Clinical Cases in Chronic Lymphocytic Leukemia - Episode 15

Case 3: Intolerance to BTK Inhibitors in CLL


Anthony Mato, MD, MSCE:Another question about intolerance, since we’re kind of on that topic with this case. Do we have a standard definition for what is intolerance to a BTK [Bruton tyrosine kinase] inhibitor? Does anybody want to put forth a definition of how we should be thinking about this…? I feel like the term comes up a lot, but it’s not necessarily the same when we’re looking at different reports or even discussing different patients. Any takers on that one?

Sameer A. Parikh, MBBS:I would throw it back to you.

Anthony Mato, MD, MSCE:I know there have been a couple of trials that have defined intolerance. There is one with umbralisib that we presented. There were 2 trials with acalabrutinib which defined intolerance. I think reassuringly, the definitions were much more similar than different, but I think that in clinical practice you may not necessarily wait for a patient to get to a grade 3 event, for example, that’s not resolving over some period of time in order to define intolerance. I think a lot of it has to do with patients’ expectations and other comorbidities. Certainly, atrial fibrillation in someone who has underlying coronary disease may need something than a younger person who has a few beats of AFib.

Sameer A. Parikh, MBBS:I think the intolerance and the threshold to switch also changes with the availability of newer agents. I think that has evolved over the past 3 to 5 years, where now we have other BTK inhibitors available such as acalabrutinib or we have venetoclax as treatment options for patients who are on ibrutinib and have intolerance.

Anthony Mato, MD, MSCE:Speaking of acalabrutinib, I’ll mention a trial that was presented at the American Society of Hematology meeting, which I thought was pretty interesting, which is sort of relevant to this patient in terms of selection of first BTK inhibitors. This is the ELEVATE TN [ELEVATE CLL TN] or treatment-naїve trial, which is a randomized clinical trial that looked at the role of acalabrutinib-based therapy in the frontline setting. Big study—over 500 patients.

The 3 arms were, again, that CLL11—which seems to be the anchor for comparison of all clinical trials lately—versus acalabrutinib with or without obinutuzumab.

While we didn’t have randomized data for ibrutinib plus or minus obinutuzumab from the iLLUMINATE data that you presented, we do have it here, although there’s a little bit of caution in that this wasn’t the primary end point of the trial. It wasn’t necessarily powered to show a difference. Here patients could have been 65 or older or younger than 65 with comorbid conditions. Here the SEER score was calculated in order to determine what a comorbid patient population looked like. Then, IPI [international prognostic index] or CLL-IPI scores were calculated to also help define risk. Follow-up here is still a little bit on the shorter side compared to the ibrutinib patients. Median follow-up is 28 months, but the primary end point was met and…the acalabrutinib-based therapy was better from the perspective of progression-free survival than the obinutuzumab plus chlorambucil.

Then there was a little bit of intriguing data presented suggesting that there may be some benefit to the obinutuzumab plus ACALA versus the ACALA as a monotherapy, although it wasn’t powered and there was an α to show that difference, which is why they reported it with just a hazard ratio and a confidence interval rather than aPvalue.

One question that comes up that none of us are going to be able to answer is whether the prior rituximab studies were negative because of the antibody or whether it’s the BTK inhibitor that seems to enhance the activity of the antibody based on a lot of preclinical observations about how BTK inhibitors can affect ADCC [antibody-dependent cellular cytotoxicity]. We probably won’t answer that now, but this offers us another option.

From the AE [adverse event] data that were presented, it seemed to be a very promising; I don’t want to say favorable because that implies a direct comparison, but a very promising adverse event profile. Unfortunately, we don’t have head-to-head data at this time, but at least in the relapsed/refractory setting we may see head-to-head data in the next couple of years between different BTK inhibitors that may shed light on differences, not only in efficacy but also in adverse events.

Transcript edited for clarity.