Evaluating the Genetic Landscape of Patients With Ultra-Stable CLL

Submitted by onc_editor on Wed, 01/31/2018 - 12:25

A recent study attempted to identify genetic biomarkers for patients with chronic lymphocytic leukemia (CLL) at diagnosis who exhibit indolent disease.

Results of the study were published in Annals of Oncology (online January 22, 2018; doi:10.1093/annonc/mdy021).

Prior research has shown CLL to follow a heterogeneous clinical course. While many patients require immediate treatment at diagnosis, other patients show an initial indolent phase followed by either quick progression or progression decades in the future. Importantly, patients who progress with initial indolent disease typically display mutated IGHV genes and a favorable fluorescence in situ hybridization (FISH) profile.

A group of Italian researchers conducted a study to better understand the relationship between ultra-stable CLL and immunogenetics. A total of 40 patients with ultra-stable CLL were enrolled and underwent extensive characterization including whole-exome sequencing, ultra-deep sequencing, and copy number aberration analysis to characterize their genomic landscape.

Patients with absence of disease progression for more than 10 years after diagnosis were included in the study. To recognize ultra-stable CLL at diagnosis, researchers utilized microarray analysis that compared ultra-stable CLL with non-ultra-stable CLL exhibiting similar immunogenetics features (eg, mutated IGHV, favorable FISH).

Whole-exome sequencing was performed in 20 ultra-stable CLL cases and 84 non-silent somatic mutations in 78 genes were identified. After re-testing in a validation cohort of 20 further ultra-stable CLL cases, no recurrent lesion was identified. Additionally, no clonal mutations of NOTCH1, BIRC3, SF3B1, and TP53 were found, including ATM and other potential progression-driving mutations.

Copy number aberration analysis identified 31 lesions, none of which exhibited poor prognostic impact. No novel recurrent lesions were identified, and most cases showed no lesions (38%) or an isolated del(13q) (31%).

Researchers reported that the expression of six genes—selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR in a cohort of 79 patients with CLL (ultra-stable CLL, n = 58; non-ultra-stable CLL, n = 21)—permitted the design of a decision-tree capable of recognizing ultra-stable disease at diagnosis.

In their concluding remarks, researchers noted that the genetic landscape of ultra-stable CLL is characterized by the absence of known unfavorable driver mutations, unfavorable copy number aberration, and of novel recurrent genetic lesions. “Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of six genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades,” they wrote.—Zachary Bessette