Eprenetapopt Survival Benefit Seen in Patients With TP53-Mutant AML

The novel, first-in-class, small molecule prompted high rates of clinical response and molecular remission in patients with oligoblastic acute myeloid leukemia (AML).

Patients with TP53-mutant oligoblastic acute myeloid leukemia (AML) responded favorably to combination treatment of eprenetapopt (APR-246) and azacitidine in a phase 1B/2 open-label, multicenter, dose-escalation, dose-expansion study. Results were recently published in Journal of Clinical Oncology.

Benefits were also seen among patients with TP53-mutant myelodysplastic syndromes (MDS), and the adverse event (AE) profile—grade 3 or higher febrile neutropenia (33%), leukopenia (29%), neutropenia (29%), and thrombocytopenia and lung infection (25% each) were the most common AEs—was similar to those seen with either eprenetapopt or azacytidine monotherapies.

The investigators were looking to see if they could improve survival outcomes among the patients with a complete remission (CR) rate below 20% who have de novo AML or MDS. Eprenetapopt, the authors note, induces cell death in TP53-mutant cancers.

“Approximately 20% of patients with TP53-mutant myelodysplastic syndromes achieve complete remission (CR) with hypomethylating agents,” the authors noted. “Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells.”

In this study, a cohort of 55 patients (median age, 66 [range, 34-85] years; 53% female; 58% ≥ 65 years; 67% classified as very high risk via revised International Prognostic Scoring System criteria) were observed following treatment with eprenetapopt plus azacitidine. There were 11 cases of AML, 40 of MDS, and 4 of MDS/myeloproliferative neoplasms. All had at least 1 TP53 mutation and were enrolled between May 2017 and February 2019. Data cutoff was November 15, 2019.

The following results were seen, with overall survival (OS) considered from therapy initiation to death or last follow-up:

  • Overall response rate (ORR) of 71%, 44% achieving CR
  • Patients with AML had an ORR of 64%, with a CR rate of 36%
  • Patients with MDS had an ORR of 73%, with a CR rate of 50% and a cytogenetic response rate of 58%
  • Patients with TP53 mutations by next-generation sequencing had a 69% CR rate
  • 38% of all patients experienced complete molecular remission, seeing significant reductions in both their TP53 variant allele frequency and p53 expression by immunohistochemistry

Also, while those with a TP53 mutation typically have a median OS of just 6 to 8 months, the median OS in the present study was 10.8 months, with patients who responded to the combination treatment having an OS close to twice that of nonresponders: 14.6 (95% CI, 12.4-16.8) vs 7.5 (95% CI, 6.1-8.7; P = .0005) months.

Median OS rates were also similar between the AML and MDS patients:

  • Patients with AML: 10.8 (95% CI, 5.1-16.5) months
  • Patients with MDS: 10.4 (95% CI, 7.6-13.3) months

And of the 35% of patients who underwent allogeneic hematopoietic stem-cell transplant (HSCT), their median OS was 36% longer, 14.7 vs 10.8 months, and the median time to HSCT was 5.6 (range, 1.7-9.7) months. Survival differences were also seen between those who received at least 4 cycles of the combination therapy prior to HSCT vs those receiving less than 4: 16.1 (95% CI, 10.4-not reported) vs 9.3 (95% CI, 8-not reported) months.

Most patients (n = 43) received the eprenetapopt/azacytidine combination in the dose-expansion phase. The overall median treatment duration was 5.2 (range, 0.4-16.8) months before discontinuation.

“The presence of a TP53 gene mutation in patients with MDS or AML confers a poor prognosis, highlighting the urgent need for novel, effective therapy in this molecularly defined subgroup,” the authors concluded. “Eprenetapopt in combination with azacytidine is well tolerated and yields high remission rates in patients with TP53-mutant MDS and AML.”

A phase 3, multicenter, open-label, randomized study is currently investigating the combination; the expected completion date is June.


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

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