Sallman on Eprenetapopt and Azacitidine in TP53-Mutant MDS/AML

David Sallman, MD, Moffitt Cancer Center, discusses the study design, objectives, and rationale behind using eprenetapopt and azacitidine together for the treatment of in patients with TP53-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-allogeneic stem cell transplantation.

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0:10 | We had a clinical trial actually published in [The Journal of Clinical Oncology], which was a maintenance clinical trial of azacitidine with eprenetapopt following stem cell transplantation. The results showed quite impressive outcomes, potentially supporting the development of a future phase 3 study.

0:30 | One big question was, could the analysis of TP53 MRD by deep sequencing, in this case, by duplex technology, further and better predict outcomes? [Currently,] there is very little data known in the transplant world about the impact of TP53 MRD.

0:48 | We [collected] bone marrow samples at multiple time points: before transplantation, after transplantation but prior to initiating therapy, and at standard disease assessment intervals—namely at day 100, 6 months, and 12 months. Using these samples, we evaluated the role of TP53 MRD in predicting whether patients would experience relapse within the context of this maintenance trial.

1:09 | TP53-mutant patients represent, really, the molecular subset with the poorest of outcomes across myelodysplastic syndromes and acute myeloid leukemia, plastic syndrome and acute myeloid leukemia. Long-term survival in these patients is only about 20%, regardless of age or fitness. This has sparked some debate about whether these patients should undergo stem cell transplantation. I believe they should, although there are cases where borderline performance status may raise legitimate questions about proceeding with the procedure.

1:39 | Novel strategies to reduce relapse risk in this group are urgently needed. Eprenetapopt is a first-in-class TP53 reactivator that has shown significant benefit when combined with azacitidine in several phase 1/2 clinical trials. Unfortunately, a pivotal phase 3 trial, while demonstrating improved complete remission rates, did not meet statistical significance. We are still awaiting the formal presentation and publication of these data.

2:05 | [Given these challenges], we conducted a maintenance trial using a slightly reduced dose from earlier studies but maintaining the same combination of eprenetapopt and azacitidine. This time, the focus was on using the regimen as a post-transplant maintenance strategy rather than as an initial treatment to improve patient outcomes.