Post-Transplant Cyclophosphamide and Unmet Needs in GVHD

Transcript:

Joseph H. Antin, MD: Post-transplant cyclophosphamide has really expanded in the last 5 to 10 years from being primarily used in haploidentical transplantation, to be more generally used in mismatched unrelated donor transplantation, and more recently in matched unrelated donor transplantation.

If you think about it, we developed methotrexate based on studies that were done by Rainer Storb, MD, and Don Thomas, MD, in the 1970s. And that basic framework has persisted for the past 30 or 40 years. Cyclophosphamide was not used initially because it was thought to be more myelotoxic. But the cool thing about cyclophosphamide is that it is not stem-cell toxic. That’s why we can mobilize stem cells from autologous transplantation off of a dose of cyclophosphamide.

It has the benefit of being very immunosuppressive but actually not stem-cell toxic. So they can be given in a large dose after stem cell infusion without inhibiting hematopoiesis.

There’s no real reason that one would particularly favor methotrexate over cyclophosphamide other than the fact that we’ve been using it for 30 or 40 years. But I think it’s quite likely, and as demonstrated in the plenary session talk this afternoon, and in a pick-the-winner phase 2 study done by the BMTCTN [Blood and Marrow Transplant Clinical Trials Network] that it will be at least as good, if not better, than methotrexate, when used in combination with a calcineurin inhibitor.

The holy grail in this business of course is doing a transplant in the absence of graph-versus-host disease with restoration of normal functional immunity, and maintain maintenance of a graph-versus-leukemia effect.

Whether we’re actually ever going to be able to catch all of those components and really have the fabled chalice in our hands I think is unknown. But that’s where we’re headed.

The mortality from graph-versus-host disease has progressively declined. I think we have a bigger armamentarium to treat graph-versus-host disease. We have a bigger armamentarium to prevent graph-versus-host disease. And so while there’s still a significant unmet need, there are still people who die of graph-versus-host disease, that number is starting to decline. I think what we need to devote our attention to, and increasingly, is leukemic relapse.

If you look at what’s happened in transplantation over the past decade or 2 decades, transplant-related mortality has been progressively been improving as we’ve gotten better at doing this. Leukemic relapse rates or lymphoma relapse rates have really not changed that much. And so what we really need to have going forward is a way of keeping the GvHD under control, but really targeting the leukemia so that overall survival will substantially improve.

Transcript Edited for Clarity