Eprenetapopt/Azacitidine After HCT is Positive in TP53-Mutated AML and MDS

Eprenetapopt combined with azacitidine as maintenance therapy after hematopoietic stem-cell transplant induced encouraging relapse-free and overall survival in patients with TP53-mutant acute myeloid leukemia and myelodysplastic syndrome.

The combination of post-hematopoietic stem-cell transplant (HCT) maintenance therapy, eprenetapopt, and azacitidine was well tolerated in patients with TP53-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

These data come from a multicenter, open-label, single-arm, phase 2 trial (NCT03931291) which evaluated the efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT in patients with TP53-mutant AML or MDS.

In this high-risk population, both the relapse-free survival (RFS) and overall survival (OS) outcomes were encouraging at 12.5 months (95% CI, 9.6 to not estimable) and 20.6 months (95% CI, 14.2 to not estimable).

“In this phase 2 study, we evaluated the combination of eprenetapopt and azacitidine as post-HCT maintenance therapy for patients with TP53-mutated MDS or AML and observed a 1-year RFS probability of 60% and a 1-year OS probability of 79%, with a median RFS of 12.5 months and a median OS of 20.6 months. The 1-year RFS for patients who received maintenance therapy with eprenetapopt and azacitidine met our prespecified hypothesis that the 1-year RFS would be ≥ 50%, on the basis of a 1-year RFS of approximately 30% reported for patients with TP53-mutated MDS,” wrote the study authors led by Asmita Mishra, MD, Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, in findings published in the Journal of Clinical Oncology.

Patients enrolled in the study were administered up to 12 cycles of eprenetapopt at a dose of intravenous (IV) 3.7 g once a day on days 1-4 and azacitidine 36 mg/m2 once daily IV/subcutaneously on days 1-5 in 28-day cycles.

The primary end points of the trial were RFS and safety, including incidence, severity, and relatedness of treatment-emergent adverse events (AEs) and/or laboratory abnormalities. Secondary end points were OS, non-relapse mortality, time to progression, cumulative incidence of relapse, and incidence of acute and chronic GVHD.

To be eligible for enrollment, patients aged 18 years and older must have had previously met pre-transplantation eligibility, received an allogeneic transplant for AML or MDS, be ≥ 30 days and ≤ 100 days from hematopoietic cell infusion, be in complete remission after the transplant and has achieved engraftment, and have a Karnofsky Performance Status of 70 or greater.

A total of 84 patients were screened for eligibility before HCT, and 55 received a transplant. Then, 33 patients were enrolled and treated with eprenetapopt plus azacitidine. Fourteen of these patients had AML, 19 had MDS, and 67% received a reduced intensity conditioning regimen.

Among those enrolled, the median age was 65 (range, 40-74) years, the median number of eprenetapopt cycles was 7 (range, 1-12), and 13 patients (39%) completed 12 planned cycles of therapy. The median time from HCT to starting therapy was 68 days.

Data revealed that with a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable). The RFS probability at 1-year was 59.9% (95% CI, 41-74). Then with a median follow-up of 17.0 months, the median overall OS was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3).

Median time to progression was 15.2 months (95% CI, 9.7-not estimable [NE]). For patients with MDS, the median time to relapse was 9.9 months (95% CI, 5.7-NE) while for AML, it was NE (95% CI, 7.7-NE).

Regarding safety, the most frequent grade ≥ 3 AEs were platelet count decreased (n = 12, 36%), white blood cell count decreased (n = 12, 36%), neutrophil count decreased (n = 9, 27%), anemia (n = 9, 27%), thrombocytopenia (n = 4, 12%), and hypertension (n = 4, 12%). The most common serious AEs included pyrexia (n = 4, 12%), febrile neutropenia and dyspnea (n = 2, 6% each).

Treatment-related AEs which led to reduction, interruption, delay, or missed dose of study treatment in 9% (n = 3), 6% (n = 2), 6% (n = 2), and 3% (n = 1) of patients, respectively. There were also 2 patients with AEs related to eprenetapopt which led to permanent discontinuation on the trial.

Central nervous system (CNS)events have been previously reported with eprenetapopt. In this trial, all-grade AEs irrespective of attribution to study treatment that may be classified as CNS-related events consisted of nausea (61%), vomiting (46%), dizziness (39%), tremor (33%), headache (21%), dyskinesia (18%), and ataxia (12%). None of these CNS-related AEs were grade 3 or higher and they were managed with standard-of-care measures.

Further, 30-day and 60-day mortalities from the time the first dose was administered were 0% and 6% (n = 2), respectively. Acute and chronic graft-versus-host disease adverse events of any grade were observed in 12% (n = 4) and 33% (n = 11) of patients, respectively.

“In conclusion, post-HCT maintenance therapy with eprenetapopt plus azacitidine in this high-risk population of patients with TP53-mutated AML or MDS led to favorable survival outcomes. These data support future exploration of this maintenance strategy in a phase 3, randomized, controlled, double-blind study of eprenetapopt plus azacitidine vs placebo plus azacitidine in patients with TP53-mutated myeloid malignancies,” concluded the study authors.

Mishra A, Tamari R, DeZern AE, et al. Eprenetapopt plus azacitidine after allogeneic hematopoietic stem-cell transplantation for TP53-mutant acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2022;40(34):3985-3993. doi:10.1200/JCO.22.00181