VIDEO: Treatment options in CLL

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We are primarily choosing between targeting Bruton's tyrosine kinase and BCL2. And the NCCN tells us that really, those are the preferred treatment selections for a patient that's either has not previously been treated or has maybe been previously treated but has not been treated with either of those two targeted options. Now, most of the people in the United States, it looks like they're getting treated with BTK inhibitors. We now have three of those. Originally, it was ibrutinib (Imbruvica; Janssen, Pharmacyclics), available starting in 2014. More recently, acalabrutinib (Calquence; AstraZeneca) as of 2019, and zanubrutinib (Brukinsa; BeiGene) in 2023 earlier this year. The NCCN, based on the comparative studies between acalabrutinib and ibrutinib as well as zanubrutinib and ibrutinib, have removed ibrutinib from the preferred treatment options. So, if you are going to treat with a BTK inhibitor, NCCN would suggest that based on the data, and I would agree, that really, you should choose between acalabrutinib and zanubrutinib.

There is another target though, BCL2, which we only have one inhibitor for this, and that's venetoclax (Venclexta; AbbVie, Genentech). It's given with an anti-CD20 drug called obinutuzumab (Gazyva; Genentech) which is a monoclonal antibody, and that's given intravenously for the first six months in sort of a dose-dense form for the first three weeks, and then it goes to monthly, and then the venetoclax is given for a year and stop. And so, that stands in stark contrast to the indefinite daily use that is required for a BTK inhibitor. The choice between those two, that's a very long and complicated discussion for most patients. We don't really have a quote, unquote, "preferred or best option" in terms of first-line treatment. There's going to be about 10% of patients that have a chromosome 17 aberration, so that's either a deletion, 17P on FISH, or a TP53 mutation. These patients seem to have the longest progression-free survivals when they're given indefinite BTK inhibition. So, zanubrutinib or acalabrutinib would be the most-chosen option for those patients. But really, outside of that group, the venetoclax or obinutuzumab represents what would be an equivalent treatment choice, and you really just try to personalize the treatment to the patient since you've got, you know, two really good targets to go after.

If the patient is really valuing time-defined therapy, or let's say if they have cardiac comorbidities and you want to avoid BTK inhibitors, or they're on an anticoagulant, venetoclax makes a lot of sense with the obinutuzumab. If it's a patient that maybe lives far from the cancer center, doesn't want to make a lot of trips back and forth to the infusion center, wants something really convenient and just doesn't mind adding a pill that's taken indefinitely, well then, a BTK inhibitor makes sense for them. I'd also throw in maybe patients with large tumor bulk, because with venetoclax, that's a negative predictor of response and you have to worry about the tumor lysis syndrome. So, BTK may make more sense for a patient like that. Patient with renal disease where you get more worried about tumor lysis, maybe BTK makes more sense there. So, all these are just little examples of how you can try to choose between what are a couple really good targets that we have to go after for CLL.