Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM)

Abstract

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.

Current Therapy of the Patients with MDS: Walking towards Personalized Therapy

“…Toxicity was acceptable, with the most common grade 3 or more AEs being febrile neutropenia and cytopenias. The results of this study are consistent with the phase II study by de GFM evaluating the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high TP53 mutated MDS and AML patients [ 76 ]. These studies have led to the ongoing pivotal phase III, multicenter, randomized study of eprenetapopt combined with AZA versus AZA alone in patients with TP53 -mutant MDS (NCT03745716).…”

Real-World Utilization of Target- and Immunotherapies for Lung Cancer: A Scoping Review of Studies Based on Routinely Collected Electronic Healthcare Data

“…This is probably because in regions other than North America, healthcare data are often scattered in different and heterogeneous databases, so that the performing studies on rare events that requires information from different healthcare settings, as in the case of lung cancer, remains a challenge [ 56 ]. Moreover, the approval of new anticancer medication in Europe is often delayed compared to the US [ 57 ], possibly contributing to the higher number of studies from the US included in this review compared to those using European Union (EU) data.…”

The Function of the Mutant p53-R175H in Cancer

“…Several ongoing clinical trials are testing the safety and efficacy of APR-246 for different cancer types (NCT03931291, NCT04214860, NCT04383938, NCT03745716, NCT04419389, NCT03588078, and NCT03072043 at ClinicalTrials.gov (accessed on 1 July 2021)). The latest result of the phase 2 trial (NCT03072043) showed combination treatment with eprenetapopt (APR-246) and azacitidine is well tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant myelodysplastic syndromes [88,89]. KSS-9 is a piperlongumine derivative with the insertion of combretastatin A4 at the C-7 position.…”