Eprenetapopt/Azacitidine Combo Elicits Promising Activity in TP53-Mutant MDS and AML


The combination of eprenetapopt and azacitidine demonstrated a promising safety profile as well as encouraging clinical activity in a high-risk population of patients with TP53-mutated myelodysplastic syndrome and acute myeloid leukemia.

Thomas Cluzeau, MD, PhD

Thomas Cluzeau, MD, PhD

The combination of eprenetapopt (APR-246) and azacitidine demonstrated a promising safety profile as well as encouraging clinical activity in a high-risk population of patients with TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), according to results of a phase 2 study (NCT03588078) that was published in the Journal of Clinical Oncology.1

Data showed that, in patients with MDS, the combination elicited an overall response rate (ORR) of 62%, consisting of a complete response (CR) rate of 47%, a marrow CR (mCR) rate of 6%, and a stable disease rate of 9%.

In the AML cohort, the ORR of 33%, which included a CR rate of 17% and an incomplete count recovery (CRi) of 10%. For patients with AML who had a low blast count, the ORR was 45%, whereas those who had more than 30% blasts had an ORR of 14%.

Moreover, after a median follow-up of 8.7 months, investigators reported a median OS of 12.1 months in the MDS cohort and 10.4 months in the AML cohort. The median OS in those with more than 30% blasts was 12.1 months and was 13.9 months in patients with a low blast count.

The intent-to-treat population had a median OS of 12.1 months, and patients who had received at least 3 cycles of therapy had a median OS of 13.7 months.

TP53 mutations are reportedly present in approximately 5% to 10% of patients with de novo MDS and AML, as well as in 25% to 40% cases of therapy-related MDS and AML.2,3 Current therapies have yielded poor outcomes for patients who have a complex karyotype or in those whose TP53 mutation is biallelic.4,5 Moreover, hypomethylating agents, such as azacitidine and decitabine, as well as intensive chemotherapy regimens, have resulted in short, poor outcomes, with CR rates ranging from 15% to 20%, and an estimated median overall survival (OS) of 6 months.6-8

Eprenetapopt is a novel, first-in-class, small molecule designed to target TP53-mutated cancers. In November 2020, the FDA granted a fast track designation to eprenetapopt as a treatment for patients with TP53-mutant AML

This phase 2, open-label, multicenter study enrolled patients with treatment-naïve high or very high International Prognostic Scoring System-R TP53-mutant MDS and AML. The trial also permitted patients with AML who had at least 30% blasts, and who had received maintenance therapy with eprenetapopt and azacitidine for up to 1 year following allogenic stem cell transplant.

Eprenetapopt was administered 6-hour intravenous infusion at a fixed dose of 4500 mg on days 1 through 4 of every 28-day cycle. Moreover, azacitidine was given subcutaneously at a standard 75-mg/m2 dose on days 4 through 10 of each 28-day cycle. Patients who had been consolidated with allogenic stem cell transplant were given dose-reduced maintenance therapy with azacitidine at 36 mg/m2 daily on days 1 to 5, and fixed-dose eprenetapopt at 3700 mg on days 1 through 4 of every 28-day cycle. Additionally, the protocol provided dose adjustments when adverse effects (AEs) occurred, as well as management guidelines for neurologic AEs.

To be eligible for enrollment, patients had to be aged 18-years or older, have an ECOG performance status of 0 to 2, and adequate renal and hepatic function. Moreover, patients who had been diagnosed with de novo MDS and chronic myelomonocytic leukemia, who were classified as intermediate, high, or very high, utilizing the International Prognostic Scoring System were included on the study. Patients with AML, including those with blasts that were both less than and greater than 30%, were also able to enroll on the study.

Patients needed to be hypomethylating agent-naïve, with no previous allograft, and at least 1 TP53 mutation identified through next-generation sequencing. Patients with therapy-related MDS were eligible for the study, provided they had at least 1-year of disease-free survival during their prior malignancy. Lastly, patients were allowed to have received prior treatment with growth factors, lenalidomide (Revlimid), and/or hydroxyurea.

The primary end point was response in evaluable patients within the intent-to-treat population, while key secondary end points included safety, OS, DOR, AML progression rate, and correlation between TP53 variant allele frequency (VAF) and response.

Between September 2018 and July 2019, patients were enrolled with a data cutoff of April 1, 2020. Thirty-four patients had MDS and 18 had AML. Additionally, 80% of patients were reported to have a complex karyotype, and 25% harbored 17p deletion. However, the investigators noted that 17p deletion may have been overlooked in patients with a complex karyotype because fluorescence in situ hybridization analysis of 17p was not assessed in many cases.

