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Chronic Lymphocytic Leukemia
Deep targeted sequencing of TP53 in
chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):789-796
Christian Brieghel,1 Savvas Kinalis,2 Christina W. Yde,2 Ane Y. Schmidt,2 Lars Jønson,2 Michael A. Andersen,1 Caspar da Cunha-Bang,1
Lone B. Pedersen,1 Christian H. Geisler,1 Finn C. Nielsen2 and
Carsten U. Niemann1
1Department of Hematology, Rigshospitalet and 2Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark
ABSTRACT
In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoim- munotherapy. Patients harboring low burden TP53 mutations with vari- ant allele frequencies of 0.3-15% have been shown to have similar dis- mal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted next-generation sequencing assay allow- ing for the detection of TP53 mutations as low as 0.2% variant allele fre- quency. Within a consecutive, single center cohort of 290 newly diag- nosed patients with chronic lymphocytic leukemia, deletion of chromo- some 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (vari- ant allele frequency >10%) or low burden (variant allele frequency ≤10%), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10%) was only evi- dent for patients with IGHV unmutated status; no impact of TP53 aber- rations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 muta- tions over 1% variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as a clinical lower limit of detection.
Introduction
Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy characterized by a heterogeneous clinical course. Prognostic and predictive markers of survival and treatment outcome are essential in management of the disease.1 Deletion of chromosome 17p [del(17p)] and TP53 mutation (TP53mut) remain the most impor- tant risk factors for progression-free survival (PFS) and overall survival (OS) follow- ing chemo- and chemoimmunotherapy (CIT).2-6 In recent years, B-cell receptor pathway inhibitors (idelalisib, ibrutinib and acalabrutinib) and Bcl-2 inhibitors (venetoclax) have demonstrated remarkable response rates and durable remissions in both treatment naïve and previously treated CLL patients with TP53 aberration (TP53ab: either del(17p) or TP53mut).7-11 Randomized clinical trials comparing CIT directly to targeted therapy in a TP53-aberrated population are still awaited. Thus, assessment of TP53ab is recommended prior to any treatment decision.12
Approximately 80% of patients with del(17p) also harbor TP53muts on the remaining allele, while a subset of patients have TP53muts without del(17p).5
Correspondence:
CARSTEN U. NIEMANN
carsten.utoft.niemann@regionh.dk
Received: April 17, 2018. Accepted: November 23, 2018. Pre-published: Decemer 4, 2018.
doi:10.3324/haematol.2018.195818
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/789
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789
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