Blood cancers

Don’t discount low-burden mutations in CLL treatment decisions: US researchers


Patients with chronic lymphocytic leukaemia (CLL) who had low-burden TP53 mutations had similar outcomes when treated first-line with Bruton tyrosine kinase inhibitor (BTKi) therapy, an analysis by US researchers has suggested.

While long-term follow up has shown continuous BTKi treatment to lead to durable remissions in patients with previously untreated TP53-altered CLL, the clinical impact for those with low-burden mutations has not been clear, they reported in the American Journal of Hematology.

With greater use of targeted therapies and next generation genomic sequencing more data is needed on how frequency of mutations and other high-risk signals such as chromosome 17p deletions influence treatment outcomes, they said.

A retrospective analysis of 130 CLL patients with baseline 17p deletion and/or TP53 mutations treated with BTKi with or without venetoclax showed four-year progression-free survival and overall survival rates of 72.9% and 83.6% respectively.

The data, which was from a single centre, showed that no baseline characteristics, including number of TP53 alterations or percentage of cells with 17p deletions, was associated with significant differences in outcomes, the researchers from The University of Texas MD Anderson Cancer Center said.

A quarter of patients had del(17p) in less than 25% of cells and 28/101 (28%) of TP53 mutations were low-burden as defined by allele frequency less than 10% and the outcomes of these patients were similar to those with high-burden lesions, the team found.

But patients with high-burden lesions were more likely to harbour other markers of chromosomal instability and there was also a trend towards shorter progression-free survival with increasing karyotypic complexity.

“This study suggests that low-burden TP53 alterations should not be ignored when assessing genomic risk in CLL in the era of targeted therapy,” they concluded.

Studies are needed to clarify treatment in these high-risk patients with TP53 mutations and “should not exclude patients with low-burden alterations”, they added.

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