Dr Hamilton Talks Tacrolimus Plus Mexotrexate With or Without Mycophenolate Mofetil for GVHD

Betty Hamilton, MD, shares results of a randomized non-inferiority trial comparing tacrolimus/methotrexate versus tacrolimus/reduced-dose methotrexate and mycophenolate mofetil for the prevention of GVHD after myeloablative-related and -unrelated allogeneic hematopoietic cell transplantation (HCT). These findings were presented at the 2021 Annual ASH Meeting.

Transcript

Hi. My name is Betty Hamilton. I'm an associate professor at the Cleveland Clinic. I'm currently the Interim Director of our Blood and Marrow Transplant Program. As many in the transplant field know, graft-versus-host disease is a major cause of morbidity and mortality after allogeneic transplant.

Tacrolimus and methotrexate is a graft-versus-host disease approach that has been considered standard over the last many decades, however, associated with a lot of severe toxicities, including mucositis.

In the transplant and GVHD fields, there have been many attempts to find a regimen that is better than tacrolimus/methotrexate and has less toxicity. However, as of yet, particularly in the myeloablative transplant setting, there hasn't been an approach that has been shown to be superior.

This trial was aiming to find something that was better tolerated and potentially just as effective, if not more effective. This was a prospective randomized trial of standard doses of tacrolimus and methotrexate compared to tacrolimus, a reduced-dose of methotrexate, and mycophenolate mofetil.

The aims of this was to compare the two groups specifically in the outcomes of acute graft-versus-host disease as well as other toxicities, specifically mucositis and other end-organ toxicities, like lung, liver, and kidney.

The study aimed to compare the two arms of tacrolimus/methotrexate and tacrolimus and reduced-dose methotrexate and mycophenolate mofetil, comparing them in regards to mucositis, organ toxicities, and acute graft-versus-host disease.

We also looked at things like survival and chronic graft-versus-host disease, but the primary aims were to look at grade 2-4 acute GVHD as well as mucositis and other toxicities.

What we found was that there was no difference between the two groups in regards to grade 2-4 acute graft-versus-host disease and that there was significantly less toxicity in the reduced-dose methotrexate arm, specifically, again, in regards to mucositis, liver toxicity, lung toxicity, and kidney toxicities.

Although I suspected that the reduced-dose methotrexate would certainly lead to less mucositis and potentially similar outcomes, the degree to which it also led to a significant reduction in other toxicities, like respiratory failure, ICU stays, kidney dysfunction, and liver dysfunction, that was actually, the extent to which it was much better tolerated.

It was a little bit surprising, even to the point where there was actually a trend towards decreased non-relapse mortality in that group.

At least at our institution in our program, we're discussing a change to our standard practice to use more of a reduced-dose methotrexate regimen. When I presented this at ASH, there are some centers that already used a little bit of a reduced-dose methotrexate.

I think this is the only study that is a prospective randomized study that really showed that there doesn't seem to be a difference between acute grade 2-4 acute GVHD but also significantly less toxicities.

The field of transplant and graft-versus-host disease, there's a lot of new approaches and exciting new novel regimens that are being used, for example, post-transplant Cytoxan. There was recently an FDA-approved treatment for the prevention of acute GVHD as well.

A potential next research question is whether a reduced-dose methotrexate with a calcineurin inhibitor, is that as effective as some of these other novel approaches?