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Predicting Survival in Patients With CLL: Focus on TP53 Mutations

By: Jenna Carter, PhD
Posted: Friday, September 3, 2021

A recent article published in Clinical Cancer Research presented findings from a retrospective study investigating the clinical impact of subclonal TP53 mutations in patients with chronic lymphocytic leukemia (CLL). The clinical and biological features of TP53 mutations with low variant allele frequency are not well understood in this population but are often linked to resistance to chemoimmunotherapy and reduced survival. Valter Gattei, MD, of the IRCCS National Cancer Institute, Aviano, Italy, and colleagues examined the impact of TP53 mutations above and below a set variant allele frequency threshold and found that TP53 mutations impacted overall and progression free survival.

“Evaluation of the TP53 mutational status is a central pillar of the prognostic algorithms used for the clinical management of CLL patients, predicting both disease progression and suboptimal response to therapy. Next-generation sequencing allows detection of TP53 mutations at a level far below the conventional sequencing threshold recommended by international guidelines,” stated Dr. Gattei and colleagues.

A total of 1,220 CLL cases were retrospectively examined and split into a training cohort (n = 684) and a validation cohort (n = 536). Deep next-generation sequencing was used to validate TP53 mutations in an independent validation cohort of 251 samples from two clinical trials in the UK. Patients were then randomly assigned into groups to receive either fludarabine, cyclophosphamide, and rituximab (FCR) or FCR-like treatments and followed for approximately 83.9 months.

Overall findings revealed that in the training cohort 97 of 684 patients bore 152 TP53 mutations, whereas, in the validation cohort, 71 of 536 patients had 109 TP53 mutations. Additionally, in both cohorts, patients with mutated TP53 experienced significantly shorter overall survival than those with TP53 wild-type disease (P < .0001), irrespective of the TP53 mutation variant allele frequency. Progression-free survival was also reduced in patients bearing high- and low-variant allele frequency mutations (P = .0058) compared with those with wild-type disease. 

Disclosure: The study authors reported no conflicts of interest.  



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