Eprenetapopt regimen beneficial after HSCT for TP53-mutant AML, myelodysplastic syndrome
Click Here to Manage Email Alerts
Maintenance therapy with eprenetapopt plus azacitidine after hematopoietic stem cell transplantation led to improved survival outcomes among patients with TP53-mutant acute myeloid leukemia or myelodysplastic syndrome, study results showed.
Updated data from the phase 2 trial, published in Journal of Clinical Oncology, suggested that the combination maintenance therapy can more than double median OS seen with current standard-of-care regimens, the investigators noted.
Background
TP53 mutations are relatively common and occur in approximately one-fifth of patients with AML or myelodysplastic syndrome (MDS), according to study background.
With median OS of approximately 8 months or less using standard-of-care maintenance treatments, patients with TP53-mutant AML and MDS typically have poor outcomes despite undergoing allogeneic HSCT, according to Asmita Mishra, MD, MBA, associate member of the blood and marrow transplant and cellular immunotherapy department at H. Lee Moffitt Cancer Center and associate professor of oncological science at University of South Florida.
Eprenetapopt (Aprea Therapeutics) is a small-molecule p53 stabilizer that works in tandem with azacitidine to induce tumor cell death.
Mishra told Healio that recent preclinical studies “have effectively demonstrated that even low doses of azacitidine in combination with eprenetapopt have a synergistic effect, resulting in reduced proliferation and nearly doubling apoptosis when used in combination.”
Most patients with TP53-mutant disease who go on to HSCT do so with minimal residual disease that cannot be measured using conventional techniques, Mishra added.
“Preclinical studies have demonstrated the synergistic activity of eprenetapopt and azacitidine against neoplastic myeloid cells and that it is likely beneficial in eliminating this minimal residual disease,” she said.
Methodology
In the multicenter, open-label trial, Mishra and colleagues sought to assess the safety and efficacy of eprenetapopt combined with azacitidine as maintenance therapy after allogeneic HSCT.
The study included 33 patients (median age, 65 years; range, 40-74; 64% men) with TP53-mutant AML (n = 14) or TP53-mutant MDS (n = 19).
Study participants received up to 12 cycles of treatment lasting 28 days per cycle. Each treatment cycle included IV eprenetapopt dosed at 3.7 g once daily on days 1 to 4 plus IV or subcutaneous azacitidine dosed at 36 mg/m2 once daily on days 1 to 5.
RFS — defined as the time from HSCT to relapse or death — and safety served as the study’s primary endpoints. Secondary endpoints included OS, mortality rate and incidence of graft-versus-host disease.
Key findings
Median follow-up was 14.5 months for RFS and 17 months for OS.
Investigators reported median RFS of 12.5 months (95% CI, 9.6 to not estimable), with a 1-year RFS probability of 59.9% (95% CI, 41-74) among patients who received combination maintenance therapy with eprenetapopt plus azacitidine after HSCT.
Further analysis showed median OS of 20.6 months (95% CI, 14.2 to not estimable) among those who received the maintenance combination therapy, with a 1-year OS probability of 78.8% (95% CI, 60.6-89.3).
The most common grade 3 or higher serious treatment-related adverse events included pyrexia (12%), febrile neutropenia (6%) and dyspnea (6%).
Four patients (12%) experienced acute GVHD, whereas 11 patients (33%) had reported chronic GVHD resulting from treatment.
Clinical implications
Mishra said the results showed the addition of eprenetapopt-based maintenance improves efficacy outcomes compared with current standard-of-care maintenance therapies or HSCT alone.
“Post-HSCT maintenance with eprenetapopt plus azacitidine was well-tolerated with acceptable safety,” Mishra told Healio. “The[se] 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-mutant myeloid malignancies, [which] is currently being explored.”
For more information:
Asmita Mishra, MD, MBA, can be reached at Moffitt Cancer Center Magnolia Campus, 12902 USF Magnolia Drive, Tampa, FL 33612; email: asmita.mishra@moffitt.org.
Perspective
Back to Top
Mishra and colleagues reported promising results from a phase 2, multicenter, open-label clinical trial of post-allogeneic HSCT maintenance with azacitidine and the first-in-class p53 reactivator eprenetapopt.
This strategy yielded median RFS of 12.5 months and OS of 20.6 months, with 1-year RFS of 59.9% and 1-year OS of 78.8%. One-year cumulative incidence of relapse was 38.3%, and 1-year non-relapse mortality was only 3.8%. Acute and chronic GVHD rates were 12% and 33%, respectively. The regimen also appeared to be reasonably well-tolerated, with most grade 3 or higher adverse events being hematologic in nature.
Although RFS and OS both appear to be superior to historical comparisons, it bears mention that only 55 of the 84 screened patients were transplanted and only 33 were started on maintenance therapy. Further, only 13 patients ultimately completed the full planned 12 months of maintenance. Thus, the patients analyzed may well not be representative of the full cohort of TP53-mutant MDS and AML.
Pretransplant TP53 variant allele frequency did not appear to correlate with outcomes for those 33 patients who received the maintenance therapy. However, this was arguably a quite select group of patients (representing only 39% of those who were screened), and there was no distinction drawn between biallelic vs. monoallelic TP53 cases. Increasingly, data suggest that it is primarily biallelic TP53 mutations that confer a significantly worse prognosis. Such an analysis might provide better insight as to the efficacy of azacitidine and eprenetapopt maintenance.
Randomized trials — as the authors noted — are needed to confirm the efficacy and safety of this regimen. As the authors pointed out, the fact that so few patients completed or even received maintenance therapy highlights the difficulty treating this patient population and the need for better options pretransplant. In particular, novel therapies are desperately needed for elderly and/or unfit patients, who are not eligible for allogeneic HSCT. It is hoped that eprenetapopt ushers in a new era of improved treatments for patients with TP53-mutant AML and MDS.
Collapse
Click Here to Manage Email Alerts