APR-246 Plus Azacitidine Is Associated With High Response Rates in MDS and AML

In a small phase IB/II trial presented at the 23rd Congress of the European Hematology Association, all four evaluable patients with TP53-mutant myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) responded to treatment with the mutant p53 activator APR-246 and azacitidine. The combination regimen also was well tolerated, reported the researchers, led by David Sallman, MD, of the Moffitt Cancer Center in Tampa, Florida.

“Mutations in TP53 are found in approximately 10 percent of patients with MDS and AML, and are associated with poor overall prognosis, including a median overall survival of six to 12 months and lack of good treatment options,” Dr. Sallman explained. “Specifically, complete response rates to azacitidine or decitabine range between 20 and 30 percent.”

This early-phase trial enrolled nine adult patients with either TP53-mutated MDS (n=6) or AML (n=3) and no prior history of treatment with hypomethylating agents. Median age was 65 years (range = 39-73 years). Most patients (89%) had very poor-risk cytogenetics and very high-risk disease (78%; according to Revised International Prognostic Scoring System for MDS Risk Assessment).

Over a four-day lead-in phase, APR-246 was administered intravenously in a 3+3 dose-escalation design, at doses of 50 mg/kg/day, 75 mg/kg/day, or 100 mg/kg/day. Following the lead-in phase, patients received APR-246 plus azacitidine 75 mg/m2, administered either subcutaneously or intravenously over a seven-day period in 28-day treatment cycles.

Safety over the six-week assessment period was the primary endpoint of this analysis, while secondary endpoints included treatment response, clonal suppression, and depth of remission.

At the time of presentation, seven patients remained on study; two patients in the 50 mg/kg cohort discontinued treatment (1 due to infection and 1 due to patient choice). The median time on study was 133 days (range = 41-248 days).

During the lead-in phase, treatment-related adverse events (AEs) included: ataxia, dizziness (n=1 each), nausea, and neuropathy (n=2 each). Additional common AEs occurring during the assessment period, after the addition of APR-246, included nausea (n=6), neutropenia (n=6), infection (n=4), and neuropathy (n=4).

All AEs except neutropenia and thrombocytopenia were grade 1 or 2, and no dose-limiting toxicities were observed.

Of the five patients who were evaluable for response, the overall response rate was 100 percent. This included four patients who achieved complete remission (CR; 3 of whom were receiving APR-246 75 mg/kg) and one who achieved marrow CR (mCR). All patients who had CR also had complete cytogenetic response, the investigators wrote.

As a secondary endpoint, the researchers also assessed patients’ minimal residual disease (MRD) following six treatment cycles, reporting that two patients had achieved MRD negativity.

“If our preliminary findings are substantiated in the phase II portion of the trial, these data would suggest that the combination of APR-246 plus azacitidine is better than our existing standards of care,” Dr. Sallman said. However, the authors noted that longer-term follow-up is needed to demonstrate the durability of responses.

“Future research also will look into this combination as a maintenance approach following allogeneic hematopoietic cell transplantation,” Dr. Sallman added. “To date, this would be the first TP53-specific, molecular-targeted therapy and could have broad importance in hematologic malignancy where TP53 is a driver of many diseases.”

The authors report no financial relationships.


Sallman D, Dezern A, Sweet K, et al. Phase 1B/2 combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Abstract #S1558. Presented at the 23rd Congress of the European Hematology Association, June 17, 2018; Stockholm, Sweden.