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Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ≥ 2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥ 2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome.

Original publication

DOI

10.1182/blood-2015-05-647578

Type

Journal article

Journal

Blood

Publication Date

29/10/2015

Volume

126

Pages

2110 - 2117

Keywords

Ataxia Telangiectasia Mutated Proteins, High-Throughput Nucleotide Sequencing, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Neoplasm Recurrence, Local, Phosphoproteins, Prognosis, Prospective Studies, RNA Splicing Factors, Ribonucleoprotein, U2 Small Nuclear, Salvage Therapy, Treatment Outcome, Tumor Suppressor Protein p53