SOHO 2024 | Should BTKi therapy be discontinued in CLL?

That is an excellent question, and I like the way you said should, because the title of what I’m asked to debate is, can BTK inhibitors be discontinued? And we all know that we can do things, but I think there’s some very good arguments for why we should not have our patients with CLL discontinue BTK inhibitors.

I think the major reason, there’s actually, I mean, there’s a few, but the major reason is the best outcomes we really have in CLL today, particularly for initial therapy, is with a strategy of continuous BTK inhibitors. So if you look at progression-free survival for first-line ibrutinib from RESONATE-2, the median progression-free survival was actually 8.9 years. So this is something Dr Berger presented at EHA this year, and I’d never seen that before, but I was really excited to see how well that works. And again, that’s a continuous strategy, and to get that benefit patients really need to be continuing them, so stopping them really just reduces the disease control they get.

And when you think about the types of responses we see with BTK inhibitors actually across all diseases but definitely in CLL they’re very slow to develop so in the same study RESONATE-2 and one year they reported a seven percent complete remission rate and then if you go out to like seven or eight years you’ve got close to a third of people achieving that remission rate or the complete remission rate. So really it takes years of exposure to reduce the disease burden, maximize your response, and get these really long-term benefits. And I know of no other study in CLL that size reporting a similar progression-free survival like median.

For example, strategies that I think have, you know, a good role in CLL, but are a little bit different would be BTK inhibitor-venetoclax combinations as a fixed-duration. Those have been studied and are highly effective. But at the same meeting, which was EHA this year, I reported follow-up from a study at our institution of ibrutinib, venetoclax and obinutuzumab fixed-duration for like around a year of treatment. And the median progression-free survival in patients taking it as an initial therapy was actually 7.4 years. So it was shorter than a continuous ibrutinib monotherapy strategy. So I think that’s really the best evidence that these really should be continuous therapies or a plan for continuous therapy. And we do see when people, you know, don’t even stop them as a plan, but due to toxicity, it’s usually about two years before people are needing treatment again.

So to maximize the benefit, these are really continuous drugs. I do think that there are some arguments towards making them fixed-duration that mostly have to do with the information we don’t have yet about how to sequence therapies over the lifespan of our CLL patients, but I think the major reason to continue them is just that to really get the benefit you get the best responses and the best progression-free survival with this dosing strategy.