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ASH 2021 | Treating patients with CLL who progress after BTK inhibitor therapy

Kerry Rogers, MD, The Ohio State University, Columbus, OH, talks on the chronic lymphocytic leukemia (CLL) treatment landscape, highlighting the treatment options available for patients who progress after Bruton’s tyrosine kinase (BTK) inhibitor therapy. Whilst venetoclax has been approved for patients with CLL, progression-free survival rates remain sub-optimal compared to BTK inhibitors. Novel approaches to targeting BTKs have been considered, including reversible BTK inhibitors and BTK degraders. Dr Rogers additionally highlights the potential of chimeric antigen receptor (CAR) T-cell therapy, which can substantially benefit certain patients. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

For patients progressing while taking a BTK inhibitor who have resistance to it, there is one currently approved drug that’s effective and that’s venetoclax. Again, the median progression-free survival is about 24 months on this. So this isn’t like a slam dunk for people with CLL, but that is certainly an option. However, these are patients I strongly encourage to consider a clinical trial...

For patients progressing while taking a BTK inhibitor who have resistance to it, there is one currently approved drug that’s effective and that’s venetoclax. Again, the median progression-free survival is about 24 months on this. So this isn’t like a slam dunk for people with CLL, but that is certainly an option. However, these are patients I strongly encourage to consider a clinical trial.

One of the really very promising types of drug then is the reversible BTK inhibitors that bind at a different site so that patients can continue benefiting from inhibition of BTK and not move to a different class of drugs. So there’s also BTK degraders that are being tested. I do think drugs with a completely novel mechanism or new targets also would be reasonable to offer patients depending on where they are in development and what’s available. So that’s, you know, standard venetoclax could be done, but really that’s an excellent opportunity to try some of these clinical trials, particularly with things that target BTK in a different way. That’s assuming someone has resistance mediated by BTK mutations that impair drug binding of the irreversible covalent BTK inhibitors.

Patients with PLCG2 mutations, which are downstream of BTK, may not benefit from the reversible BTK inhibitors because it’s a downstream lesion. So you can keep inhibiting BTK, but they’ll continue to have that pro-survival signal through B-cell receptor signaling, BTK is in the B-cell receptor signaling cascade. And the other thing is you know whatever you go to next, you’re probably going to have to do something that will get them a really long-term benefit, especially if they’re young and very fit, or even older and fit, but have a lifespan of more than like a couple years, you’re going to have to think about what you’re going to do down the line.

And this is also a time to discuss like CAR T-cell therapy down the line or need for that in the future, you know, not everybody gets, you know, not everybody benefits from CAR-T in the same way, but people that benefit can have a very durable benefit. So that’s very important to discuss with patients. And I like to start thinking about talking to people about what the next few things are down the line if they become resistant to a BTK inhibitor.

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