ASH 2024 | Driver mutations predicting clinical outcomes upon MRD-guided venetoclax plus ibrutinib in R/R CLL

So for patients with relapsed-refractory CLL, I believe that we’ll still consider rituximab- venetoclax based on the MURANO trial to be the standard of care. But we have very few registration trials for this patient population. But we had a Phase II trial, the HOVON-141/VISION trial, looking at MRD-guided ibrutinib-venetoclax for the population of patients with relapsed-refractory CLL. As a caveat, this was in the area where first-line treatment had been kinase inhibitor immunotherapy. And what we see here is that we can actually achieve very sustainable remissions for patients, even if we stop patients achieving an undetectable MRD state after ibrutinib-venetoclax. We next wanted to assess if we can predict which patient population would actually be very likely to achieve undetectable MRD and for patients achieving undetectable MRD who would need to stay on treatment. And to do that, we sequenced a targeted lymphoid panel from mutations at time of baseline because we have not seen any of the well-known risk factors like IGHV mutational status, IGHV unmutated status, or complex karyotype or TP53 aberrations to correlate with the risk of progression or with the chance of achieving undetectable MRD. And based on this panel of driver mutations, we saw that four different mutations called BCL2, not BCLX, actually identified the population that would have a shorter progression-free survival. So this is the next step towards personalizing treatment for patients with CLL, even in the relapsing factor setting.

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