Treatment with ibrutinib does not induce a &lt;I&gt;TP53&lt;/I&gt; clonal evolution in chronic lymphocytic leukemia

Cafforio, Luciana; Raponi, Sara; Cappelli, Luca Vincenzo; Ilari, Caterina; Soscia, Roberta; Propris, Maria Stefania De; Mariglia, Paola; Rigolin, Gian Matteo; Bardi, Antonella; Peragine, Nadia; Piciocchi, Alfonso; Arena, Valentina; Mauro, Francesca Romana; Cuneo, Antonio; Guarini, Anna

doi:10.3324/haematol.2020.263715

Cited by 5 publications

(7 citation statements)

References 15 publications

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“…Brieghel and colleagues 20 did find that excluding TP53 ‐m with a VAF < 1% did not affect predictive performance for patients treated with ibrutinib. We captured VAF dynamics of TP53 ‐m in a minority of patients only, though other studies suggest that clonal expansion of TP53 ‐m during treatment with targeted therapy (unlike CIT) is uncommon and not associated with inferior outcomes 18,31 …”

Section: Discussionmentioning

confidence: 99%

“…We captured VAF dynamics of TP53-m in a minority of patients only, though other studies suggest that clonal expansion of TP53-m during treatment with targeted therapy (unlike CIT) is uncommon and not associated with inferior outcomes. 18,31 Studies demonstrating the efficacy of the combination BTKi + VEN in treatment naïve CLL continue to be reported, but whether a fixed duration of combination therapy (that may be associated with increased toxicity) has advantages over sequencing novel agents or over continuous BTKi is still unknown. This is particularly pertinent to patients with high-risk genomics.…”

Section: (B) (A)mentioning

confidence: 99%

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TP53‐altered chronic lymphocytic leukemia treated with firstline Bruton's tyrosine kinase inhibitor‐based therapy: A retrospective analysis

et al. 2022

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Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL); however, it is unknown how variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] influences efficacy of firstline BTKi. We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting. A total of 104/130 (80%) patients had del(17p). TP53-m was noted in 89/110 (81%) patients tested; there were 101 unique TP53-m with an available VAF. The 4-year progression-free survival (PFS) and overall survival (OS) rates were 72.9% and 83.6%.No baseline characteristics including IGHV mutation status and number of TP53 alterations were associated with significant differences in PFS or OS, though a trend toward shorter PFS with increasing karyotypic complexity (hazard ratio 1.08, p = .066) was observed. Del(17p) was identified in <25% of cells in 26/104 (25%) of patients, and 28/101 (28%) of TP53-m were low-burden with a VAF of <10%; outcomes of these patients were similar to those with high-burden lesions. This study suggests that low-burden TP53 alterations should not be ignored when assessing genomic risk in CLL in the era of targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Section: (B) (A)mentioning

confidence: 99%

TP53‐altered chronic lymphocytic leukemia treated with firstline Bruton's tyrosine kinase inhibitor‐based therapy: A retrospective analysis

et al. 2022

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“…A small proportion of TP53 mutations increased. After a prolonged follow-up of greater than 2 years, the overall stability of low-burden TP53 mutations was noted, supporting the notion of the lack of specific positive selection of TP53 mutations under conditions of ibrutinib treatment (31). Nevertheless, all these observations need to be confirmed in a cohort of patients treated with novel agents in the frontline setting.…”

Section: Impact Of Targeted Agents On Low-burden Tp53 Mutationsmentioning

confidence: 68%

“…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).…”

Section: Impact Of Targeted Agents On Low-burden Tp53 Mutationsmentioning

confidence: 99%

Section: Impact Of Targeted Agents On Low-burden Tp53 ...mentioning

confidence: 99%

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

2022

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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.

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The spectrum of subclonal TP53 mutations in chronic lymphocytic leukemia: A next generation sequencing retrospective study

Luca

Cerruti

Lastraioli

et al. 2022

Hematological Oncology

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Chronic lymphocytic leukemia (CLL) is a hematological disorder with complex clinical and biological behavior. TP53 mutational status and cytogenetic assessment of the deletion of the corresponding locus (17p13.1) are considered the most relevant biomarkers associated with pharmaco-predictive response, chemo-refractoriness, and worse prognosis in CLL patients. The implementation of Next Generation Sequencing (NGS) methodologies in the clinical laboratory allows for comprehensively analyzing the TP53 gene and detecting mutations with allele frequencies ≤10%, that is, "subclonal mutations". We retrospectively studied TP53 gene mutational status by NGS in 220 samples from 171 CLL patients. TP53 mutations were found in 60/220 (27.3%) samples and 47/171 (27.5%) patients. Interestingly, subclonal mutations could be detected in 31/60 samples (51.7%) corresponding to 25 patients (25/47, 53.2%). We identified 44 distinct subclonal TP53 mutations Giovanna Cutrona and Mariella Dono contributed equally to this article.

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Treatment with ibrutinib does not induce a <I>TP53</I> clonal evolution in chronic lymphocytic leukemia

Abstract: Not available.

Cited by 5 publications

References 15 publications

TP53‐altered chronic lymphocytic leukemia treated with firstline Bruton's tyrosine kinase inhibitor‐based therapy: A retrospective analysis

TP53‐altered chronic lymphocytic leukemia treated with firstline Bruton's tyrosine kinase inhibitor‐based therapy: A retrospective analysis

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

The spectrum of subclonal TP53 mutations in chronic lymphocytic leukemia: A next generation sequencing retrospective study

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