Low-burden TP53 mutations in CLL: clinical impact and clonal
evolution within the context of different treatment options

J 2021

Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options

MALČÍKOVÁ, Jitka, Šárka PAVLOVÁ, Barbara KUNT VONKOVÁ, Lenka RADOVÁ, Karla PLEVOVÁ et. al.

Basic information

Original name

Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options

Authors

MALČÍKOVÁ, Jitka (203 Czech Republic, belonging to the institution), Šárka PAVLOVÁ (203 Czech Republic, belonging to the institution), Barbara KUNT VONKOVÁ (203 Czech Republic, belonging to the institution), Lenka RADOVÁ (203 Czech Republic, belonging to the institution), Karla PLEVOVÁ (203 Czech Republic, belonging to the institution), Jana KOTAŠKOVÁ (203 Czech Republic, belonging to the institution), Karol PÁL (703 Slovakia, belonging to the institution), Barbara DVOŘÁČKOVÁ (203 Czech Republic, belonging to the institution), Marcela ŽENATOVÁ (203 Czech Republic, belonging to the institution), Jakub HYNŠT (203 Czech Republic, belonging to the institution), Eva ONDROUŠKOVÁ (203 Czech Republic, belonging to the institution), Anna PANOVSKÁ (203 Czech Republic, belonging to the institution), Yvona BRYCHTOVÁ (203 Czech Republic, belonging to the institution), Kristýna ZÁVACKÁ (203 Czech Republic, belonging to the institution), Boris TICHÝ (203 Czech Republic, belonging to the institution), Nikola TOM (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution), Michael DOUBEK (203 Czech Republic, belonging to the institution) and Šárka POSPÍŠILOVÁ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Blood, Washington DC, USA, American Society of Hematology, 2021, 0006-4971

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 25.476

RIV identification code

RIV/00216224:14740/21:00119667

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1182/blood.2020009530

UT WoS

000739837800009

Keywords in English

Low-burden TP53 mutations; CLL; clinical impact; clonal evolution

Abstract

V originále

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.

Links

EF16_026/0008448, research and development project

Name: Analýza českých genomů pro teranostiku

GA19-11299S, research and development project

Name: Úloha transpozibilních elementů u hematologických malignit

Investor: Czech Science Foundation

GA19-15737S, research and development project

Name: Alternativní mechanismy deregulace p53 dráhy u chronické lymfocytární leukémie

Investor: Czech Science Foundation, Alternative mechanisms of deregulation of the p53 pathway in chronic lymphocytic leukemia

MUNI/A/1595/2020, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII (Acronym: VýDiTeHeMa VIII)

Investor: Masaryk University

NV19-03-00091, research and development project

Name: Komplexní prognostický a prediktivní panel pro pacienty s chronickou lymfocytární leukémií: nástroj sekvenování nové generace vhodný pro klinickou praxi i studium genetického pozadí průběhu choroby

Investor: Ministry of Health of the CR

90132, large research infrastructures

Name: NCMG II

Citovat

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. 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.

@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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