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.

Základní údaje

Originální název

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

Autoři

MALČÍKOVÁ, Jitka (203 Česká republika, domácí), Šárka PAVLOVÁ (203 Česká republika, domácí), Barbara KUNT VONKOVÁ (203 Česká republika, domácí), Lenka RADOVÁ (203 Česká republika, domácí), Karla PLEVOVÁ (203 Česká republika, domácí), Jana KOTAŠKOVÁ (203 Česká republika, domácí), Karol PÁL (703 Slovensko, domácí), Barbara DVOŘÁČKOVÁ (203 Česká republika, domácí), Marcela ŽENATOVÁ (203 Česká republika, domácí), Jakub HYNŠT (203 Česká republika, domácí), Eva ONDROUŠKOVÁ (203 Česká republika, domácí), Anna PANOVSKÁ (203 Česká republika, domácí), Yvona BRYCHTOVÁ (203 Česká republika, domácí), Kristýna ZÁVACKÁ (203 Česká republika, domácí), Boris TICHÝ (203 Česká republika, domácí), Nikola TOM (203 Česká republika, domácí), Jiří MAYER (203 Česká republika, domácí), Michael DOUBEK (203 Česká republika, domácí) a Šárka POSPÍŠILOVÁ (203 Česká republika, garant, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 25.476

Kód RIV

RIV/00216224:14740/21:00119667

Organizační jednotka

Středoevropský technologický institut

DOI

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

UT WoS

000739837800009

Klíčová slova anglicky

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

Štítky

14110212, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 15. 10. 2024 14:25, Ing. Martina Blahová

Anotace

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.

Návaznosti

EF16_026/0008448, projekt VaV

Název: Analýza českých genomů pro teranostiku

GA19-11299S, projekt VaV

Název: Úloha transpozibilních elementů u hematologických malignit

Investor: Grantová agentura ČR, The role of transposable element activity in hematological malignacies

GA19-15737S, projekt VaV

Název: Alternativní mechanismy deregulace p53 dráhy u chronické lymfocytární leukémie

Investor: Grantová agentura ČR, Alternativní mechanismy deregulace p53 dráhy u chronické lymfocytární leukémie

MUNI/A/1595/2020, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII (Akronym: VýDiTeHeMa VIII)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII

NV19-03-00091, projekt VaV

Název: 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: Ministerstvo zdravotnictví ČR, Comprehensive prognostic and predictive panel for chronic lymphocytic leukemia: a next-generation sequencing tool suitable for clinical practice and study of genetic architecture behind the disease progress

90132, velká výzkumná infrastruktura

Název: 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 a 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, roč. 138, č. 25, s. 2670-2685. ISSN 0006-4971. Dostupné z: 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 a 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, roč.~138, č.~25, s.~2670-2685. ISSN~0006-4971. Dostupné z: https://dx.doi.org/10.1182/blood.2020009530.

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