iwCLL 2025 | Managing patients with CLL who relapse after triplet therapy

I think this is a really important question, and I would just highlight that different approaches have been taken across these studies. So if you look at, for example, our BOVen study of Zanubrutinib and Obinutuzumab and Venetoclax, as well as the AVO phase two study, not the phase three study, but in the phase two study, both of these studies incorporated retreatment options. Now, these retreatment options were done in a very different way than what we would do as a standard approach, right? So in both studies, we allowed for retreatment at MRD conversion. We did not require iwCLL progression. We also did not require that they meet iwCLL criteria for initiation of additional lines of therapy, which is what we would do outside of a clinical trial. And so interpreting how we approach retreatment, both in the AVO study and with BOVen, I think requires some additional discussion. But in each of these studies, we retreated with the BTK inhibitor and venetoclax. 

So in Dr David’s study, they gave acalabrutinib and venetoclax at retreatment. With BOVen, we gave zanubrutinib and venetoclax at retreatment. And in both cases, we saw that retreatment was quite effective with very high rates of response, as well as with achievement of undetectable measurable residual disease in a number of these patients, and that remissions do appear quite durable. 

The question is, what is the right approach in the real world setting? And I look at it from this perspective. If somebody has received a triplet therapy, I tend to, outside of a retreatment clinical trial option, I would either give the covalent BTK inhibitor again, or I would give venetoclax with or without obinutuzumab, and I would do this based on the durability of response. I’m more inclined to using venetoclax-free treatment, for example, on a patient who’s had at least one year or preferably at least two years, but at least one year of a treatment-free interval for covalent BTK inhibitor-based therapy. I do not feel that you need quite the same duration of treatment-free interval between lines of therapy. I also look at how well these patients have tolerated the prior agents. So if they, for example, had difficulty with the covalent BTK inhibitor, but they tolerated venetoclax quite well, I’m more inclined in that direction and vice versa. So it really is an individualized decision based on the response, remission duration off therapy, and prior tolerability.

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