Robak, Tadeusz

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EDITORIALwww.journals.viamedica.pl/acta_haematologica_polonica 7575Acta Haematologica Polonica 2021Number 2, Volume 52, pages 75–76DOI: 10.5603/AHP.2021.0012ISSN 0001–5814e-ISSN 2300–7117Copyright © 2021 The Polish Society of Haematologists and Transfusiologists, Insitute of Haematology and Transfusion Medicine. All rights reserved.Address for correspondence: Tadeusz Robak, Department  of Hematology, Medical University of Lodz and Copernicus  Memorial Hospital, Ciolkowskiego 2, Lodz, Poland,  e-mail: tadeusz.robak@umed.lodz.plReceived: 18.01.2021 Accepted: 19.01.2021This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.TP53 mutations in chronic lymphocytic leukemiaTadeusz RobakDepartment of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, PolandThe prognostic and predictive value of del (17p)/TP53 mu-tation in patients with chronic lymphocytic leukemia (CLL) is well established [1, 2]. An abnormality in TP53 indepen-dently predicts rapid CLL progression and shorter survival, even in the era of novel agents. In addition, patients with TP53 abnormalities or 17p(del) demonstrate significantly decreased time to treatment initiation than those without TP53 aberration [3]. Although CLL patients with leukemia cells characterized by del(17p) and/or TP53 mutation have a poor prognosis when treated with fludarabine- -based chemotherapy [1], they do significantly better when treated with non-chemotherapeutic agents such as small molecule inhibitors of Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), or B-cell lymphoma 2 (BCL-2) inhibitors. Such TP53 abnormalities are now included in the IPI-CLL (International Prognostic Index for Chronic Lymphocytic Leukemia) prognostic model for CLL: patients with 17p deletion, TP53 mutation, or both, are considered to be at high risk [4].For many years, the standard of care has been based on the detection of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) [1]. As monoallelic mutations of TP53 equally affect treatment results, novel methods such as next-generation sequencing (NGS) and functional assays have been developed to improve detection of TP53 abnor-malities. In several European countries, and in North Ame-rica, molecular tests for TP53 abnormalities are routinely used as a part of CLL prognostication. Most Polish centers have only used the FISH method to identify TP53 locus re-moval (i.e. 17p deletion); however, as monoallelic muta-tions also have significant negative prognostic impact, it is also recommended to screen for both TP53 mutations and deletions. The most common approach to such screening is NGS, and this is the most convenient option for routine analysis. In addition, ultra-deep NGS permits the detection of minor clones with TP53 mutations, even below 1% [5].Pepek et al. [6], in this issue of “Acta Haematologica Polonica”, report the results of a study examining the use of NGS in identifying TP53 mutations in relapsed and re-fractory chronic lymphocytic leukemia (CLL) patients in Poland. The study was initiated by the Polish Adult Leuke-mia Group (PALG) as an observational study and educa-tional project aimed primarily at providing Polish hema-tologists with the possibility of testing TP53 mutations by NGS. Additional objectives were to provide laboratory and clinical experience on TP53 mutations in CLL, and to identify subclonal TP53 mutations and other selected gene abnormalities which play a possible pathogenic and prognostic role in CLL.TP53 abnormalities are less common in previously-un-treated CLL patients than in relapsed or refractory patients. In addition, while no more than 5% of CLL patients are be-lieved to carry the 17p deletion at diagnosis, it has been recorded in over 40% of patients with refractory CLL [7]. It is well established that TP53 mutation analysis should be performed in CLL patients before treatment initiation, and that patients with TP53 mutation should be considered for alternative treatment approaches. In the recent guidelines regarding the detection of tumor protein p53 expression, Eichhorst et al. [2] for the first time have recommended the use of FISH to identify chromosome 17 deletion [del(17p)]; if del(17p) is absent, TP53 sequencing should be perfor-med to detect the presence of TP53 gene mutation. In such cases, it is recommended to test at least exons 4–10, but exons 2–11 should be evaluated. As additional genetic abnormalities can be acquired during the course of the disease, genetic analyses for del(17p)/TP53 mutations) should be repeated before the onset of any subsequent treatment in relapsed patients [8–10].In conclusion, NGS analysis represents a sensitive and reproducible technique for the screening of TP53 gene mu-tations, and should be performed routinely in CLL patients before each treatment initiation.Authors’ contributionsTR — sole author.Acta Haematologica Polonica 2021, vol. 52, no. 2www.journals.viamedica.pl/acta_haematologica_polonica76Conflict of interestNone.Financial supportNone.EthicsThe work described in this article has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments invol-ving humans; EU Directive 2010/63/EU for animal exper-iments; Uniform Requirements for Manuscripts submitted to Biomedical Journals.References1. Te Raa GD, Kater AP. TP53 dysfunction in CLL: implications for progno-sis and treatment. Best Pract Res Clin Haematol. 2016; 29(1): 90–99, doi: 10.1016/j.beha.2016.08.002, indexed in Pubmed: 27742075.2. Eichhorst B, Robak T, Montserrat E, et al. ESMO Guidelines Commit-tee. Electronic address: clinicalguidelines@esmo.org. Chronic lympho-cytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, tre-atment and follow-up. Ann Oncol. 2021; 32(1): 23–33, doi: 10.1016/j.annonc.2020.09.019, indexed in Pubmed: 33091559.3. Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 muta-tions in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aber-rant karyotype. Leukemia. 2009; 23(1): 117–124, doi: 10.1038/ /leu.2008.274, indexed in Pubmed: 18843282.4. An international prognostic index for patients with chronic lymp-hocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016; 17(6): 779–790, doi: 10.1016/s1470-2045(16)30029-8.5. Malcikova J, Pavlova S, Kozubik KS, et al. TP53 mutation analysis in clinical practice: lessons from chronic lymphocytic leukemia. Hum Mutat. 2014; 35(6): 663–671, doi: 10.1002/humu.22508, indexed in Pubmed: 24415659.6. Pepek M, Pula B, Machnicki MM, et al. Results of Polish Adult Leuke-mia Study Group (PALG) project assessing TP53 mutations with next--generation sequencing technology in relapsed and refractory chronic lymphocytic leukemia patients — 18 months update. Acta Haematol Pol. 2021; 52(2): 94–102, doi: 10.5603/AHP.2021.0015.7. Rigolin GM, Saccenti E, Bassi C, et al. Extensive next-generation sequencing analysis in chronic lymphocytic leukemia at diagnosis: clinical and biological correlations. J Hematol Oncol. 2016; 9(1): 88, doi: 10.1186/s13045-016-0320-z, indexed in Pubmed: 27633522.8. Malcikova J, Tausch E, Rossi D, et al. European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) — TP53 network. ERIC re-commendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpre-tation. Leukemia. 2018; 32(5): 1070–1080, doi: 10.1038/s41375-017-0007-7, indexed in Pubmed: 29467486.9. Kantorova B, Malcikova J, Smardova J, et al. TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods. Tumour Biol. 2015; 36(5): 3371–3380, doi: 10.1007/ /s13277-014-2971-0, indexed in Pubmed: 25527155.10. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chro-nic lymphocytic leukemia. Blood. 2016; 127(17): 2122–2130, doi: 10.1182/blood-2015-07-659144, indexed in Pubmed: 26837699. 

TP53 mutations in chronic lymphocytic leukemia

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TP53 mutations in chronic lymphocytic leukemia

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