Azacitidine Plus APR-246 Induces Promising Activity, Safety in TP53-Mutant MDS and AML

In an interview with Targeted Oncology, Thomas Cluzeau, MD, PhD, discussed the findings from the phase 2 study of azacitidine plus APR-246 as treatment of patients with TP53-mutant myelodysplastics syndrome and acute myeloid leukemia. He also highlighted the next steps for this treatment regimen.

Thomas Cluzeau, MD, PhD

Thomas Cluzeau, MD, PhD

Patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who have TP53 mutations have very poor outcomes. Azacitidine alone induces 40% responses and 20% complete responses (CRs), as well as a short duration of response and a median overall survival (OS) of 8 months. However, APR-246 led to p53 protein reconfirmation, reactivating its proapoptotic and cell cycle arrest functions, ultimately receiving a Breakthrough Therapy designation for patients with MDS.

A phase 2 study, presented during the 25th Congress of the European Hematology Association (EHA), evaluated the combination of azacitidine plus APR-246 in treatment-naïve patients with previously not allografted intermediate, high, or very high Revised International Prognostic Scoring System (IPSS-R) TP53­-mutant MDS and AML. In the trial, patients received 4500 mg of intravenous APR-246 per day in 6-hour infusions on days 1 through 4, followed by azacitidine 75 mg/m2 on days 4 through 10 in a 28-day cycle.

Overall, 52 patients were enrolled to the study with a median age of 74 years (range, 44-87), and 34 patients had MDS, and 18 had AML. All patients had received at least 1 treatment cycle as of March 1, 2020. Common treatment-related toxicities occurring in 20% or more of patients included febrile neutropenia (36%) and neurological toxicities (40%). The neurological events did not exceed grade 3, occurring in grade 3 severity in only 3 patients. These events appeared to be correlated with lower glomerular filtration rate at treatment onset (P <.01) and higher age (P =.05). Neurological events were also resolved with temporary dose interruptions, and no recurrences were observed after dose reductions of APR-246.

The overall response rate (ORR) was 76%, whereas the ORR in the 28 evaluable patients with MDS was 75% and 56% among those in the intent-to-treat population.

In an interview with Targeted Oncology, Thomas Cluzeau, MD, PhD, head of hematology department, Central University Hospital of Nice, in Nice, France, discussed the findings from the phase 2 study of azacitidine plus APR-246 as treatment of patients with TP53-mutant MDS and AML. He also highlighted the next steps for this treatment regimen.

TARGETED ONCOLOGY: Could you first discuss the rationale for this regimen?

Cluzeau: The rationale of this study was that today 5% to 10% of AML or MDS are detected with TP53 mutations. It was more in the AML, which was closer to 40%. These patients have a really poor prognosis with a low rate of CR using as azacitidine alone, and also a short median OS around 6 to 9 months, so it's necessary to develop some other therapeutic strategy to improve these bad results with azacitidine.

APR-246 is a conformational analog of TP53, and this drug could change the conformation of TP53mutations and wild-type TP53. The TP53 pathway becomes functional, and apoptosis could be in used in this cell after using the APR-246.

There were some in vitro and in vivo analyses showing a synergistic effect of the combination, so that’s why we decided to evaluate the combination in these patients.

TARGETED ONCOLOGY: Could you expand upon the patient populations that were included in the study?

Cluzeau: The population of this study was treatment-naive patients not allografted. It was patients with MDS with intermediate-high or a very high IPSS-R in patients with AML, including AML, with more than 30% of blasts.

TARGETED ONCOLOGY: What are the findings presented at this year's EHA meeting?

Cluzeau: In terms of safety, the combination is good and is comparable to azacitidine [alone] except for neurological AEs. We observed 40% of neurological AEs, but only 6% were grade 3 or 4. This neurosurgical toxicity was manageable. It was reversible in all patients after direct discontinuation, and there is no recurrence after reintroduction of the drag after a dose reduction.

In terms of response, we observed promising results in terms of responses. The ORR was 58%, including 37% CRs. If we focus only on the evaluable patients who received at least 3 cycles and add marrow evaluation after 3 cycles, their ORR was 77%, including 49% CRs. If we analyze subgroups in MDS patients, the ORR was 75%, including 57% CRs, and for AML with low blast count, the ORR was 78%, including 33% CRs.

In terms of OS with a median follow up of 9.7 months, the median OS was 12.1 months. If we focus on patients who received at least 3 cycles, the median OS was 13.7 months, so it was a really good response in this high-risk population.

TARGETED ONCOLOGY: What are the next steps for this research?

Cluzeau: The next steps are ongoing. There is an international phase 3 study evaluating azacitidine plus APR-246 in TP53-mutated MDS, so the phase 3 is ongoing. The other next step is to combine azacitidine plus APR-246 to venetoclax (Venclexta). There is an ongoing phase 1 study evaluating the combination with azacitidine and APR-246 with venetoclax in TP53-mutated AML.

TARGETED ONCOLOGY: What is your take home message?

Cluzeau: Today I think APR-246 show higher rates of CR and ORRs in TP53-mutated MDS and AML patients. The median OS is very promising, showing 12 months which seems better than azacitidine alone or azacitidine with another drug. This seems promising.


Cluzeau T, Sebert M, Rahmé R, et al. APR-246 combined with azacitadiner in tp53 mutated myelodysplatics syndrome (mds) and acute myeloid leukemia. A phase 2 study by the groupe grancophone des myelodysplasies (gfm). Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181.

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