In a Groupe Francophone des Myélodysplasies phase II study reported in the Journal of Clinical Oncology, Cluzeau et al found that the combination of eprenetapopt and azacitidine produced high response rates in previously untreated patients with high-risk TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eprenetapopt is a first-in-class drug that results in p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.

As stated by the investigators, “TP53-mutated MDS and AML have very poor outcome[s] irrespective of the treatment received, including 40% responses (20% complete remission) with azacitidine alone, short response duration, and a median overall survival of approximately 6 months.”

Study Details

In the multicenter study, 52 patients—including 34 with MDS and 18 with AML (7 with > 30% marrow blasts)—with high or very high International Prognostic Scoring System risk were enrolled between September 2018 and July 2019. Patients received eprenetapopt via 6-hour intravenous infusion daily at a fixed dose of 4,500 mg on days 1 to 4 of each 28-day cycle. Azacitidine was given at 75 mg/m² via subcutaneous injection daily on days 4 to 10 of each 28-day cycle.

Key Findings

Data cutoff was in April 2020, with all patients enrolled for 9 months or longer and a median follow-up of 9.7 months.

Among patients with MDS, the overall response rate was 62%, including complete remission in 47% of patients. Median duration of response was 10.4 months (range = 2.8–16.8+ months) among all responders and 11.4 months (range = 6.5–16.8+ months) among those with complete remission. 

Among patients with AML, the overall response rate was 33%, including complete remission in 17% (27% among patients with < 30% blasts and 0% among those with > 30% blasts). Median duration of response was 12.7 months (range = 6.0–17.3+ months) among all responders and 14.0 months (range = 11.3–17.3+ months) among those with complete remission.

Among responders, 73% achieved TP53-negativity (variant allele frequency < 5%). Median overall survival was 12.1 months in patients with MDS, 13.9 months among patients with AML and < 30% blasts, and 3.0 months among patients with AML and > 30% blasts.

Grade 3 or 4 febrile neutropenia occurred in 36% of patients. Neurologic adverse events of any grade occurred in 40% of patients, with the most common being ataxia (25%); grade 3 or 4 neurologic events occurred in 6%. Neurologic toxicity was associated with lower glomerular filtration rate at treatment onset (P < .01) and older age (P = .003).

The investigators concluded: “In this very high-risk population of [patients with] TP53-mutant MDS and AML, eprenetapopt combined with azacitidine was safe and showed potentially higher overall response rate and complete remission rate, and longer overall survival than reported with azacitidine alone.”

Pierre Fenaux, MD, PhD, of GFM, APHP, and Paris University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Groupe Francophone des Myéelodysplasies. For full disclosures of the study authors, visit ascopubs.org.