-
Je něco špatně v tomto záznamu ?
Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options
J. Malcikova, S. Pavlova, B. Kunt Vonkova, L. Radova, K. Plevova, J. Kotaskova, K. Pal, B. Dvorackova, M. Zenatova, J. Hynst, E. Ondrouskova, A. Panovska, Y. Brychtova, K. Zavacka, B. Tichy, N. Tom, J. Mayer, M. Doubek, S. Pospisilova
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Freely Accessible Science Journals od 1946 do Před 1 rokem
Open Access Digital Library od 1946-01-01
Open Access Digital Library od 1946-01-01
ROAD: Directory of Open Access Scholarly Resources
Elsevier Open Archive Journals od 1946 do Před 1 rokem
Odkazy
PubMed
33945616
DOI
10.1182/blood.2020009530
Knihovny.cz E-zdroje
- MeSH
- chronická lymfatická leukemie genetika terapie MeSH
- dospělí MeSH
- imunoterapie MeSH
- Kaplanův-Meierův odhad MeSH
- klonální evoluce * účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace účinky léků MeSH
- nádorové buňky kultivované MeSH
- nádorový supresorový protein p53 genetika MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Patients with 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, 14.8× and 11.8×, respectively) in contrast to treatment with less intense treatment regimens (1.6×) and no treatment (0.8×). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). 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.
- 000
- 00000naa a2200000 a 4500
- 001
- bmc22011645
- 003
- CZ-PrNML
- 005
- 20240103104834.0
- 007
- ta
- 008
- 220425s2021 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1182/blood.2020009530 $2 doi
- 035 __
- $a (PubMed)33945616
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Malcikova, Jitka $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000336506698
- 245 10
- $a Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options / $c J. Malcikova, S. Pavlova, B. Kunt Vonkova, L. Radova, K. Plevova, J. Kotaskova, K. Pal, B. Dvorackova, M. Zenatova, J. Hynst, E. Ondrouskova, A. Panovska, Y. Brychtova, K. Zavacka, B. Tichy, N. Tom, J. Mayer, M. Doubek, S. Pospisilova
- 520 9_
- $a Patients with 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 $a Patients with 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 $a Patients with 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, 14.8× and 11.8×, respectively) in contrast to treatment with less intense treatment regimens (1.6×) and no treatment (0.8×). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). 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.
- 650 _2
- $a dospělí $7 D000328
- 650 _2
- $a senioři $7 D000368
- 650 _2
- $a senioři nad 80 let $7 D000369
- 650 _2
- $a protokoly antitumorózní kombinované chemoterapie $x terapeutické užití $7 D000971
- 650 12
- $a klonální evoluce $x účinky léků $7 D060965
- 650 _2
- $a ženské pohlaví $7 D005260
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a imunoterapie $7 D007167
- 650 _2
- $a Kaplanův-Meierův odhad $7 D053208
- 650 _2
- $a chronická lymfatická leukemie $x genetika $x terapie $7 D015451
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a lidé středního věku $7 D008875
- 650 _2
- $a mutace $x účinky léků $7 D009154
- 650 _2
- $a nádorové buňky kultivované $7 D014407
- 650 _2
- $a nádorový supresorový protein p53 $x genetika $7 D016159
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Kunt Vonková, Barbara $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000315289743 $7 xx0248649
- 700 1_
- $a Radova, Lenka $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/000000018103148X
- 700 1_
- $a Plevova, Karla $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000261488877 $7 xx0158852
- 700 1_
- $a Kotaskova, Jana $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000316727346
- 700 1_
- $a Pal, Karol $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000277264691
- 700 1_
- $a Dvorackova, Barbara $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $1 https://orcid.org/0000000310858767
- 700 1_
- $a Zenatova, Marcela $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $1 https://orcid.org/0000000238556085
- 700 1_
- $a Hynst, Jakub $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/000000020079845X
- 700 1_
- $a Ondrouskova, Eva $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $1 https://orcid.org/0000000308300692
- 700 1_
- $a Panovska, Anna $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $1 https://orcid.org/0000000349553039
- 700 1_
- $a Brychtova, Yvona $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $1 https://orcid.org/000000031038870X
- 700 1_
- $a Zavacka, Kristyna $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/000000020753051X
- 700 1_
- $a Tichý, Boris $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000192527974 $7 xx0312236
- 700 1_
- $a Tom, Nikola $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000174400515
- 700 1_
- $a Mayer, Jiri $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000305679887
- 700 1_
- $a Doubek, Michael $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000212696282
- 700 1_
- $a Pospisilova, Sarka $u Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; and $u Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000171362680
- 773 0_
- $w MED00000807 $t Blood $x 1528-0020 $g Roč. 138, č. 25 (2021), s. 2670-2685
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/33945616 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20220425 $b ABA008
- 991 __
- $a 20240103104829 $b ABA008
- 999 __
- $a ok $b bmc $g 1789316 $s 1162843
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2021 $b 138 $c 25 $d 2670-2685 $e 20211223 $i 1528-0020 $m Blood $n Blood $x MED00000807
- LZP __
- $a Pubmed-20220425