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Jennifer R. Brown, MD, PhD


Incorporating Low-Burden TP53 Variants Into Treatment Decision-Making in CLL

By: Justine Landin, PhD
Posted: Tuesday, April 5, 2022

Patients with chronic lymphocytic leukemia (CLL) and TP53 mutations with variant allele frequencies as low as 0.1% to 10% may benefit from targeted treatments, according to Sarka Pospisilova, MD, of Masaryk University, Brno, Czech Republic, and colleagues. In fact, low-burden TP53 variations were associated with clonal expansion and reduced overall survival when patients underwent standard CLL treatment, but targeted treatment did not have this effect. The findings of this study were published in the journal Blood.

“Increased risks associated with high-burden TP53 defects support the use of targeted agents for patients with low-burden TP53 mutations in the first-line setting to prevent undesirable clonal expansion that can facilitate genomic instability and further clonal evolution,” stated the study investigators.

Tumor cells separated from peripheral blood were obtained from patients with CLL at the University Hospital Brno. Patients were either entering first-line treatment (n = 511) or were in relapse and entering first-line targeted treatment with BCR or BCL2 inhibitors (n = 159). TP53 mutations were identified using the whole coding region via amplicon-based targeted next-generation sequencing. TP53 variants were identified using polymerase chain reaction amplification of an affected exon/repeated sample.

In the first-line treatment group, 16% of patients were found to have low-burden variant allele frequency (0.1%–10%), which was associated with a reduction in overall survival. However, this was observed only in patients who had not received targeted therapy. Additionally, low-burden TP53 variants showed the highest expansion rates when patients were treated with a regimen including fludarabine, cyclophosphamide, and rituximab (FCR), compared with less-intense regimens or no treatment at all. In the relapse group, 33% of patients harbored low-burden TP53 variants. This group received targeted treatment, and there appeared to be no acceleration of the clonal expansion of low-burden TP53-mutated subclones.

The authors concluded: “When the technical quality is guaranteed, we propose that mutations below 10% variant allele frequency should also be clinically reported.”

Disclosure: For full disclosures of the study authors, visit

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