ESH CLL 2026 | Clonal evolution and genetic drivers of progression in CLL

Yes, I have presented clonal evolution in CLL and so clonal evolution refers to the natural process through which cancer cells continuously accumulate genetic events leading to intraclonal heterogeneity and to provide an advantage within a tissue ecosystem. And so there are two major driving forces. The first is diversification, genetic diversification. The second is the selective pressure exerted by the immune system or therapeutic intervention. So it makes total sense in CLL because in CLL, the CLL is marked by multiple subclones coexisting, while the mutational burden is relatively low compared with other cancers. And so the clinical evolution has been a theme that was reactivated through the advent of next-generation sequencing that was able to detect subclones at unprecedented resolution. So in CLL, we were able to quantify clonal evolution and by doing multiple sampling over time to assess the subclonal composition and how it changes over time through the shift of subclones. So it has nominated key CLL drivers as providing an advantage in vivo in patients. And the ultimate stage of clonal evolution in CLL is the Richter transformation, and we have recently highlighted the Richter drivers, including numerous copy number variations and dramatic genetic lesions, such as chromothripsis, kataegis, and whole-genome doubling, that was in line with the macroevolution model. And interestingly, these copy number variations were detectable in the peripheral blood, in the cell-free DNA of patients with Richter transformation. And so it has a clear clinical application, taking into account that this was also possible to detect each month before clinical transformation. And so the other interest of studying clonal evolution is to understand and optimize resistance. So we have highlighted clonal evolution on venetoclax, which is a BCL2 inhibitor, so that is to BCL-2 mutation, but we also highlighted through in vivo modeling of clonal evolution on venetoclax, the amplification of MCL-1, and we have recently confirmed it in a large cohort of patients, among these patients who relapsed after diverse venetoclax regimens, highlighting that a third of the cohort had MCL1 amplification with limited overlap with BCL2 mutations. So we can certainly hope that better understanding, better quantifying clonal evolution will help in optimizing the therapeutic sequencing in CLL.

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