Abstract
In chronic lymphocytic leukemia (CLL), TP53 abnormalities are associated with reduced survival and resistance to chemoimmunotherapy (CIT). The recommended threshold to clinically report TP53 mutations is a matter of debate given that next-generation sequencing technologies can detect mutations with a limit of detection of approximately 1% with high confidence. However, the clinical impact of low-burden TP53 mutations with a variant allele frequency (VAF) of less than 10% remains unclear. Longitudinal analysis before and after fludarabine based on NGS sequencing demonstrated that low-burden TP53 mutations were present before the onset of treatment and expanded at relapse to become the predominant clone. Most studies evaluating the prognostic or predictive impact of low-burden TP53 mutations in untreated patients show that low-burden TP53 mutations have the same unfavorable prognostic impact as clonal defects. Moreover, studies designed to assess the predictive impact of low-burden TP53 mutations showed that TP53 mutations, irrespective of mutation burden, have an inferior impact on overall survival for CIT-treated patients. As low-burden and high-burden TP53 mutations have comparable clinical impacts, redefining the VAF threshold may have important implications for the clinical management of CLL.
Highlights
The heterogeneous clinical course of chronic lymphocytic leukemia has highlighted the need to define prognostic and predictive markers to improve the management of patients [1]
Blakemore et al.’s [34] LRF CLL4 clinical trial could not demonstrate inferior survival associated with cases harboring
The main focus of this review was to demonstrate that lowburden TP53 mutations have an impact on chronic lymphocytic leukemia (CLL) survival
Summary
The heterogeneous clinical course of chronic lymphocytic leukemia has highlighted the need to define prognostic and predictive markers to improve the management of patients [1]. Longitudinal retrospective studies based on NGS sequencing of fludarabine relapsed/refractory TP53 mutated patient samples showed that low-burden TP53 mutations were detected early in the disease course and before the onset of chemotherapy These pre-treatment samples were initially screened using Sanger sequencing, and mutations were missed due to the lack of sensitivity of the technique. The fact that a given low-burden TP53 variant detected at the time of treatment initiation is found at relapse after a fludarabine-based regimen clearly demonstrates that these minor clones are not sequencing artifacts and highlights the need to redefine this threshold for optimal clinical practice. Given the natural clonal evolution of the disease with time, TP53 minor clones can be acquired during the disease course, independent of any pressure of selection induced by chemotherapy This finding justifies early and iterative screening for TP53 abnormalities during follow-up and before each new line of treatment with a sensitive sequencing technique.
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