Faculty, Staff and Student Publications

Publication Date

7-1-2025

Journal

Hemasphere

DOI

10.1002/hem3.70164

PMID

40657305

PMCID

PMC12255903

PubMedCentral® Posted Date

7-13-2025

PubMedCentral® Full Text Version

Post-print

Abstract

TP53 gene mutations (mTP53) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR-246) is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in mTP53 cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents-naïve mTP53 higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1-4) + azacitidine 75 mg/m2 sc/iv × 7 days in 28-day cycles. The primary objective was the complete remission (CR) rate by International Working Group (IWG) 2006 criteria. In total, 100 patients were enrolled with a median age of 68 years (34-87; 47% male). Febrile neutropenia occurred in 37% of patients. Thirty- and 60-day mortality was 1% and 7%, respectively. By intention-to-treat, overall response rate by IWG was 69% with 41% CR. The median duration of CR was 10.2 months (95% CI 8.7-11.8). With a median follow-up of 52 months, median overall survival (OS) was 11.8 months (95% CI 9.4-14.3). Although allogeneic hematopoietic cell transplantation (allo-HCT) was borderline predictive of OS in the overall cohort by landmark analysis (14.7 vs. 14.4 months; P = 0.046), OS was significantly improved in allo-HCT patients based on CR/TP53 next-generation sequencing (NGS) negativity (P = 0.00085; 2-year OS of 54%). In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well-tolerated with synergistic response rates in mTP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HCT, validating NGS clearance as a critical biomarker of allo-HCT outcomes in mTP53 patients.

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.