Sequential karyotypic and FISH analysis in patients with CLL show evidence of genomic evolution in 10 – 20% of cases. In addition, telomere dysfunction has been shown to correlate with genomic instability and thus may be involved in genomic evolution. Since specific deletions have been found to be associated with different disease prognosis, the acquisition of secondary aberrations may impact on disease progression. To investigate this, DNA samples of 29 patients presenting with either stage A0 CLL or mBL were analysed at two different time points, PT and FU (median time between sample: 85 months. Patients were grouped as either stable (for 5 or more years) or progressive (treated within 3 years). High resolution Affymetrix SNP6.0 array was used to investigate copy number aberrations and loss of heterozygosity at both time points and FISH/karyotype data was used for confirmation and validation.. In addition, the high resolution STELA technique was used to measure telomere length at each time point. It was found that patients with progressive as well as stable disease had acquired secondary aberrations at FU, including novel deletions and gains. Telomere loss was also found in both groups of patients. 11q/17p aberrations and large (>2Mb) but not small (<2Mb) 13q deletion (P=0.03) were associated with genomic evolution and telomere loss. Several established biomarkers, including IgVH mutational status shown not such correlation. A number of patients identified as good risk at diagnosis, acquired adverse genomic features at follow-up. These included the acquisition of a class II 13q deletion and a complex genomic profile. Finally, case studies enabled a more detailed analysis and revealed the presence of secondary aberrations in conjunction with sudden shifts in WBC count that are a marker of disease progression. This study supports the need to detect genomic changes throughout the course of the disease, and genomic aberrations can be acquired and effect prognosis