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

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Publikace nespadá pod Ústav výpočetní techniky, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

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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

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Blood
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://ashpublications.org/blood/article/138/25/2670/475902/Low-burden-TP53-mutations-in-CLL-clinical-impact
Doi http://dx.doi.org/10.1182/blood.2020009530
Klíčová slova Low-burden TP53 mutations; CLL; clinical impact; clonal evolution
Popis 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.
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