Combination Eprenetapopt Plus Azacitidine Beneficial for TP53-Mutated MDS, AML, and MPN

Eprenetapopt plus azacitidine induced clinical responses and molecular remissions in patients with TP53-mutated myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPNs), according to a study published in the Journal of Clinical Oncology.

TP53 mutation in patients with MDS or AML is associated with poor prognosis, thus there is a need for effective therapies for these patients. This open-label, multicenter, dose-escalation and dose-expansion, phase Ib/II study assessed the safety, recommended phase II dose, and efficacy of eprenetapopt plus azacitidine in 55 patients with TP53-mutated MDS (n=40), AML (n=11), or MDS/MPN (n=4) with 20% to 30% marrow blasts.

The overall response rate was 71%, and the complete response (CR) rate was 44%. Among patients with MDS, 73% (n=29) responded, with 50% (n=20) achieving CR and 58% (n=23) achieving a cytogenetic response. Among patients with AML, the overall response and CR rates were 64% (n=7) and 36% (n=4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% vs. 25%; P=0.006).

Patients who responded to the combination therapy had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission. Median overall survival (OS) was 10.8 months, and significant improvement were observed in patients who responded (14.6 months) versus those who did not (7.5 months; P=0.0005).

Overall, about one-third of patients (n=19/55; 35%) underwent allogeneic hematopoietic cell transplantation (HCT). The researchers noted that historically, the proportion of patients with MDS who proceed to HCT is less than 10%. In the cohort that underwent HCT, median OS was 14.7 months, which the researchers called “encouraging.”

Adverse events (AEs) were similar to those reported for azacitidine or eprenetapopt monotherapy; the most common grade ≥3 AEs were febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

The researchers concluded, “Eprenetapopt in combination with azacitidine is well-tolerated and yields high remission rates in patients with TP53-mutant MDS and AML.”