Relapsed/Refractory CLL: CV Safety Data With Available Therapies


Comprehensive insight to cardiovascular safety data with available therapies and how current understandings may impact the management of patients with relapsed/refractory chronic lymphocytic leukemia.


Andrew H. Lipsky, MD: I tend to think of hypertension on BTK [Bruton tyrosine kinase] inhibitors as a sort of cumulative effect that increases with time on therapy. For a lot of patients, upfront, it’s not as much of a consideration. That being said, if someone comes into the office, and they’re already on 4 or 5 antihypertensive agents, I might look to utilize a BTK inhibitor that has potentially less of the [adverse] effect [AE] in frontline or second-line therapy. Keeping in mind that it’s often the relapsed/refractory patients who have the most significant comorbidities just on account of being older, I certainly think that I would, at this point, prefer a second-generation BTK inhibitor over a first-generation BTK inhibitor. Whether there are significant differences in the amount of hypertension between the 2 second-generation and BTK inhibitors, I think, in my own experience, it would be somewhat difficult to tease that out. There are cross-trial comparisons you could make there. But for my purposes, I’m slightly reticent to make that exact comparison.

It’s clearly important to take a thorough cardiac history. That’s a necessary precondition of contemplating starting any BTK inhibitor therapy in a CLL [chronic lymphocytic leukemia] patient. The most potentially concerning event that we’d be talking about here is ventricular arrhythmia. We have seen that there is a rare, though well-established, signal for sudden cardiac death on ibrutinib, presumably on the account of new onset of ventricular arrhythmias. I think that the data for second-generation BTK inhibitors is less mature, but may have more positive notes on that front. But in terms of specific comparisons there, there are certainly less cardiac events for acalabrutinib vs ibrutinib. Although if you look at projected analysis, they’re still may be some excess signal on acalabrutinib compared to the general population.

The data we have thus far for zanubrutinib may be the most promising, although it’s the least mature. But if you look, for example, in the final ALPINE [trial] analysis [NCT03734016], there were no grade 5 [events]—that’s deaths from cardiac adverse events [AE], in the zanubrutinib group. But there was a 1.9% cumulative incidence for ibrutinib. So, again, this is with limited follow-up, but that may be an encouraging finding when it comes to that signal, which we really don’t want to see.

With respect to atrial fibrillation [A-fib] and atrial arrhythmias, this is also clearly a consideration. We don’t want to have new incident, atrial fibrillation in the patient, if we can avoid it. But when it does occur, it’s certainly more manageable in the clinic. Atrial fibrillation, when starting a BTK inhibitor, for example, is not a contraindication. I have a lot of patients with coagulation with the BTK inhibitor who are doing fine with well-controlled A-fib. So I think it’s certainly safe to say that both acalabrutinib and zanubrutinib have a lesser incidence of atrial AEs than ibrutinib.

If you want to do some comparisons here, I can quote some numbers with different levels of follow-up. For example, the rate of all-grade atrial events in head-to-head comparison was 5% for zanubrutinib vs 12% for ibrutinib. Grade 3 atrial events was 2% for zanubrutinib vs 4% for ibrutinib. If you want to throw the acalabrutinib comparisons in there, keep in mind the follow-up duration is going to be different; the rate of all grade A-fib in the relapsed/refractory setting was 9% for acalabrutinib and 5% greater than or equal to grade 3. So overall, I think that atrial fibrillation is a consideration better with the second-generation and there is not an absolute contraindication to starting therapy. [It’s] manageable when it does occur. Taking a cardiac history really is of the utmost importance when contemplating this therapeutic modality.

I think about utilizing real-world data for basically 2 key scenarios. I often quote this data when I talk with my patients about what happens when you switch from one BTK inhibitor to another. For example, there’s data that when switching from ibrutinib to acalabrutinib, only 40% of patients experience a recurrence of their toxicity, and two-thirds of the time that’s at a lower grade when it occurs. Similarly, when switching to zanubrutinib from another BTK inhibitor, be that ibrutinib or acalabrutinib, I often quote that three-quarters of patients do not experience a recurrence of their prior toxicity. So that’s a great use of real-world data.

Another really good use of real-world data is to provide reassurance in terms of sequencing. We know from real-world studies that have been published that sequencing from a BTK inhibitor to venetoclax or from venetoclax to a BTK inhibitor, in the real world, those are both effective strategies for patients. And that provides reassurance, and I quote that data there.

Transcript edited for clarity.

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