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

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 des...

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Published in:	Blood Vol. 138; no. 25; pp. 2670 - 2685
Main Authors:	Malcikova, Jitka, Pavlova, Sarka, Kunt Vonkova, Barbara, Radova, Lenka, Plevova, Karla, Kotaskova, Jana, Pal, Karol, Dvorackova, Barbara, Zenatova, Marcela, Hynst, Jakub, Ondrouskova, Eva, Panovska, Anna, Brychtova, Yvona, Zavacka, Kristyna, Tichy, Boris, Tom, Nikola, Mayer, Jiri, Doubek, Michael, Pospisilova, Sarka
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-12-2021 American Society of Hematology
Subjects:	Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - therapeutic use Clonal Evolution - drug effects Female Humans Immunotherapy Kaplan-Meier Estimate Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - therapy Lymphoid Neoplasia Male Middle Aged Mutation - drug effects Tumor Cells, Cultured Tumor Suppressor Protein p53 - genetics
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Summary:	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. •Low-burden TP53 mutations in CLL do not significantly affect the response duration to chemo- and/or immunotherapy, but shorten OS.•Clonal expansion of low-burden TP53 mutations in CLL is associated with intense chemoimmunotherapy, but not with targeted therapy. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J. Malcikova, S. Pavlova, and B.K.V. contributed equally to this study as first authors.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood.2020009530