An Adverse Prognostic Effect of Homozygous TET2 Mutational Status on the Relapse Risk of Acute Myeloid Leukemia Patients of Normal Karyotype

Purpose

Ten-eleven-translocation oncogene family member 2 (TET2) mutations play leukemogenic roles in patients with acute myeloid leukemia (AML). However, the prognostic significance of such mutations in normal-karyotype (NK) AML patients remains controversial, especially that of homozygous TET2 mutations. n the present study, we attempted 1) to evaluate the prevalence of TET2 mutations in NK-AML patients; 2) to clarify the prognostic role played by TET2 mutation, especially homozygous mutation, in NK-AML patients; and, 3) to analyze associations among TET2 mutations and other mutations frequently observed in NK-AML patients, including those in FLT3-ITD, NPM1, and CEBPA.

Patients and Methods

We included 407 patients with NK-AML in the present study. NK-AML patients were diagnosed from October 1998 to September 2012 in seven participating institutes, and the median patient age was 52 years (range, 15–84 years). Sixty-five different TET2 mutations were detected in 54 patients (13.3%), of which 13 nonsense, 30 frameshift, and 22 missense and, homozygous mutations in 14 patients (25.9%) among TET2 mutated patients.

Results

A TET2 mutation was associated with poor prognostic features such as older age (p<0.001) or a high WBC count (p=0.013). Upon multivariate analysis, older patients (p=0.012, OR: 0.442, 95% CI 0.233-0.839), an NPM1 mutation (p=0.004, OR: 2.256, 95% CI 1.301-3.912), and a CEBPA mutation (p=0.001, OR: 5.031, 95% CI 1.921-13.173) were confirmed to be independent risk factors for complete remission (CR), but no TET2 mutation influenced CR (p=0.441, OR: 0.744, 95% CI 0.351-1.578). Upon multivariate analysis of factors affecting relapse incidence (RI), event-free survival (EFS), and overall survival (OS); performance of allogeneic stem cell transplantation (allo-SCT), and mutations in NPM1, CEBPA, or FLT3-ITD mutations, were independent risk factors for RI, EFS, and OS, but neither a TET2 mutation alone nor older age had any prognostic impact on RI, EFS, or OS. However, patients with homozygous TET2 mutations experienced a shorter EFS (p=0.046) and a higher relapse rate (p=0.010) than those with non-homozygous TET2 mutations or who were of TET2 wild-type status. Homozygous TET2 mutational status was an independent adverse prognostic factor for relapse upon multivariate analysis (p<0.001; HR 1.519; 95% CI 1.105-2.086), suggesting that the TET2 mutation exerted a threshold effect on relapse risk.

Conclusion

In summary, the TET2 mutation did not impact treatment outcomes, but homozygous TET2 mutational status did affect (elevate) the relapse rate, in particular. Our data suggest that homozygous TET2 mutational status increases the relapse risk in NK-AML patients.