Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study.

Abstract

Complex karyotype identified by chromosome-banding analysis has been shown to have prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genomewide detection of copy-number alterations (CNA) and could therefore be well equipped to detect the presence of a complex karyotype. Current knowledge on genomic arrays in CLL is based on outcomes of single-center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2,293 arrays from 13 diagnostic laboratories according to established standards. CNA were found outside regions captured by CLL fluorescence in situ hybridization probes in 34% of patients, and several of them, including gains of 8q, deletions of 9p and 18p (P<0.01), were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided into three distinct prognostic subgroups based on the number of CNA. In multivariable analysis only high genomic complexity, defined as ≥5 CNA, emerged as an independent adverse prognosticator for time to first treatment (hazard ratio: 2.15; 95% confidence interval: 1.36-3.41; P=0.001) and overall survival (hazard ratio: 2.54, 95% confidence interval: 1.54-4.17; P<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and, in terms of risk stratification, performed at least as well as simultaneous chromosome banding analysis as carried out in 122 patients. Our findings indicate that genomic array is an accurate tool for CLL risk stratification.