Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine

Abstract

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.

Activating STING1-dependent immune signaling inTP53mutant and wild-type acute myeloid leukemia

“…In a recent study we showed that DNMTi + PARPi treatment increases STING1 expression in TNBC and OC cells ( 26 ). To evaluate whether this mechanism explains DNMTi + PARPi efficacy in AML ( 18 ), we first characterized basal STING1 expression in primary AML TCGA samples and in AML cell lines. In TCGA, AML samples with WT TP53 have significantly higher levels of STING1 than samples with TP53 mutations ( Fig.…”

“…We have been exploring addition of Poly (ADP ribose) polymerase inhibitors (PARPis) to DNMTis ( 18 ). PARPis are approved for use in the clinic to treat BRCA-deficient or homologous recombination–deficient (HRD) breast, ovarian, and prostate cancers (BC, OC, and PC) ( 19 – 21 ).…”

Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis

“…The presence of p53 mutation leads to extremely poor prognosis [ 44 , 45 ]. Bories et al described a worse OS in patients with any p53 mutation and treated with azacitidine but found no association for response [ 46 ]. Regarding the use of decitabine in p53-mutated AML, Welch et al found a higher response rate in patients with p53 mutations compared to wild-type patients after 10-day treatment (100% and 41%, respectively) [ 47 ].…”

“…Aldoss et al described a comparable response rate between patients treated with venetoclax in combination with either a 5- or a 10-day regimen of decitabine [ 48 ]. As these results are not profoundly conclusive, the systematic classification of patients with p53 mutations will merit further investigation in conventional therapy and in the emerging field of p53-pathway-targeted therapies [ 46 ].…”

TP53 mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms

“…Recently, the hypomethylating agents (HMAs) decitabine and azacitidine +/-the BCL-2 inhibitor venetoclax have emerged as promising therapeutics for patients with TP53-mutant myeloid neoplasms 7 . However, the various clinical studies testing HMAs +/-venetoclax in TP53mutant AML/MDS patients have yielded conflicting results [7][8][9][10][11][12][13][14][15][16][17][18] as to whether TP53 mutations are predictive for superior outcomes (summarized in Table S1), and several pre-clinical studies suggested that, indeed, TP53 loss increases sensitivity to HMAs 19,20 .…”