Clinical Impact of Clonal, Subclonal Mutations in Chronic Leukemia

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Clonal and subclonal mutations of NOTCH1 and TP53 have an impact on clinical outcome.
Clonal and subclonal mutations of NOTCH1 and TP53 have an impact on clinical outcome.

Clonal and subclonal mutations of NOTCH1 and TP53, clonal mutations of SF3B1, and ATM mutations in chronic lymphocytic leukemia (CLL) have an impact on clinical outcome, a study published in the journal Blood has shown.1

Because genomic aberrations may be critical to the progression of CLL, researchers sought to characterize the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in a large number of CLL cases using ultra-deep next-generation sequencing.

For the study, investigators analyzed the mutations status of 406 untreated CLL cases and examined clonal dynamics in longitudinal samples of 48 patients with CLL.

Results showed that TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), NOTCH mutations in 21.8% (14.2% clonal, 7.6% subclonal), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal).

Researchers found that both clonal and subclonal NOTCH mutations, clonal SF3B1 mutations, and ATM mutations were associated with a shorter time to first treatment regardless of IGHV mutational status.

In contrast, clonal and subclonal TP53 and clonal NOTCH1 mutations, in combination with the IGHV mutational status, predicted for shorter overall survival.

RELATED: Venetoclax Safe, Active in Relapsed CLL, SLL With Poor Prognostic Features

When looking at the longitudinal samples, the study demonstrated that clonal evolution mostly occurred in cases with mutations in the initial samples. Of note, researchers mainly observed clonal evolution after chemotherapy, but also in treatment-naïve patients.

“These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients,” the authors conclude.

Reference

  1. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53SF3B1BIRC3NOTCH1 and ATM mutations in chronic lymphocytic leukemia [published online ahead of print February 2, 2016]. Blood. doi: 10.1182/blood-2015-07-659144.

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