Patients had a median of 1 TP53 mutation (range, 1-3), with 25% of patients having 2 or more mutations. Additionally, the TP53 mutation clone was dominant in 83% of patients. Moreover, patients had a median baseline TP53-mutant VAF of 20%, while 19% had a baseline VAF of over 50%.

At the time of cut off, 23% of patients (n = 12) were still receiving combination treatment, including 4 who had received a stem cell transplant, and 2 who had started allogeneic posttransplant maintenance therapy. In total, 25% of patients discontinued treatment before the cycle 3 bone marrow evaluation due to severe infection (n = 6), disease progression (n = 4), multiorgan dysfunction (n = 2), and consent withdrawal (n = 1). Investigators reported a median treatment duration of 8.6 months (range, 0.3-17.3 months).

The median duration of response (DOR) was 11.3 months in the overall population (95% CI, 2.8-17.3+), and the median duration of CR was 11.7 months (6.5-17.3+). In patients with MDS specifically, the median DOR was 10.4 months (95%, 2.8-16.8+), and a median duration of CR of 11.4 months (95% CI, 6.5-16.8+). Patients with AML who had blasts of 20% to 30% had a median DOR of 14.0 months (95% CI, 6.0-17.3+) and a median duration of CR of 14.0 months (95% CI, 11.3-17.3+). Lastly, for patients with AML who had 30% blasts or more, the median DOR was 11.5 months while the median duration of CR was not evaluable.

Additional data indicated that 39 patients had been treated with at least 3 cycles of the combination and went on to receive bone marrow evaluation after 3 cycles, if evaluable. Within this population, among patients with MDS, the ORR was 75%, consisting of a CR rate of 57%, a mCR rate of 7%, and a stable disease rate of 11%. In the AML cohort, the ORR was 55%, which included a CR rate of 36%, and a CRi rate of 18%. Moreover, patients with AML who had low blasts had an ORR of 55%, while those with 30% blasts of more had an ORR of 50%.

Investigators also examined the correlation between TP53 VAF and response.

“When combining MDS and AML to have sufficient patient numbers, 22 [73%] of the responders achieved TP53 VAF levels below the 5% threshold, and 9 [30%] TP53 VAF levels below the 0.1% threshold,” lead study author Thomas Cluzeau, MD, PhD, of Centre Hospitalier Universitaire of Nice in Nice, France, and coinvestigators wrote in the paper. “Eighteen of the 22 patients with no detectable mutant TP53 at the 5% threshold were already negative at the first response assessment after cycle 3, and the remaining 4 patients after cycle 6. Eight of the 9 patients with no detectable mutant TP53 at the 0.1% threshold were already negative after cycle 3, and the remaining patient after cycle 6.”

Additionally, TP53 VAF decrease was strongly associated with response (P <.0001), CR achievement (P = .002), and duration of response (P <.0001). Moreover, achieving TP53 VAF level below the 5% threshold was found to be associated with longer DOR (P <.001) and significantly longer OS at 13.9 months vs 5.0 months, respectively (P <.0001). Achieving TP53 VAF level below the 0.1% threshold was also associated with better outcomes, with a median OS of not reached vs 10.7 months, respectivly (P = .05).

In terms of safety, 40% of all patients experienced all-grade neurologic AEs, 6% of which were of grade 3/4. Notably, 37% of patients experienced grade 3/4 febrile neutropenia.

Neurologic toxicity was found to be fully reversible within 5 days of discontinuation, with no recurrence following dose reduction. Thirteen patients required a dose reduction, 9 of whom required 1 dose reduction, and 2 who needed 2 dose reductions. A single patient with antibiotic-related renal failure discontinued treatment early due to a neurologic AE that was related to treatment with eprenetapopt. The regimen had a 30-day mortality of 0% and a 60-day mortality of 8%.


  1. Cluzeau T, Sebert M, Rahmé R, et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J Clin Oncol. 2021;39(14):1575-1583. doi:10.1200/JCO.20.02342
  2. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496-506. doi:10.1056/NEJMoa1013343
  3. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616-3627. doi:10.1182/blood-2013-08-518886
  4. Sallman DA, Komrokji R, Cluzeau T, et al. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. Leukemia. 2016;30:666-673. doi:10.1038/leu.2015.304
  5. Montalban-Bravo G, Kanagal-Shamanna R, et al. Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes. Blood Adv. 2020;4(3):482-495. doi:10.1182/bloodadvances.2019001101.
  6. Bally C, Adès L, Renneville A, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leukemia Res. 2014;38(7):751-755. doi:10.1016/j.leukres.2014.03.012.
  7. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. doi:10.1016/S1470-2045(09)70003-8.
  8. Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. B J Haem. 2013;160:660-672. doi:10.1111/bjh.12203
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