ESH CLL 2026 | Mechanisms of venetoclax resistance and treatment options in CLL

So we’re here at the ESH-CLL meeting in Stockholm, and I am giving a lecture here on venetoclax resistance mechanisms, which are manifold, and most of the work that has been done so far in this area has looked at patients on continuous venetoclax-based approaches, and really the first mechanism that was identified was mutations in the BCL2 gene, in particular initially a G101V mutation in BCL2, but subsequently the development of several other resistance mutations in BCL2 itself. But it’s become clear in recent years that genetic mechanisms of venetoclax resistance are not alone, and that in fact functional resistance mechanisms are also quite important. This can relate to upregulation of other BCL2 family members in the anti-apoptotic class such as MCL-1 and BCL-XL. This may be particularly relevant in lymph node and bone marrow microenvironments. And work that we did in my lab looks at hyperphosphorylation as an event that may further contribute to venetoclax resistance. By phosphorylation of various BCL-2 family members, this can lead to impairment of venetoclax effects, and this can be reversed through hyperphosphorylation removal or phosphatase activation. So the good news is that even in patients who develop resistance to venetoclax, if they’re naive to prior BTK inhibitors, they should be still quite sensitive to them. So responses are not quite as good as they would be necessarily in a previously untreated patient, but we should still expect the majority of patients to respond to a BTK inhibitor. Now, there are other patients who have had a BTK inhibitor, then get venetoclax, and then go back to a BTK inhibitor. In that scenario, the BTK inhibitor is not usually so effective, at least covalent BTK inhibitors. And that’s where we might think about using a non-covalent inhibitor.

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