Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

PURPOSE Outcomes are poor in TP53-mutant (m TP53) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), even after allogeneic hematopoietic stem-cell transplant (HCT). Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. PATIENTS AND METHODS We conducted a phase II, multicenter, open-label trial to assess efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT (ClinicalTrials.gov identifier: NCT03931291 ). Patients with m TP53 MDS or AML received up to 12 cycles of eprenetapopt 3.7 g once daily intravenously on days 1-4 and azacitidine 36 mg/m2 once daily intravenously/subcutaneously on days 1-5 in 28-day cycles. The primary outcomes were relapse-free survival (RFS) and safety. RESULTS Of the 84 patients screened for eligibility before HCT, 55 received a transplant. Thirty-three patients ultimately received maintenance treatment (14 AML and 19 MDS); the median age was 65 (range 40-74) years. The median number of eprenetapopt cycles was 7 (range 1-12). With a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable) and the 1-year RFS probability was 59.9% (95% CI, 41 to 74). With a median follow-up of 17.0 months, the median overall survival (OS) was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3). Thirty-day and 60-day mortalities from the first dose were 0% and 6% (n = 2), respectively. Acute and chronic (all grade) graft-versus-host disease adverse events were reported in 12% (n = 4) and 33% (n = 11) of patients, respectively. CONCLUSION In patients with m TP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population.

Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

“…Within those clinical trials, some results are promising. The use of eprenetapopt in patients diagnosed with hematologic malignancies and solid tumors has been proven safe [ 68 , 69 , 70 , 71 ], while, in another study, it was confirmed to give better results when combined with azacitidine [ 72 ], even greater than azacitidine alone [ 73 ], in patients with leukemias.…”

Ferroptosis in lymphoma: Emerging mechanisms and a novel therapeutic approach

“…Drugs targeting the p53-mediated ferroptosis pathway, including eprenetapopt (or APR-246) and kayadiol, are new research hotspots. APR-246 reactivates the transcriptional activity of the mutant p53 by promoting its binding to target genes, thereby showing efficacy in p53-mutated tumors ( Cluzeau et al, 2021 ; Mishra et al, 2022 ). APR-246 reactivates the transcriptional activity of mutant p53 by promoting their binding to its target genes and is effective in p53-mutated tumors ( Cluzeau et al, 2021 ; Mishra et al, 2022 ).…”

“…APR-246 reactivates the transcriptional activity of the mutant p53 by promoting its binding to target genes, thereby showing efficacy in p53-mutated tumors ( Cluzeau et al, 2021 ; Mishra et al, 2022 ). APR-246 reactivates the transcriptional activity of mutant p53 by promoting their binding to its target genes and is effective in p53-mutated tumors ( Cluzeau et al, 2021 ; Mishra et al, 2022 ). APR-246 can induce tumor protein p53 TP53-mutation-mediated cell death in DLBCL through ferroptosis by p53-dependent ferritinophagy ( Hong et al, 2022 ).…”

Eprenetapopt in the Post-Transplant Setting: Mechanisms and Future Directions

“…In the companion to this article, Mishra et al 9 evaluated the combination of eprenetapopt with azacitidine as maintenance therapy after ASCT for TP53 -mutant AML/MDS. This phase II trial enrolled 33 patients with TP53 -mutant AML/MDS with a median age of 65 years who underwent ASCT in at least a morphologic marrow remission or better.…”

“…14,18,19 Despite these encouraging results, the pivotal frontline phase III trial in TP53-mutant higher-risk MDS did not meet the prespecified primary end point despite an improved CR rate of 33% with eprenetapopt and azacytidine compared with a CR rate of 22% with azacytidine alone. 20 In the companion to this article, Mishra et al 9 evaluated the combination of eprenetapopt with azacitidine as maintenance therapy after ASCT for TP53-mutant AML/MDS. This phase II trial enrolled 33 patients with TP53-mutant AML/MDS with a median age of 65 years who underwent ASCT in at least a morphologic marrow remission or better.…”