Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

Abstract

PURPOSE:

TP53-mutated (TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.

PATIENTS AND METHODS:

This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients.

RESULTS:

Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset (P < .01) and higher age (P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.

CONCLUSION:

In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

• Authors: Thomas Cluzeau, Marie Sebert, Ramy Rahmé, Stefania Cuzzubbo, Jacqueline Lehmann-Che, Isabelle Madelaine, Pierre Peterlin, Blandine Bève, Habiba Attalah, Fatiha Chermat, Elsa Miekoutima, Odile Beyne Rauzy, Christian Recher, Aspasia Stamatoullas, Lise Willems, Emmanuel Raffoux, Céline Berthon, Bruno Quesnel, Michael Loschi, Antoine F Carpentier, David A Sallman, Rami Komrokji, Anouk Walter-Petrich, Sylvie Chevret, Lionel Ades, Pierre Fenaux
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 39 Issue 14 Pg. 1575-1583 (05 10 2021) ISSN: 1527-7755 [Electronic] United States
• PMID: 33600210 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Quinuclidines
• Tumor Suppressor Protein p53
• Azacitidine
• eprenetapopt

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Azacitidine (administration & dosage, adverse effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality)
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (drug therapy, genetics, mortality)
• Quinuclidines (administration & dosage, adverse effects)
• Tumor Suppressor Protein p53 (genetics)