Chronic Lymphocytic Leukemia OS Affected by Low-Burden Mutations

Low-burden mutations, or minor clones, of TP53 abnormalities were once thought to be of little significance but that is no longer the case, according to a recent report.

Even low-burden TP53 mutations have an impact on chronic lymphocytic leukemia (CLL) survival, according to a recent analysis.

It is already known that TP53 abnormalities are linked with reduced survival and resistance to chemoimmunotherapy (CIT) in CLL, but this analysis, published in Frontiers in Oncology, indicates that a new threshold is needed in order to better manage to identify TP53-mutated cases.

The clinical impact of low-burden TP53 mutations with a variant allele frequency (VAF) of less than 10% has been debated and the significance unclear, the authors said. The 10% threshold was set by the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) in 2018; the current recommendation is to report TP53 mutations above that level.

However, now that next-generation sequencing (NGS) technologies can detect mutations with a limit of detection of approximately 1% with high confidence, a more thorough assessment of which mutations are clinically significant to future outcomes is vital.

A recent analysis examined the low-burden TP53 mutations, or minor clones, in CLL by looking at their prognostic and predictive impact in 6 different cohorts.

High-risk CLL is indicated by the deletion of the 17p chromosome—Del(17p)—and mutations at TP53 loci, predicting a worse prognosis and predict chemoresistance. Knowing this status is necessary for initial treatment choices as well as subsequent ones, the authors said.

Del(17p) is the most common abnormality affecting the TP53 gene in CLL; less common are cases solely with a TP53 gene mutation(s) or and less often a 17p deletion.

Although conventional karyotyping combined with fluorescence in situ hybridization (FISH) could detect cells with the deletion of the TP53 chromosome with good sensitivity, this original method failed to catch up to 40% of individuals with only gene mutations. Combining FISH with Sanger sequencing improved detection, but it was not until NGS that the clonal heterogeneity of CLL could be examined.

TP53 abnormalities account for about 10% of naïve-treatment patients, but they are found in more than 40% of patients with fludarabine-refractory CLL, showing the clonal evolution of TP53 mutation induced by chemotherapy.

Newer longitudinal studies using NGS sequencing before and after fludarabine treatment in patients who became resistant show that low-burden TP53 mutations were present before treatment began and expanded at relapse to become the predominant clone, the authors said. The pathogenicity of the mutations was confirmed using different databases.

“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,” they wrote.

In other studies, sequential samples from treated patients showed that “low-burden mutations that initially occur in a minority of cells are true mutations that expand under selective pressure.”

In regard to the influence of low-burden mutations on overall survival (OS), 1 study did not see a clinical impact but did identify an intermediate-risk group. This study had a threshold of 12% for discriminating low- and high-burden TP53 mutations and a minimum VAF >1%, the authors said.

Another study showed that neither high nor low burden TP53 mutations at the time of CLL diagnosis had an impact on OS.

But most studies on treatment-naïve patients showed that low-burden TP53 mutations significantly lowered OS compared with cases without the mutations; in addition, the impact on OS was the same for minor clones or high-burden TP53 mutations.

“These observations suggest that TP53 mutation testing should be performed exclusively before treatment,” the authors said. In addition, lowering the VAF threshold to below >1% could be important for treatment decisions.

Reference

Lazarian G, Cymbalista F, Baran-Marszak F Impact of low-burden TP53 mutations in the management of CLL. Front Oncol. Published online February 8, 2022. doi:10.3389/fonc.2022.841630