April 24, 2022
2 min read
Mishra A, et al. Abstract 39. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
Mishra reports research funding from Novartis. Please see the abstract for all other researchers’ relevant financial disclosures.
Eprenetapopt plus azacitidine maintenance therapy significantly improved outcomes for patients with TP53-mutated acute myeloid leukemia and TP53-mutated myelodysplastic syndrome, according to study results.
Asmita Mishra, MD, assistant member of the department of blood and marrow transplant at H. Lee Moffitt Cancer Center and Research Institute and assistant professor of oncology at University of South Florida, presented the phase 2 trial results at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
“Relapse remains the number one cause of transplant failure — especially for patients with TP53-mutated disease, who have extremely poor outcomes despite allogeneic hematopoietic stem cell transplantation,” Mishra told Healio. “We, therefore, aimed to improve outcomes for patients with this abnormality.”
Background and methods
Eprenetapopt (APR-246, Aprea Therapeutics), a small molecule p53 stabilizer, works synergistically with azacitidine to induce tumor cell death, according to study background.
Mishra and colleagues conducted a multicenter, open-label, phase 2 trial to assess the safety and efficacy of eprenetapopt (APR-246; Aprea Therapeutics) combined with azacitidine as maintenance therapy after allogeneic HSCT.
The study included 33 patients (median age, 65 years; 64% men) with TP53-mutant AML (n = 14) or TP53-mutant myelodysplastic syndrome (MDS; n = 19).
Most patients (79%) had a Karnofsky performance status of 80 or higher, and 76% received reduced-intensity conditioning.
Among the 25 patients with available molecular data from pre-stem cell transplant samples, 88% had a residual detectable TP53 gene mutation, 36% had more than one TP53 mutation and 36% had non-TP53 gene mutations.
Patients received eprenetapopt dosed at 3.7 g daily on days 1 to 4, combined with 36 mg/m2 daily azacitidine on days 1 to 5 every 28 days for up to 12 cycles.
At data cutoff, patients had received a median seven treatment cycles. Six patients (18%) remained on treatment.
The most common reasons for treatment discontinuation included completion of 12 treatment cycles (n = 9) and disease release (n = 9).
Researchers reported a median RFS of 368 days (95% CI, 233 to not evaluable), with a 1-year RFS rate of 58%. Median OS was 586 days (95% CI, 369 to not evaluable), with a 1-year OS rate of 79%.
The most common treatment-emergent adverse events included nausea, vomiting, diarrhea, dizziness, tremor, fatigue and cytopenias.
Grade 3 or higher treatment-emergent adverse events that occurred among at least 10% of patients included cytopenias and hypertension. Serious treatment-emergent adverse events that occurred in at least two patients included pyrexia, febrile neutropenia and dyspnea.
Four patients experienced acute graft-versus-host disease events, 10 patients experienced chronic GVHD events, and two patients developed severe chronic GVHD.
“The combination therapy was safe and tolerable, with most treatment-emergent adverse events comprising known complications in the post-transplant period,” Mishra told Healio. “Moreover, 42% of patients were able to complete the 12 cycles of treatment, and we did not find apparent treatment-related increase in GVHD.”
“Given these exciting and encouraging results, we believe pursing additional maintenance paradigms targeting p53 is warranted and needed,” Mishra said. “Randomized studies to further evaluate efficacy of this combination in the post-transplant setting are in current development.”