LLM 2021 | Treating CLL after intolerance or progression on BTKi

Because most caregivers would be administering ibrutnib initially, and that’s certainly been the case because that drug has been evaluated and tested extensively for almost a decade, or over a decade now. We’re usually talking about ibrutnib as a drug that’s given initially in the discontinuation. If it’s for intolerance, it’s reasonable to think of switching to acalabrutnib. There are a few studies that have suggested that acalabrutnib can be given after ibrutnib where the clinical response is maintained, and also that the adverse events are not necessarily augmented, or that there are new adverse events.

In addition, while we’re talking about intolerance. If a physician, not a caregiver, is switching from ibrutnib to acalabrutnib, there is a recent trial, the ELEVATE R/R trial, which is the first head-to-head comparison of the two drugs that suggests that both drugs have equal clinical outcomes. That was a non-inferiority designed trial, but it does look like progression-free survivorship is equivalent for both drugs. So if one is switching from ibrutnib to acalabrutnib, you can be pretty confident that you will be able to maintain that clinical response, and that the toxicities will not necessarily be augmented.

In addition, an important outcome of that head-to-head comparison is it appears that cardiovascular events with acalabrutnib are lesser, so there is a lesser incidence of hypertension over the years, as well as atrial fibrillation, which are two major concerns for individuals that are treating or prescribing drugs for CLL patients who need to be on these drugs. For ibrutnib treated patients, there’s an obvious other drug. And then for acalabrutnib treated patients initially, there isn’t necessarily a lot of data on whether ibrutnib could be used subsequently. But if it’s for intolerance, perhaps that is not necessarily an easier transition, and many physicians may choose to go to a different mechanism of action drug, such as a BCL-2 inhibitor, such as venetoclax.

For individuals who progress on ibrutnib, so they have disease progression, and would go on acalabrutnib, we have to remember that those two drugs have similar mechanism of action. And so, if there are mutations that are present in the clone, such as a BTKi mutation, or PCL gamma mutation, which are the two most common mutations that we know about, it’s likely that individual will also be a refractory to acalabrutnib. Those are potentially going to be supplanted by newer BTKis, which are reversible, as opposed to the two current approved FDA drugs, ibrutnib and acalabrutnib, which are irreversible BTKi inhibitors. I wanted to make sure to mention that.

There are these newer drugs are being tested, and look very promising and would be alternatives for use of BTKis in the future.