Eprenetapopt (APR-246), a novel first-in-class mutant p53 reactivator, in combination with azacitidine was found to be well tolerated and yielded high clinical response and molecular remission rates in patients with TP53-mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML), according to the results of research published in the Journal of Clinical Oncology.

The phase 1b/2 study (ClinicalTrials.gov Identifier: NCT03072043) evaluated safety, recommended phase 2 dosing, and efficacy of eprenetapopt in combination with azacitidine in 55 adult patients with TP53-mutant MDS (n=40), AML (n=11), and MDS/myeloproliferative neoplasms (n=4).

Enrollment took place between May 2017 and February 2019, and all patients had been enrolled for at least 6 months at the point of data cutoff (November 15, 2019). No dose-limiting toxicities occurred during the dose-escalation phase of the study; thus, in phase 2, eprenetapopt was administered at a fixed dosage of 4500 mg/d with a standard azacitidine dosage (75 mg/m2 subcutaneously or intravenously for 7 days). The primary endpoint was complete remission.

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Overall, the median patient age was 66 years (range, 34-85 years). Following treatment, the overall response rate was 71%, with 44% of patients achieving complete remission. Overall response and complete remission rates were 73% and 50% in patients with MDS and 64% and 36% in patients with AML, respectively.

Patients with only TP53 mutations had higher rates of complete remission (69%) than those who also had complex karyotypes (25%; P = .006). Patients with responses showed significant reductions in TP53-variant allele frequency, with 38% achieving complete molecular remission.

Responding patients had a longer median overall survival compared with nonresponding patients (14.6 vs 7.5 months; P = .0005). Among all patients, 35% (19/55) underwent allogeneic hematopoietic stem cell transplantation and had a median overall survival of 14.7 months.

The adverse event profile of the combination treatment was similar to that reported for azacitidine and eprenetapopt monotherapies. The most common grade 3 or greater adverse events were febrile neutropenia (33%), leukopenia (29%), neutropenia (29%), thrombocytopenia (25%), and lung infection (25%), and the most common serious adverse events were febrile neutropenia (25%), lung infection (20%), respiratory failure (7%), and sepsis (7%). In total, 3 patients died due to causes not related to treatment (2 pneumonia and 1 sepsis).

“Together, these data support the ongoing pivotal phase 3, multicenter, randomized study

of eprenetapopt in combination with azacitidine versus azacitidine alone in patients with TP53-mutant MDS [(ClinicalTrials.gov identifier: NCT03745716)],” concluded the authors.

Disclosures: Some authors declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. Published online January 15, 2021. doi:10.1200/JCO.20.02341