Eprenetapopt Plus Azacitidine in TP53 -Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM)
Open accessAbstract
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.
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Hematological and neurological toxicities, as well as impaired renal function, have been reported in patients receiving eprenetapopt.
“Hematological and neurological toxicities, as well as impaired renal function, have been reported in patients receiving eprenetapopt (3, 4)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [3]
The Results (Safety; page not available) report hematologic toxicities and neurologic adverse events in patients receiving eprenetapopt plus azacitidine. They do not establish impaired renal function as a treatment toxicity: lower kidney function was associated with neurologic events, and the one reported case of renal failure was attributed to antibiotics. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBoth phase 1 clinical trials demonstrated that patients who responded to eprenetapopt and azacitidine had significantly improved overall survival compared to nonresponders.
“Both phase 1 clinical trials demonstrated that patients who responded to eprenetapopt and azacitidine had significantly improved overall survival compared to nonresponders (3, 4)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [3]
The Results > Survival section (page unavailable) reports significantly longer overall survival in responders than nonresponders (15.6 versus 3.8 months; P < .0001). But this source reports that finding from its own phase II trial, not a phase 1 trial, and it does not establish the finding for both trials named in the citing sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredKnowing CIP2A status in recurrent ovarian tumors may help predict clinical response to APR-246.
“These results indicate that diagnostic identification of CIP2A status in recurrent OvCa tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246 currently in clinical development (22,23).”
From Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype (2022) · cites this paper as [22]
In a drug screen comparing HEY control and CIP2A-silenced cells, APR-246 was the most apparent sensitizer, reducing viability by more than 50% in CIP2A-silenced cells while control cells were practically insensitive.
“The most apparent sensitization effect was observed with APR-246 (PRIMA-1Met/Eprenetapopt) (15,19–22). Whereas HEY-CTLshRNA cells were practically insensitive to APR-246, HEY-CIP2AshRNA cells showed a >50% reduction in cell viability (Fig. 1A).”
From Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype (2022) · cites this paper as [22]
The paper previously reported Phase 2 results of two parallel trials of APR-246 + AZA with similar improvements in CR rates and favorable outcomes versus historical cohorts.
“We previously reported the Phase 2 results of two parallel trials of APR‐246 + AZA with similar improvements in CR rates and favorable outcomes versus historical cohorts.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [26]
The seven patients with >30% blasts included in GFM had very poor outcomes (0% CR, OS of 3 months).
“Although only seven patients with >30% blasts were included in the study by the GFM, this group had very poor outcomes (0% CR, OS of 3 months).”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [26]
APR-246 has been studied in a clinical trial in ovarian cancer and showed promising clinical activity in a recent phase II trial in acute myeloid leukemia.
“APR-246 (Eprenetapopt) has been studied in clinical trial in OvCa (19), and it showed promising clinical activity in a recent phase II trial in acute myeloid leukemia (AML) (18).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [18]
Currently, APR-246 is studied in clinical trials in AML and myelodysplastic syndromes, and in various other solid cancer types.
“Currently, APR-246 is studied in clinical trials in AML and myelodysplastic syndromes (18), and in various other solid cancer types (https://www.clinicaltrials.gov).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [18]
Diagnostic identification of CIP2A low status in human recurrent ovarian cancer tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246.
“These results indicate that diagnostic identification of CIP2A low status in human recurrent OvCa tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246 currently in clinical development (18,19).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [18]
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References 23 · Cited by 279
- Authors
- Cluzeau, T., Sebert, M., Rahmé, R., Cuzzubbo, S., Lehmann-Che, J., Madelaine, I., Peterlin, P., Bève, B., Attalah, H., Chermat, F., Miekoutima, E., Rauzy, O. B., Recher, C., Stamatoullas, A., Willems, L., Raffoux, E., Berthon, C., Quesnel, B., Loschi, M., Carpentier, A. F., Sallman, D. A., Komrokji, R., Walter-Petrich, A., Chevret, S., Ades, L., & Fenaux, P.
- Affiliations
- Inserm (FR)
- GFM
- Assistance Publique – Hôpitaux de Paris (FR)
- Pharmacy Department, Hospital Saint Louis, APHP, Paris, France
- Grupo de Física Matemática (PT)
- Centre Henri Becquerel (FR)
- Hôpital Cochin (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Moffitt Cancer Center (US)
- SBIM, Hospital Saint Louis, APHP, and Paris University, Paris, France
- Hôpital Saint-Louis (FR)
- Corresponding author
- Fenaux, Pierre
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2021-05-10
- Volume
- 39
- Issue
- 14
- Pages
- 1575-1583
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC8099409
- OpenAlex
- W3131928636
- Cited by
- 279
- References
- 23
- Citations by year
- 2026: 30 · 2025: 44 · 2024: 38 · 2023: 65 · 2022: 65 · 2021: 32 · 2020: 1 · 2012: 1
- FWCI
- 32.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-18-IBHU-0003)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- APR-246, azacitidine, TP53 mutation, myelodysplastic syndrome, acute myeloid leukemia, p53 reactivation, combination therapy, complete remission, variant allele frequency, febrile neutropenia, neurological adverse events, overall survival, very high-risk patients
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Humans, Middle Aged, Mutation, Myelodysplastic Syndromes, Quinuclidines, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53
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