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

Abstract

Chronic lymphocytic leukemia (CLL) patients with TP53 mutations experience chemo-refractory disease and are therefore indicated for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter of debate. Here we describe clonal evolution scenarios of low-burden TP53 mutations and analyzed their clinical impact in a "real-world" CLL cohort. TP53 status was assessed by targeted NGS in 511 patients entering first-line treatment with chemo/immunotherapy and 159 relapsed patients treated with targeted agents. Within the pre-therapy cohort, 16% of patients carried low-burden TP53 mutations (0.1-10% VAF). While their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). For a subgroup with TP53 mutations of 1-10% VAF, the impact on OS was only observed in patients with unmutated IGHV that 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 FCR in both first and second-line treatment (median VAF increase 14.8x and 11.8x, respectively) in contrast to treatment with less intense chemo/immunotherapy regimens (1.6x) and without treatment (0.8x). In the relapsed 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-mut 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.

Impact of Low-Burden TP53 Mutations in the Management of CLL

“…The impact of TP53 mutations on OS also depended on the composition of the cohort with different proportions of patients carrying mutated IGHV or 17p deletion or variable times to diagnosis. Indeed, newly diagnosed patients often harbor mutated IGHV, and TP53 abnormalities may not have a negative impact on the indolent disease course (23,(28)(29)(30)35). These observations suggest that TP53 mutation testing should be performed exclusively before treatment.…”

“…While TP53 abnormalities account for approximately 10% of naïve-treatment patients, these abnormalities are found in greater than 40% of patients with fludarabine-refractory CLL, which highlights the phenomenon of clonal evolution of TP53 mutation induced by chemotherapy (13). Despite the current recommendations that consider <10% of minor clones to be of uncertain significance, accumulating evidence based on longitudinal studies argues for the clinical relevance to report TP53 minor clones (15,18,20,(23)(24)(25). NGS sequencing of serial samples before and after treatment has allowed characterization of the dynamics of the minor clones under treatment and demonstrated their biological and clinical relevance.…”

“…Given that TP53-mutated patients can benefit from targeted therapies with improved remission duration, there is a need to evaluate the impact of these therapies on the evolution of the TP53-mutated clone. Data on the clonal evolution of low-burden TP53 mutations upon targeted treatment are limited (23,31). Malcikova et al showed that upon the use of BcR or bcl2 inhibitors as a second line of treatment, the percentage of VAF in the residual lymphocytosis remains stable, which reflects the efficacy of these treatments on the mutated clones (23).…”

“…Data on the clonal evolution of low-burden TP53 mutations upon targeted treatment are limited (23,31). Malcikova et al showed that upon the use of BcR or bcl2 inhibitors as a second line of treatment, the percentage of VAF in the residual lymphocytosis remains stable, which reflects the efficacy of these treatments on the mutated clones (23). Indeed, BcR and bcl2 inhibitors target the BcR signaling pathway and apoptosis, respectively, and therefore overcome the p53 pathway.…”

“…Given that TP53 -mutated patients can benefit from targeted therapies with improved remission duration, there is a need to evaluate the impact of these therapies on the evolution of the TP53 -mutated clone. Data on the clonal evolution of low-burden TP53 mutations upon targeted treatment are limited ( 23 , 31 ). Malcikova et al.…”