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.

Trial registration: ClinicalTrials.gov NCT03588078.

Conflict of interest statement

Thomas CluzeauConsulting or Advisory Role: Abbvie, Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche, Takeda, Syros PharmaceuticalsSpeakers' Bureau: Novartis, Amgen, Sanofi, Astellas PharmaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Pfizer, Sanofi Jacqueline Lehmann-CheConsulting or Advisory Role: AstraZeneca, Roche Pierre PeterlinConsulting or Advisory Role: Jazz Pharmaceuticals, Abbvie, Astellas Pharma, Daiichi Sankyo/Lilly Odile Beyne RauzyTravel, Accommodations, Expenses: Novartis Christian RecherConsulting or Advisory Role: Roche, Pfizer, Incyte, Novartis, Otsuka, Astellas Pharma, Daiichi Sankyo, Macrogenics, Janssen, Abbvie, Jazz Pharmaceuticals, Amgen, CelgeneResearch Funding: Abbvie, Roche, MaaT Pharma, Daiichi Sankyo, Agios, Chugai Pharma, Astellas Pharma, Jazz Pharmaceuticals, Novartis, Amgen, CelgeneTravel, Accommodations, Expenses: Gilead Sciences, Daiichi Sankyo, Novartis, Amgen, Celgene, Sanofi, Incyte Aspasia StamatoullasHonoraria: CelgeneConsulting or Advisory Role: TakedaTravel, Accommodations, Expenses: Pfizer Lise WillemsHonoraria: Abbvie, Janssen, Novartis Emmanuel RaffouxTravel, Accommodations, Expenses: Abbvie, Roche Bruno QuesnelResearch Funding: Daiichi Sankyo Europe GmbH Michael LoschiConsulting or Advisory Role: Astellas Pharma, Iqone, NovartisTravel, Accommodations, Expenses: Novartis/Pfizer, MSD Antoine F. CarpentierStock and Other Ownership Interests: AltevaxHonoraria: Gilead SciencesConsulting or Advisory Role: Bristol-Myers Squibb David A. SallmanConsulting or Advisory Role: Syndax, Novartis, Magenta Therapeutics, Kite Pharma, Intellia Therapeutics, Gilead Sciences, Bristol-Myers Squibb, Aprea AB, Abbvie, Celyad, AgiosSpeakers' Bureau: Bristol-Myers Squibb, Incyte, AgiosResearch Funding: Jazz Pharmaceuticals, CelgenePatents, Royalties, Other Intellectual Property: Intellectual Property Patent for LB-100 in MDS Rami KomrokjiStock and Other Ownership Interests: AbbvieConsulting or Advisory Role: Acceleron Pharma, Abbvie, Geron, Jazz Pharmaceuticals, Bristol-Myers Squibb, Incyte, NovartisSpeakers' Bureau: Bristol-Myers Squibb, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Incyte Lionel AdesResearch Funding: CelgeneHonoraria: Novartis, Silence Therapeutics, BerGenBio, Jazz Pharmaceuticals, Abbvie, Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: CelgeneNo other potential conflicts of interest were reported.

Figures

FIG 1.

Spectrum of TP53 mutations in all patients (N = 52) at baseline. CR, complete remission; CRi, CR with incomplete count recovery; DBD, DNA binding domain; HI, hematologic improvement; mCR, marrow CR; NE, not evaluable; PR, partial remission; PRD, proline-rich domain; REG, C-terminal regulatory domain; SD, stable disease; TAD, transactivation domain; TET, tetramerization domain.

FIG 2.

OS (A) in the overall population, (B) in MDS and AML, (C) in patients who received at least three cycles, and (D) in responders versus nonresponders. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; OS, overall survival.

FIG 3.

Co-occurring somatic mutations.

FIG A1.

Correlation between response and presence or absence of comutation or biallelic mutation. Correlation between CR and presence or absence of comutation or biallelic mutation. CR, complete remission.

FIG A2.

Correlation between dose reduction and age.