TP53

Subclonal TP53 mutations in acute myeloid leukemia

A group of German and Austrian researchers investigated the clinical characteristics and prognostic impact of subclonal TP53 mutations (defined by a variant allele frequency of < 20%) in a large cohort of patients with acute myeloid leukemia (AML). The results of the study were published ahead of print in Haematologica.

Targeted sequencing was performed on diagnostic samples obtained from 1,537 intensively treated patients with AML who were enrolled in three prospective multi-center trials (HD98A, HD98B, and 07-04) conducted by the German-Austrian AML Study Group (AMLSG) were analyzed in this study. One-hundred and eight pathogenic TP53 mutations were found in 6.4% (98/1,537) of patients.  Patients with TP53 mutations were categorized into three groups according to their variant allele frequency (VAF), > 40% (n = 61) representing the major AML clone, 20%–40% (n = 19), and < 20% (n = 18) representing subclones.

The main objectives of the study were to assess the difference in overall survival (OS) and event-free survival (EFS) between AML patients with a TP53 wild-type status and those with subclonal TP53 mutations.

Key findings:
  • There was a significant association between complex karyotypes and TP53 mutations with a VAF of > 40% and 20%–40% but not for subclonal ones with a VAF of < 20%
  • Complete remission rate was significantly lower in patients with TP53 mutation compared to TP53 wild type patients: 48.0% vs. 84.9%, P < 0.001
  • Relapse rate was significantly higher in patients with TP53 mutation compared to TP53 wild type patients: 68.1% vs. 47.8%, P = 0.007
  • 3-year OS rate in patients with TP53 mutations and TP53 wild type: 8.3% (95% CI, 4.3–16.2) vs. 49.1% (95% CI, 46.5–51.8), P < 0.0001
  • Compared to patients with TP53 wild type, 3-year OS rate in patients with TP53 mutations with a VAF of > 40%, 20%–40%, and < 20% was significantly worse: 11.5% vs. 5.3% vs. 0%, P < 0.001
  • 3-year EFS rate in patients with TP53 mutations and TP53 wild type: 6.3% (95% CI, 2.9–13.6) vs. 38.3% (95% CI, 35.9–40.9), P < 0.0001
  • Compared to patients with TP53 wild type, 3-year EFS rate in patients with TP53 mutations with a VAF of > 40%, 20%–40%, and < 20%: 9.8% vs. 0% vs. 0%, P < 0.0001

In summary, TP53 mutated subclones defined by VAF < 20% are negative prognostic factors for patients with AML.

The researchers concluded that the findings of their study further corroborates the “use of next-generation sequencing technologies for risk stratification of patients with AML.”

References
  1. Prochazka K. T. et al. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica. 2018 Oct 11. DOI: 10.3324/haematol.2018.205013. [Epub ahead of print].
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