Clonal Evolution in Chronic Lymphocytic Leukemia is Scant in Relapsed But Accelerated in Refractory Cases

Abstract

Clonal and subclonal evolution is involved in the progression of chronic lymphocytic leukemia (CLL). To link evolutionary patterns to different disease courses, we performed a long-term longitudinal mutation profiling study of a cohort of CLL patients. Tracking of somatic mutations and their changes in allele frequency over time and assessing the underlying cancer cell fraction revealed highly distinct evolutionary patterns. Surprisingly, in long-term stable disease and in relapse after long-lasting clinical response to treatment, subclonal shifts are minor. In contrast, in refractory disease major clonal shifts occur although little impact occurs on leukemia cell counts. As this striking pattern in refractory cases is not linked to a strong contribution of known CLL driver genes, the evolution is mostly driven by treatment-induced selection of sub-clones underlining the need for novel, non-genotoxic treatment regimens.