Latest Updates in Graft-Versus-Host Disease Prophylaxis

Shernan Holtan, MD, University of Minnesota, Minneapolis, Minnesota, explores the most recent data and clinical trials in terms of graft-versus-host-disease (GVHD) prophylaxis and transplantation.

Transcript:

I'm Shernan Holtan, associate professor of medicine at the University of Minnesota. My focus is on graft-versus-host disease research.

Let's talk about updates in graft-versus-host disease prophylaxis. Recently, the Blood and Marrow Transplant Clinical Trials Network completed a phase 3 clinical trial of tacrolimus and methotrexate —basically, the combination that we've been using for decades for GVHD prophylaxis— compared to post-transplant cyclophosphamide/tacrolimus and [mycophenolate mofetil] (MMF). This was in the setting of reduced-intensity transplants. Grafts were well-matched peripheral blood stem cell grafts.

In that phase 3 study, we showed significant reduction in acute and chronic graft versus disease with the post-transplant cyclophosphamide arm, but no increase in the risk of relapse or fatal complications. This means that the composite endpoint of graft versus host disease-free relapse-free survival was significantly better in the post-transplant cyclophosphamide arm. And this is the first time we've seen such a significant difference in these rates of acute and chronic graft-versus-host disease, without paying for it with other toxicities, that this is leading to a paradigm shift in our field. 

We're seeing the use of post-transplant cyclophosphamide in well-matched transplants significantly increase around the country, and even around the world. Now, this is an important development, because we see low rates of acute and chronic graft-versus-host disease with post-transplant cyclophosphamide. This differs from some recent studies that have been done with abatacept, which is also a very important development in our field. It's the first ever FDA-approved drug for the prevention of acute graft-versus-host disease, but this drug does not prevent chronic graft-versus-host disease, which is a limitation.

Now, there is a limitation potentially with post-transplant cyclophosphamide (PTCy), in pediatric transplantation specifically. In the myeloablative setting, we, at the University of Minnesota, recently published outcomes of myeloablative transplantation with well-matched donors using post-transplant cyclophosphamide, and we included children and adults in that study. And adults had, again, excellent outcomes, in terms of graft-versus-host disease control, but the relapse rate was about 30% at 2 years. It was significantly higher in the pediatric population, with a relapse rate of up to about 50% at 2 years in pediatrics. So even though we have very low rates of acute and chronic graft-versus-host disease with PTCy, in myeloablative transplantation as well, the relapse rate in pediatric patients is giving some people pause.

My personal opinion is that, perhaps this is showing that abatacept may be best used in a pediatric setting, where there is already a lower risk of chronic graft-versus-host disease. This is just my personal opinion. Based upon the data that's available, I think we clearly have more to go, in terms of developing the optimal GVHD prophylaxis regimen, that not only doesn't interfere with the graft-versus-leukemia effect, but can potentially enhance it as well. 

What we're doing at Minnesota is a study right now where we substitute a new drug that actually has anti-leukemia activity for MMF in a PTCy platform. Specifically, we're studying post-transplant cyclophosphamide, sirolimus, and an Aurora kinase A inhibitor, instead of MMF, to see if we can both keep GVHD rates really low, but also reduce the risk of relapse. This is really the remaining unmet need in allogeneic transplantation.

Source: 

Bolaños-Meade J, Hamadani M, Wu J, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. New Eng J Med. Published online June 22, 2023. doi:10.1056/nejmoa2215943