Thread by @NicoGagelmann

Long awaited study (at least for me) on maintenance after hematopoietic cell transplant (BMT) for patients with TP53 acute myeloid leukemia (AML) or myeloid dysplastic syndrome (MDS) @JCO_ASCO ascopubs.org/doi/full/10.12…
Congrats to all !
It's a tricky one. A🧵#leusm #bmtsm #mdssm

Prologue: TP53 mutation is present in ~15-20% and is associated with a poor prognosis in AML and MDS, even in patients who undergo BMT. acsjournals.onlinelibrary.wiley.com/doi/10.1002/cn…

Eprenetapopt is a prodrug, small-molecule p53 reactivator, converted into an active moiety, 2-methylene quinuclidine-3-one, stabilizing p53 and targets cellular redox balance to increase oxidative stress & induce cell death.

Synergistic activity with azacitidine in preclinical study provided the rationale for combination studies with eprenetapopt in patients with myeloid malignancies.

However, so far, azacitidine did not show significant benefit as single agent maintenance strategy after BMT!

Given the suggested activity of eprenetapopt plus azacitidine in the clinical setting, authors conducted a phase II study to assess the efficacy and safety of eprenetapopt in combination with azacitidine as maintenance therapy after BMT in patients with TP53 mutated AML or MDS.👇

First important fact: patient selection for analysis👇
84 patients were screened, of whom 55 actually received BMT (65%). Of those, 33 were enrolled and treated with eprenetapopt plus azacitidine. These 33 patients are analyzed.

A selection of a selection of a selection.

The median age was 65 (range 40-74) years, 14 patients had AML and 19 had MDS, and most (67%) received a reduced intensity conditioning regimen. Many patients (64%) were in complete remission at time of BMT and and 79% already received hypomethylating agent before BMT.

As a reminder: analyzed are patients that made it to maintenance 33/84. Until then 2 deaths are reported, although rate likely higher because many were excluded with active disease.

Median follow-up was 17 months, median overall survival was 21 months, 79% at 1 year.

Non-relapse mortality was impressively low with 4% at 1 year.

Supplement shows no difference in overall outcome between MDS and AML.

Safety: mostly hematologic adverse events, 36% having grade 3 or higher thrombocytopenia or leukopenia; 27% with serious anemia or neutropenia, respectively. 1 case of nonhematologic serious adverse event, i.e. abdominal pain. Otherwise any grade nausea (61%), vomiting (46%)...

Exploratory analyses has caveat: only 29/33 analyzed patients had samples ready to analyze and 24/29 had detectable TP53 before BMT.
No significant correlation between allele frequency of pre-BMT TP53 allele with completion of treatment or overall outcome.

Author conclusion: maintenance with eprenetapopt+azacitidine in high-risk population with TP53 AML/MDS led to favorable survival, supporting exploration of this maintenance strategy in a phase III, randomized study of eprenetapopt+azacitidine vs placebo+azacitidine.

Thread conclusion:
-important effort
-highly selected population (as credited in Discussion) will increase selection bias in prospective studies with risk to skew results in favor of treatment arm (need to be accounted for)
-why does it work when TP53 dynamics dont play a role?

End of thread. Congrats to the group and happy to receive comments and suggestions from experts in the field. We all hate TP53, let's fight this beast together! #bmtsm #leusm #mdssm