The combination therapy of eprenetapopt plus azacytidine showed favorable efficacy and safety in patients with TP53-mutant myelodysplastic syndrome (MDS) and oligoblastic acute myeloid leukemia (AML). Patients with biallelic TP53 mutations or complex karyotype at baseline, a high-risk subpopulation, had higher complete response rates than patients who do not display these features [1]. Dr. David Sallman (H. Lee Moffitt Cancer Center, FL, USA) explained that the impact of TP53 mutations in MDS is large. “TP53 mutations occur in up to 20% of the patients with MDS and AML, resulting in inferior overall survival (OS) outcomes. The current therapies for this population are insufficient.” The combination regimen of eprenetapopt, a first-in-class p53 reactivator, plus azacytidine was evaluated in 2 phase 2 trials (NCT03072043, NCT03588078) with a combined cohort size of 100 patients with TP53-mutant MDS or oligoblastic AML. The primary endpoint was the complete response (CR) rate. The overall response rate was 69% and the CR rate was 43%. The median time to CR or partial response (PR) was 3.1 months. In addition, 40% of the patients achieved TP53 clearance (variant allele frequency [VAF] <5%), as assessed by next-generation sequencing (NGS) analysis. Furthermore, after 28 months of follow-up, TP53-negative patients displayed a median OS of 15.8 months, compared with 10.1 months in TP53-positive patients (P=0.0019). TP53 clearance was strongly correlated with CR rates, especially in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). After 28 months of follow-up, median OS was not reached in patients who achieved TP53 clearance and received allogeneic HSCT, whereas patients who did not achieve TP53 clearance but underwent allogeneic HSCT, had a median OS of 9.1 months. This result indicates that TP53 clearance (confirmed by NGS testing) is an important biomarker of allogeneic HSCT outcomes in patients with mutant TP53. Notably, patients who had only confirmed TP53 mutations at baseline had higher CR rates (52%) than patients who also showed non-TP53 mutations (30%). Moreover, patients with biallelic TP53 mutations or complex karyotype at baseline had higher CR rates (49%) than other patients (8%). The combination regimen of eprenetapopt and azacytidine was generally safe and well-tolerated. The most common non-haematologic adverse events (AEs) were nausea/vomiting (58%), ataxia (26%), and dizziness (23%), mostly grade 1 or 2 events. Febrile neutropenia was the most serious AE, occurring in 37% of the patients. However, the 30-day and 60-day mortality rates were low, with 1% and 7%, respectively.

  1. Sallman DA, et al. Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutants Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML). O637, ASH 2021 Scientific Sessions, 11–14 December.

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