Combination Treatment With Eprenetapopt and Azacitidine Shows Promise for TP53-Mutant MDS and AML

“The [phase 1b/2] data [are] promising and support the current phase 3, multicenter trial, which we hope will lead to FDA approval and a new much-needed treatment option for this patient population,” said David Sallman, MD.

Combination treatment with eprenetapopt (APR-246) and azacitidine is well-tolerated, yielding high rates of clinical response and molecular remissions among patients with TP53-mutant myelodysplastic syndrome (MDS) and oligoblastic acute myeloid leukemia (AML), according to a phase 1b/2 study (NCT03072043) published in the Journal of Clinical Oncology.1

“Patients with TP53-mutant disease, which is roughly 10% to 20% of AML and de novo MDS cases, don’t have many options for therapy with nondurable responses to standard therapy,” David Sallman, MD, assistant member of the Malignant Hematology Department at Moffitt Cancer Center, said in a press release.2 “There is clearly a need for new targeted therapies for this patient population.”

In this study, investigators sought to determine safety, recommended phase 2 dose, and efficacy of eprenetapopt plus azacitidine in patients with TP53-mutant MDS or AML with 20% to 30% marrow blasts. Overall, 55 patients with at least 1 TP53 mutation—including 40 with MDS, 11 with AML, and 4 with MDS/myeloproliferative neoplasms—were treated.

The primary end point of the study was complete remission (CR) as defined by the 2006 International Working Group criteria. Key secondary end points included overall response rate (ORR), duration of response, and overall survival (OS).

The ORR was 71%, including 44% who achieved CR. Of those with MDS, 29 responded (73%) with 20 achieving CR (50%) and 23 having a cytogenetic response (58%). Among patients with AML, 7 responded (64%) and 4 achieved CR (36%). Of note, patients with only TP53 mutations by next-generation sequencing, or those with no other mutations detected, had higher rates of CR (69% vs 25%; P =.006).

Moreover, patients who responded were found to have significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with a total of 21 (38%) achieving complete molecular remission (variant allele frequency < 5%).

At the time of the data cutoff date, 3 patients (5%) were continuing study treatment and 22 (40%) had discontinued study treatment to proceed to hematopoietic stem-cell transplant (HSCT). The median time to HSCT was 5.6 months (range, 1.7-9.7 months).

Overall, 19 of 55 patients (35%) underwent allogeneic HSCT, with a median OS of 14.7 months.

At the time of data cutoff, there were 10 patients (18%) in post-transplant follow-up and 13 (24%) who discontinued therapy due to progressive disease. Discontinuation rates were similar for patients with MDS and AML. The median treatment duration was 5.2 months (range, 0.4-16.8 months).

Median OS was 10.8 months by landmark analysis. The results suggested that median OS was significantly longer for patients who received at least 4 cycles of treatment. Further, among patients who responded, median OS was longer at 14.6 months versus 7.5 months in nonresponding patients (P =.0005).

Regarding safety, adverse events (AEs) were revealed to be comparable to those reported for azacitidine or eprenetapopt monotherapy. The most common grade 3 or greater AEs were febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). No treatment-related AEs led to permanent discontinuation of eprenetapopt and the mortality rate with the combination was low with only 1 death reported within 30 days.

Similar to the current study findings, results from a phase 2 study of eprenetapopt and azacitidine by the Groupe Francophone des Myélodysplasies (NCT03588078) demonstrated comparable response rates. According to the investigators, together these data support the ongoing pivotal, multicenter, randomized phase 3 study (NCT03745716) of eprenetapopt in combination with azacitidine versus azacitidine alone in patients with TP53-mutant MDS.

“The data [are] promising and supports the current phase 3, multicenter trial, which we hope will lead to FDA approval and a new much-needed treatment option for this patient population,” added Sallman.


1. Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. Published online January 15, 2021. doi: 10.1200/JCO.20.02341

2. Investigational combo therapy shows benefit for TP53 mutant MDS and acute myeloid leukemia patients. News release. Moffitt Cancer Center. Published January 21, 2021. Accessed February 18, 2021.