Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes | Aplastic Anemia and MDS International Foundation (AAMDSIF) Return to top.

Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes

Journal Title: 
Journal of clinical oncology: official journal of the American Society Clinical Oncology
Primary Author: 
Sallman DA
Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, Cluzeau T, Sweet KL, McLemore A, McGraw KL, Puskas J, Zhang L, Yao J, Mo Q, Nardelli L, Al Ali NH, Padron E, Korbel G, Attar EC, Kantarjian HM, Lancet JE, Fenaux P, List AF, Komrokji RS
Original Publication Date: 
Friday, January 15, 2021
Bone Marrow Disease(s): 

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

Methods: This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).

Results: Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

Conclusion: Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.