Biallelic ATM alterations detected at diagnosis identify a subset of treatment-naïve chronic lymphocytic leukemia patients with reduced overall survival similar to patients with p53 deletion

Abstract

The prognostic impact of biallelic ATM abnormalities (ATM mutation and concurrent 11q deletion) remains unknown. We studied ATM, BIRC3, SF3B1, and NOTCH1 genes in 118 treatment-naïve CLL patients at diagnosis. Patients with biallelic ATM alteration had a similar time to first treatment (TTFT) and shorter overall survival (OS) compared with patients with isolated 11q deletion and shorter TTFT and OS when compared to patients with wild-type ATM. Furthermore, biallelic ATM alteration (HR: 6.4; p ≤ 0.007) was significantly associated with an increased risk of death similar to p53 deletion (HR: 6.1; p ≤ 0.004), superior to 11q deletion alone (HR: 2.8; p ≤ 0.022) and independent of other significant parameters such as age, advanced clinical stage, and complex karyotype. Our results suggest the identification of ATM mutations in CLL patients with 11q deletion at diagnosis is clinically relevant and predicts disease progression, poor response to the treatment, and reduced OS independent of other molecular prognostic factors.

Keywords:

• ATM mutation
• 11q deletion
• prognostic markers
• p53 deletion
• chronic lymphocytic leukemia

Acknowledgements

The authors wish to thank Natividad Polo of the Molecular Cytogenetics laboratory who helped with karyotype analysis, Isabel Millán who helped with statistical analysis, Davide Rossi for providing a set of primers for BIRC3 mutational screening, and Martin Hadley-Adams for reviewing the English language.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online as “ICMJE Disclosure Form” at http://dx.doi.org/10.1080/10428194.2016.1213829.