ASH 2021 | Customizing Care in CLL With BTK Inhibitors

We had a really great session on how to customize care in CLL, specifically centered around BTK inhibitors. So it was myself and my co-presenters, Dr John Byrd and Dr Jacqueline Barrientos, who each covered a different aspect of it. As I’m sure most people are aware by now, BTK inhibitors are an extremely important class of drugs for people with CLL, really has changed the natural history of the disease but it’s important to know how to use them. Not only when to select BTK inhibitors over other good therapies like venetoclax, who might most benefit from them, but also specifically how to manage toxicities with them. And then I was talking about sequencing BTK inhibitors with other agents, which one to pick first, what to do if people become resistant. And I think these are really important questions.
The adverse event or toxicity management is really important, because these are continuously dosed, very long-term therapies. Even what could seem to be a minor toxicity can really impact someone’s life over the period of years that they might take the drug. And we’re fortunate now that there are three covalent, irreversible BTK inhibitors that all have a similar mechanism. Ibrutinib, which was a first-in-class, then acalabrutinib and zanubrutinib, which isn’t approved at this time in CLL, but has a lot of data and can be used off-label. So not only how to manage toxicities but also just the idea that for responding patients, switching between the available agents for adverse events can be a really important way to handle kind of intolerance. Resistance to one of those three drugs really means resistance to all of them so I would not expect that someone who had progressed on ibrutinib would benefit from acalabrutinib and BTK inhibitor resistance is an important problem and will continue to be so as more people are taking these drugs and then relapse or have progressive disease after taking them.
Venetoclax is the current FDA-approved standard of care drug that the most data after BTK inhibitors but the median progression-free survival in a dedicated study in this population is only about 24 months. And for CLL patients that could otherwise expect a very long survival, this isn’t really sufficient. We spent a lot of time focusing on kind of how to think about patients with BTK resistance and I think one of the better strategies now is to move to a reversible BTK inhibitor that binds at a different site that can be useful in patients with resistance mediated by BTK C481S mutation. That’s a drug binding site and these reversible covalent drugs bind at a different site and kind of get around that so it allows patients to continue to benefit from BTK inhibition.
And then also kind of this exciting area for BTK inhibitor resistance and especially those who are also resistant to venetoclax, which are called double-refractory, not only novel mechanism drugs, in some cases, reversal with BTK inhibitors but also cellular therapy such as CAR-T is something that’s still investigational but could be very important for patients kind of in that area.
There was also some time spent on how to select patients for BTK inhibitors, like who might best benefit. And I think the strongest data in terms of disease biology is going to be patients with deletion 17p or TP53 disruptions, where you really see very similar progression-free survival to people without that high risk feature with continuous BTK inhibitor. And that’s not the case with the fixed duration venetoclax regimens. Really those high risk patients biologically benefit more from BTK inhibition. And then of course there’s patient factors as always that should drive therapy selection. Everyone in the field going back longer than I’ve been working in this field has tried so hard to make CLL therapy not only be more effective but also more tolerable. And in doing that, we now have the advantage of having not only two outstanding classes of targeted agents, BTK inhibitors in the BCL2 inhibitor, which right now is venetoclax really that’s approved but also having these available, you can look at patients’ preferences and comorbidities in a lot of cases and pick a good therapy.
Our session was really centered around BTK inhibitors but really touches on these important topics surrounding their use and so it’s a really nice kind of discussion of how best to use BTK inhibitors in clinical practice for CLL and these very important considerations.