s our first foray into randomized studies, and so we’ll really be able to make cleaner comparisons between the new interventions and the standard of care, which is the ACCESS study, and hopefully, with the design, we’ll learn faster. If certain interventions aren’t working, we’re able to retire them and move new ones in as the science evolves. I like that aspect. It’s faster, cleaner, and more efficient for patients in the transplant centers.