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. 2025 Jul 13;9(7):e70164.
doi: 10.1002/hem3.70164. eCollection 2025 Jul.

Long-term follow-up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML

David A Sallman  1 , Rami S Komrokji  1 , Amy E Dezern  2 , Marie Sebert  3   4 , Guillermo Garcia-Manero  5 , Ramy Rahmé  3   4 , Eric S Winer  6 , Jacqueline Lehmann-Che  7 , Gail J Roboz  8 , Isabelle Madelaine  7 , Mikkael A Sekeres  9 , Pierre Peterlin  3   10 , Onyee Chan  1 , Odile Beyne-Rauzy  3   11 , Andrew Kuykendall  1 , Christian Recher  3   11 , Amy McLemore  1 , Aspasia Stamatoullas  12 , Ling Zhang  1 , Lise Willems  3   13 , Qianxing Mo  14 , Emmanuel Raffoux  3   4 , Lisa Nardelli  1 , Céline Berthon  3   15 , Najla H Al Ali  1 , Bruno Quesnel  3   15 , Eric Padron  1 , Hagop M Kantarjian  5 , Alan F List  16 , Lionel Ades  3   4 , Jeffrey E Lancet  1 , Pierre Fenaux  3   4 , Thomas Cluzeau  3   17
Affiliations

Long-term follow-up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML

David A Sallman et al. Hemasphere. .

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.

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Conflict of interest statement

David A. Sallman reports research funding from Aprea Therapeutics and consulting and/or other AbbVie, Agios, Akesobio, Avencell Europe GmbH, Bluebird Bio, BMS, Geron, Gilead Sciences, Janssen Global Services, Jazz Pharmaceuticals, Kite Pharma, Molecular Partners AG, Novartis, Servier Pharmaceuticals, Shattuck Labs, Syndax Pharmaceuticals, Syros Pharmaceuticals, and Takeda Pharmaceutical. Rami S. Komrokji consulting and/or other fees from AbbVie, Acceleron Pharma, Agios Pharmaceuticals, Alexion Pharmaceuticals, BMS, Celgene, CTI Biopharma, Daiichi Sankyo, Geron, Janssen Biotech, Jazz Pharmaceuticals, Novartis Pharma, Pfizer, PharmaEssentia, Servier Pharmaceuticals LLC, Taiho Oncology, and Takeda Oncology. Amy E. Dezern consulted for Taiho; received honoraria from BMS, Novartis, and Gilead; and served as chair of a data safety monitoring board for Geron. Guillermo Garcia‐Manero consulted for Acceleron; received honoraria and research funding from AbbVie, Astex, Bristol Myers Squibb, Curis, Genentech, and Novartis; received honoraria from Aprea; and received research funding from Gilead. Eric S. Winer has served on advisory boards for Novartis, Takeda, and Curis. Gail J. Roboz consulted or served on advisory boards or data and safety monitoring committees for AbbVie, Actiunuim, Agios, Amgen, Astellas, AstraZeneca, Bluebird, Blueprint, Bluebird Bio, BMS, Catamaran, Celgene, Daiichi, GSK, Helsinn, Janssen, Jasper, Jazz, Mesoblast, Novartis, Pfizer, Roche, Syndax, Takeda, and Trovagene and received research support from Janssen. Mikkael A. Sekeres has received advisory board fees from Geron Corporation, BMS/Celgene, Novartis, and Kurome. M.A.S. received research funding from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; consults or serves on advisory or data safety monitoring boards for AbbVie, BMS/Celgene, Forma, Geron Corporation, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, and TG Therapeutics; and has equity in Karyopharm and Ryvu. Onyee Chan reports honoraria for consulting from Bristol Myers Squibb (BMS) and research funding from Jazz Pharmaceuticals. Andrew Kuykendall reports consulting and/or other fees from AbbVie, Blueprint Medicines, Celgene, Constellation, CTI Biopharma, Incyte, Novartis, Prelude, Protagonist, and Sierra Oncology; grant funding from BMS, Constellation, Novartis, Prelude, Protagonist, and Sierra Oncology. Eric Padron consulting and/or other fees from Blueprint Medicines, Novartis, and Taiho Oncology. Hagop M. Kantarjian received grants from AbbVie, Amgen, Ascentage, BMS, Daiichi‐Sankyo, Immunogen, Jazz, and Novartis and received honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen, KAHR, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda. Alan F. List is employed by and has equity in Precision BioSciences and has served as a consultant for Halia Therapeutics, CTI Biopharma, and Aileron. Jeffrey E. Lancet reports consulting and/or other fees from AbbVie, Boxer Capital, BMS, Jasper Therapeutics, Jazz Pharmaceuticals, Novartis Pharma, and Servier Pharmaceuticals. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Outcomes to treatment with APR‐246 + azacitidine. (A) Overall survival based on intention‐to‐treat for the combined Phase 2 cohorts. (B). Landmark analysis of responders and nonresponders at 6 months in patients who achieved complete remission (CR) and/or TP53 negativity (variant allele frequency < 5%).
Figure 2
Figure 2
(A) Overall survival (OS) based on landmark analysis at 6 months in patients based on bone marrow transplantation (BMT) status. (B) OS based on landmark analysis at 6 months based on BMT status and achievement of complete remission (CR) and/or TP53 negativity (variant allele frequency < 5%).
See this image and copyright information in PMC

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