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@article{1836757,
author = {Malčíková, Jitka and Pavlová, Šárka and Kunt Vonková, Barbara and Radová, Lenka and Plevová, Karla and Kotašková, Jana and Pál, Karol and Dvořáčková, Barbara and Ženatová, Marcela and Hynšt, Jakub and Ondroušková, Eva and Panovská, Anna and Brychtová, Yvona and Závacká, Kristýna and Tichý, Boris and Tom, Nikola and Mayer, Jiří and Doubek, Michael and Pospíšilová, Šárka},
article_location = {Washington DC, USA},
article_number = {25},
doi = {http://dx.doi.org/10.1182/blood.2020009530},
keywords = {Low-burden TP53 mutations; CLL; clinical impact; clonal evolution},
language = {eng},
issn = {0006-4971},
journal = {Blood},
title = {Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options},
url = {https://ashpublications.org/blood/article/138/25/2670/475902/Low-burden-TP53-mutations-in-CLL-clinical-impact},
volume = {138},
year = {2021}
}
TY - JOUR
ID - 1836757
AU - Malčíková, Jitka - Pavlová, Šárka - Kunt Vonková, Barbara - Radová, Lenka - Plevová, Karla - Kotašková, Jana - Pál, Karol - Dvořáčková, Barbara - Ženatová, Marcela - Hynšt, Jakub - Ondroušková, Eva - Panovská, Anna - Brychtová, Yvona - Závacká, Kristýna - Tichý, Boris - Tom, Nikola - Mayer, Jiří - Doubek, Michael - Pospíšilová, Šárka
PY - 2021
TI - Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options
JF - Blood
VL - 138
IS - 25
SP - 2670-2685
EP - 2670-2685
PB - American Society of Hematology
SN - 00064971
KW - Low-burden TP53 mutations
KW - CLL
KW - clinical impact
KW - clonal evolution
UR - https://ashpublications.org/blood/article/138/25/2670/475902/Low-burden-TP53-mutations-in-CLL-clinical-impact
N2 - Patientswith chronic lymphocytic leukemia (CLL) bearing TP53 mutations experience chemorefractory disease and are therefore candidates for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter for debate. Herein, we describe clonal evolution scenarios of low-burden TP53 mutations, the clinical impact of which we analyzed in a "real-world" CLL cohort. TP53 status was assessed by targeted next-generation sequencing (NGS) in 511 patients entering first-line treatment with chemo- and/or immunotherapy and 159 patients in relapse before treatment with targeted agents. Within the pretherapy cohort, 16% of patients carried low-burden TP53 mutations (0.1% to 10% VAF). Although their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). In a subgroup with TP53 mutations of 1% to 10% VAF, the impact on OS was observed only in patients with unmutated IGHV who had not received targeted therapy, as patients benefited from switching to targeted agents, regardless of initial TP53 mutational status. Analysis of the clonal evolution of low-burden TP53 mutations showed that the highest expansion rates were associated with fludarabine, cyclophosphamide, and rituximab regimen in both first- and second-line treatments (median VAF increase, 14.8x and 11.8x, respectively) in contrast to treatment with less intense treatment regimens (1.6x) and no treatment (0.8x). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1x). Sporadic cases of TP53 mutations' clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53 variants in clinical decision making.
ER -
MALČÍKOVÁ, Jitka, Šárka PAVLOVÁ, Barbara KUNT VONKOVÁ, Lenka RADOVÁ, Karla PLEVOVÁ, Jana KOTAŠKOVÁ, Karol PÁL, Barbara DVOŘÁČKOVÁ, Marcela ŽENATOVÁ, Jakub HYNŠT, Eva ONDROUŠKOVÁ, Anna PANOVSKÁ, Yvona BRYCHTOVÁ, Kristýna ZÁVACKÁ, Boris TICHÝ, Nikola TOM, Jiří MAYER, Michael DOUBEK and Šárka POSPÍŠILOVÁ. Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options. \textit{Blood}. Washington DC, USA: American Society of Hematology, 2021, vol.~138, No~25, p.~2670-2685. ISSN~0006-4971. Available from: https://dx.doi.org/10.1182/blood.2020009530.
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