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

Abstract

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.

Genetic alterations in Thai adult patients with acute myeloid leukemia and myelodysplastic syndrome—excess blasts detected by next-generation sequencing technique

“…However, this observation is not supported by data from controlled clinical trials [4,33]. New agents, such as the p53 reactivator APR-246 or the monoclonal anti-CD47 antibody magrolimab that have shown The underlined figures indicate the most common mutation found by each study, whereas the bold figures denote the three most common mutations that each study reported F, female; M, male, NR, not reported promising activity in this high-risk subset of AML, are currently in clinical development [34,35]. Apart from the limited transplant access, the poor OS and RFS rates of our patients were possible because age > 65 years and unfavorable genetic mutations (especially the TP53 mutation) were adverse factors.…”

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

“…Preclinical studies have shown that eprenetapopt is efficient on its own, while it is also synergizing with AZA in TP53-mutated MDS and AML cell lines and in TP53-mutated cells from MDS and AML patients [ 75 ]. A phase Ib/II study to determine the safety and efficacy of eprenetapopt (APR-246) with AZA in patients with TP53 -mutant MDS or AML with a low percentage of blasts has recently been published, with highly promising results [ 55 ] ( Table 2 ). The ORR of the 51 patients enrolled (40 MDS) was 71%, with CR in 44%.…”

Acute Myeloid Leukemia Evolving from Myeloproliferative Neoplasms: Many Sides of a Challenging Disease

“…Indeed, the immunologic effect by HSCT appears to be largely ineffective in this subgroup, possibly, also due to an immunosuppressive phenotype conferred by the TP53 mutant [37]. Alternative therapeutic approaches should be explored for this category of patients, including the incorporation of a novel agent capable of restoring the normal TP53 conformation and function, such as APR-246 [38], and the introduction of maintenance strategies after HSCT in order to enhance the graft versus leukemia effect.…”