Among patients with chronic lymphocytic leukemia (CLL), targeted resequencing of expanded gene panels may help to illustrate how genetic mutations affect disease prognosis, according to research published in Leukemia.1
Advances in technology have begun to permit increasingly sophisticated analyses of genetic mutations across oncology. In CLL in particular, mutations of TP53, ATM, BIRC3, SF3B1, NOTCH1, RPS15, EGR2, or KRAS are linked to worse outcomes, including overall survival. However, the relationships between these mutations, outcomes, and other factors such as clinical status, immunogenetic background, and copy number alterations in individual patients are unknown.
The phase 3 UK LRF CLL4 trial (CLL4; ClinicalTrials.gov Identifier: NCT00004218), which suggested that fludarabine plus cyclophosphamide yields superior progression-free survival compared with that seen with fludarabine or chlorambucil, included 777 patients with a large amount of biometric data. For the present paper, researchers evaluated data from 499 pretreatment samples from CLL4 “to investigate the incidence, clinicobiological associations, and prognostic [influence] of a panel of 22 genes recurrently mutated in CLL.”
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Overall, the researchers identified 623 mutations, with a mean mutation rate of 1.25 per patient (range, 0-7 per patient) in 335 patients; 93% of all included patients had at least 1 mutation or copy number alteration.
Mutated EGR2 (hazard ratio [HR], 2; P =.012) and TP53 (HR, 1.95; P <.0001) conferred a worse progression-free survival, while mutated BRAF, KRAS, MYD88, NFKBIE, NOTCH1 + 3′UTR, NRAS, RPS15, and SF3B1 did not. All of these mutations were, however, linked with to worse overall survival, particularly EGR2 (HR, 2.91; P <.0001), RPS15 (HR, 2.37; P =.02), and NRAS (HR, 2.21; P =.011).
“Taken together, [these results] demonstrate that a more expansive genomic screening approach provides additional clinical information, thereby helping to establish the precise importance of genetic alterations in the context of other established and emerging biomarkers,” the researchers wrote.
Reference
1. Blakemore SJ, Clifford R, Parker H, et al. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial [published online February 3, 2020]. Leukemia. doi: 10.1038/s41375-020-0723-2
