Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax

Abstract

Background: TP53 mutation (TP53^mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53^mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53^mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).

Methods: Patients with newly diagnosed AML received decitabine 20 mg/m² for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53^mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.

Results: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53^mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53^mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53^mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53^mut AML were comparable to historical results with 10-day decitabine alone.

Conclusions: Patients with TP53^mut AML have lower response rates and shorter survival with DEC10-VEN.

Keywords: TP53; acute myeloid leukemia (AML); decitabine; outcome; venetoclax.

Fig 1.

a. TP53 mutations mapped according to response b. mutational landscape of TP53 mutated acute myeloid leukemia treated with 10-day decitabine and venetoclax. >1 type of mutation refers to patients with a missense and frameshift mutation or missense and nonsense mutation, etc.

Fig 2

a. Overall survival (OS) by TP53 mutation status. b. Relapse Free Survival (RFS) by TP53 mutation status. c. OS by response in TP53 mutated acute myeloid leukemia (AML). d. OS in TP53 mutated AML patients by measurable residual disease (MRD) status.

Fig 3.

Outcomes in patients with newly diagnosed TP53^mut AML with 10-day decitabine with venetoclax vs 10-day decitabine alone, a. morphologic response and measurable residual disease (MRD) status, b. overall survival, and c. relapse-free survival. CR = complete response, CRi = CR with incomplete hematologic response, MLFS = morphologic leukemia-free state