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TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics
Elias Campo,1 Florence Cymbalista,2 Paolo Ghia,3 Ulrich Jäger,4 Sarka Pospisilova,5 Richard Rosenquist,6 Anna Schuh7 and Stephan Stilgenbauer8
Haematologica 2018 Volume 103(12):1956-1968
1Hospital Clinic of Barcelona, University of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, and CIBERONC, Spain; 2Hôpital Avicenne, AP-HP, UMR INSERMU978/Paris 13 University, Bobigny, France; 3Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; 4Medical University of Vienna, Austria; 5Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 7University of Oxford, UK and 8Internal Medicine III, Ulm University, Germany and Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany
All authors contributed equally to this work
ABSTRACT
Chronic lymphocytic leukemia is associated with a highly hetero- geneous disease course in terms of clinical outcomes and respons- es to chemoimmunotherapy. This heterogeneity is partly due to genetic aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p [del(17p)], resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoim- munotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations [both del(17p) and TP53 mutations] before each line of treatment to allow for appropriate treatment decisions that can optimize patients’ outcomes. The current report reviews the diagnostic methods to detect TP53 disrup- tion better, the role of TP53 aberrations in treatment decisions and cur- rent therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing tech- nologies for accurate identification of TP53 mutations and the impor- tance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new thera- peutic alternatives become available.
Introduction
Chronic lymphocytic leukemia (CLL) is associated with a highly heterogeneous disease course, with some patients surviving for more than 10 years without need- ing treatment, and others experiencing rapid disease progression and poor out- comes despite effective chemoimmunotherapy.1-3 This heterogeneity is partly explained by the diverse genetic aberrations identified in CLL patients.4-6 In partic- ular, deletions in chromosome 17p [del(17p)] resulting in loss of the TP53 gene, which encodes the tumor-suppressor protein p53, are associated with a poor prog- nosis. Furthermore, mutations of TP53 are also associated with poor prognosis independently of the presence of del(17p).7 Collectively, these deletions and muta- tions will be referred to as TP53 aberrations.
TP53 aberrations belong to the strongest prognostic and predictive markers guid- ing treatment decisions in CLL, and are associated with markedly decreased sur-
Correspondence:
ghia.paolo@hsr.it
Received: May 23, 3018.
Accepted: October 26, 2018. Pre-published: November 15, 2018.
doi:10.3324/haematol.2018.187583
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/1956
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