High-risk clonal evolution in chronic B-lymphocytic leukemia: single-center interphase fluorescence in situ hybridization study and review of the literature

Background We studied the relation of clonal evolution (CE) in Chronic B-lymphocytic leukemia (CLL) with prognostic factors and the correlation between CE and disease progression and overall survival. Methods With interphase fluorescence in situ hybridization (FISH) analysis, we looked for 11q22 deletion, 17p13 deletion, and trisomy 12. A second FISH was performed approximately 3 yr after the first one or earlier in case of disease progression. Results High-risk CE, defined as the acquisition of a new 11q or 17p deletion, was observed in 11.5% (11/95) of patients with CLL. The relative risk of CE was not influenced by CD38 and ZAP-70 expression, mutational status of the immunoglobulin heavy chain gene (IgVH), lymphocyte doubling time, and genomic aberrations observed with the first FISH or by treatment given between the sequential genetic analyses. Patients with high-risk CE had a significant shorter survival time (59 months vs. not reached, P = 0.0367). Multivariate analysis identified CE as the strongest independent prognostic marker regarding survival [hazard ratio (HR) 4.1, P = 0.01]. Clonal fluctuation, defined as disappearance of the 11q or 17p deletion, was seen in 11.5% (11/95) of patients. Most patients lost the high-risk clone after treatment despite persistence of a malignant clone. The disappearance of these genomic aberrations did not ameliorate outcome. A few patients have lost spontaneously a small 17p clone. Conclusion This study confirms that CE and clonal fluctuation are common phenomena in CLL. CE was not limited to patients with pre-existing adverse prognostic factors. Acquiring high-risk CE was identified as the strongest independent prognostic factor for impaired survival.