Clinical Implications of the Phase III BMT CTN 1703 Trial

Transcript:

Corey Cutler, MD, MPH FRCPC: ASH [American Society of Hematology annual meeting] has come and gone. We all saw the results of the BMT CTN 1703 trial, the PROGRESS 3 trial. We now need to decide what we’re going to do. Yi-Bin, why don’t you briefly review what that trial was and tell us about the major results, and then we’ll go around the table and see how that’s going to change our practice.

Yi-Bin Chen, MD: PROGRESS 3, also known as CTN 1703, is a phase 3 randomized trial in reduced-intensity transplantation. The eligible population were donors who were either fully matched, related or unrelated, or had a single antigen mismatch. Although, the vast majority of patients enrolled were recipients of fully matched transplants and used peripheral blood stem cells as the graft source. Again, these were all reduced-intensity conditioning regimens and had hematological malignancies as their diagnosis. The randomization was to figure out if a post-transplant cyclophosphamide [PTCy]-based GVHD [graft versus host disease] prophylaxis regimen was inferior or superior to what had been the standard for years, which was tacrolimus and methotrexate. This was a 1:1 randomization, and the primary end point was a composite event-free survival end point called GRFS, or graft versus host disease relapse-free survival, where the events were death, relapse of the underlying disease, severe grade 3 to 4 acute GVHD, or chronic GVHD requiring the initiation of systemic immunosuppression.

What we saw in the results was that patients treated with post-transplant cyclophosphamide had a significantly higher 1-year GRFS rate than those treated with traditional tacrolimus-methotrexate. The differences were driven mainly by less severe acute GVHD and less chronic GVHD requiring systemic treatment. Overall rates of nonrelapse mortality were similar. Overall rates of disease relapse were similar, and there weren’t any big differences in progression-free or overall survival. Based on those results, many in the community have suggested that post-transplant cyclophosphamide with tacrolimus and mycophenolate should become the standard of care in a reduced-intensity transplant setting when using a fully matched, related or unrelated donor.

Corey Cutler, MD, MPH FRCPC: Speak on behalf of your colleagues, Hannah. Tell us how the results of this trial are going to change medical practice at your center.

Hannah K. Choe, MD: The clearest decision point would be that for reduced intensity and fully matched donors, PTCy can be employed. Expanding that to myeloablative [cases] is not as clear. There are very few data supporting the myeloablative [setting]. For those, we’ll still lean toward probably tacrolimus and methotrexate versus a clinical trial. A clinical trial, if given the option, would be No. 1. Then, for haploidenticals, which we are increasingly doing, PTCy remains the gold standard. So I do think it will be adopted very quickly.

Corey Cutler, MD, MPH FRCPC: I agree. Now, why don’t you tell us about the myeloablative setting because the PROGRESS 2 trial, which involved a therapeutic arm that was based on the Memorial Sloan Kettering [Cancer Center] regimen, had very different results. Doris, you want to tell us about the standards in ablative transplant and whether PTCy is going to change care there?

Doris M. Ponce, MD: That’s a good question. In terms of those results, the primary end point of the study was chronic rapid disease-free survival [CRFS]. In that primary end point, the CD34-selected arm was inferior compared with standard of care and PTCy. Based on that, we are having conversations about what triggered an inferior CRFS in these patients, even though the rate of chronic rapid disease is significantly lower. Some of it has to do, looking into our data, with infection risk and immune reconstitution. At Sloan Kettering, we are introducing and using more widely, and we’ll probably extend more PTCy. We’re using it more comfortably in mismatched unrelated donors. In the matched setting, we are looking for strategies on how to customize ATG [antithymocyte globulin]. The CD34-selected [setting] does have a platform that includes ATG. We’re now doing ATG by PK [pharmacokinetics], and we think that could improve the risk of delayed immune reconstitution and infection. It’s still a platform that we haven’t abandoned. We think we can enhance that because…it’s a CNI [calcineurin inhibitor]-free regimen. It won’t be abandoned, I think there will be a TCD [T-cell depletion] 2.0.

Corey Cutler, MD, MPH FRCPC: You mentioned ATG, or antithymocyte globulin. It’s used very commonly in Canada, it’s used extensively in Europe. It’s not used as much in the United States outside of aplastic anemia. Why do you think it’s not used, and do you think there is a role for it in standard transplants in the United States?

Hannah K. Choe, MD: At Ohio State [University] it was eliminated a few years back and taken out completely. The concern for ATG is the risk of infections and viral infections. The upfront benefit with it…it’s advertised for acute GVHD, but the benefit comes with chronic GVHD. Now, what may be interesting to see over the course of time here is with less severe acute GVHD, are we going to be seeing as much chronic GVHD anyway? The use of ATG may become less over time with that adoption, with that culture shift.

Corey Cutler, MD, MPH FRCPC: It’s important to mention abatacept in this setting as we talk about GVHD prevention regimens. It is the only drug that’s approved in the prophylaxis setting. It was approved on the basis of the ABA2 trial, which was a combination of an open-label phase 2 study in mismatched unrelated donor transplant, where it had very promising data in comparison to a historical control. The data were less strong in [8/8 matched] transplantations in a truly prospective randomized trial. Do you use it at [Massachusetts General Hospital] for standard of care, either in the mismatched setting or in the matched unrelated setting?

Yi-Bin Chen, MD: We don’t use it routinely. As you mentioned, the big difference seemed to be in the mismatched unrelated donor setting. For the last several years, our standard prophylaxis regimen for that donor source was post-transplant cyclophosphamide. We’ve had great success with that, as have others, as what’s been published, and so it’s difficult to stray. The other issue is the abatacept trials didn’t show any decrease in the incidence of significant chronic graft versus host disease. There are ongoing trials with a longer course of abatacept, which we’re participating in, in the mismatched unrelated donor setting and so forth, to try to figure that out. As the community shifts more toward the prevention of chronic GVHD as a priority, it would make testing other regimens more important.

Corey Cutler, MD, MPH FRCPC: That’s the ABA3 trial you’re referring to that’s ongoing, which randomizes to short versus long course abatacept. There was an interesting abstract presented by Leslie Kean, [MD, PhD,] looking at historical data from the CIBMTR [Center for International Blood and Marrow Transplant Research] in comparison to the prospective abatacept data. The abatacept data looked promising even against PTCy, but I don’t think any of us would take historically controlled data against a prospective cohort and call that definitive quite yet.

Transcript edited for clarity.