ASH 2025 | Relationship between dose & BTK occupancy with ibrutinib monotherapy in previously untreated CLL

The TAILOR study is a study that is prospectively trying to determine whether decreasing the dosage of ibrutinib, which is the first-in-class covalent BTK inhibitor, may be equally efficacious knowing that the current administered dose or recommended dose may correlate with a lot of potential toxicities. And so as we all know, BTK inhibitors such as ibrutinib come with an increased risk of atrial fibrillation, increased risk of hypertension, arthralgias, bleeding events. And so all of these potential toxicities that are driven by the use of this drug have made this drug fall out of favor. Even the NCCN guidelines are now recommending that it is no longer a preferred drug. Right now, the current NCCN recommends the use of second-generation covalent BTK inhibitors such as acalabrutinib, or zanubrutinib. 

So we have data retrospectively and anecdotally that many of our patients can do well if we don’t use the full dose of the medication, instead do a lower dose. So this TAILOR study had two arms. One of them is a fixed-duration treatment strategy, similar to the CLL17, which is a combination of ibrutinib with venetoclax, and the other arm is for patients that are on ibrutinib monotherapy. 

And so the data that I presented was on patients that were on the ibrutinib monotherapy arm. We had 42 samples. Half of them were randomized to receive ibrutinib at the full dose of 420 milligrams once daily. And the other arm was the group that had only the first month, the full dose. And then after that, they were prospectively decreased on the dose to 280 milligrams once daily, continuous daily dosing. So the study was performed to obtain samples pre-start of the therapy, on cycle one day one, and several hours just to determine PK, and also at cycle four. 

So what we found out was that for both arms, the BTK occupancy was identical even though the PKs on the arm that had the prospective reduction on the dosage had lower plasma concentration. So we’re hoping that we can eventually, when we have enough events, we can correlate this with outcomes to see if what matters is not the PK level of the drug in the serum, rather the BTK occupancy, which has been what we have postulated for many years, and we have some preclinical data, but we don’t have any prospective data. And so we don’t have that data yet, we’re still waiting for enough events to determine whether this is, you know, like real or not. There’s a couple of things that are important to note is that there’s a lot of intervariability within the patients that are on ibrutinib, but overall, when you look at the BTK occupancy, it’s, you know, super high, it’s like over 98%. So the drug does have a good BTK occupancy, which should lead to a very efficacious drug, as we have seen on the data that has been presented at this year’s ASH.

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