Optimal Toxicity Management With BTK Inhibitors in CLL

Brad S. Kahl, MD: Toxicity management with BTK [Bruton tyrosine kinase] inhibitors is something we’ve all been getting better at as we’ve gained experience using these agents. Fortunately, the second-generation BTK inhibitors seem to have less risk for toxicity. Nowadays I’m much more likely to prescribe a second-generation BTK inhibitor in CLL [chronic lymphocytic leukemia]. Acalabrutinib isn’t the only choice. Another 1, zanubrutinib, will probably get approval relatively soon, and then we’ll have 2 second-generation BTK inhibitors. Both appear to be better tolerated than ibrutinib.

Zanubrutinib was compared head-to-head against ibrutinib in a trial that was presented at the EHA [European Hematology Association Congress] as a late-breaking abstract. Zanubrutinib had less risk for hypertension and it had less risk for atrial fibrillation and atrial flutter. Interestingly, there was a suggestion it might be more efficacious. The response rate was better for zanubrutinib compared with ibrutinib. That was a surprise to most of us because we always had assumed the efficacy would be essentially the same between these agents, but here are some data suggesting zanubrutinib may be more active.

For me, there are just not a whole lot of reasons to prescribe ibrutinib anymore in CLL. Maybe the 1 exception would be if you had a patient on a proton pump inhibitor, which is considered a contraindication to acalabrutinib—and you don’t have access to zanubrutinib because it’s not approved—then that would be the situation in which I’d go to ibrutinib. Probably in every other situation I would lean toward a second-generation BTK inhibitor.

There was an interesting study at ASCO [American Society of Clinical Oncology Annual Meeting] that looked at risk factors for toxicity. They looked at single nucleotide polymorphism in patients that had been prescribed BTK inhibitors, and they found 4 snips in 3 genes that were predictive for cardiovascular toxicity to ibrutinib. You may be able to identify the patients at the highest risk for getting hypertension or getting atrial fibrillation. But if you have better BTK inhibitors, it may not even be necessary to do that.

The final thing I’ll say about toxicity management is that, at least for me personally, when people get hypertension from a BTK inhibitor, I find it to be very hard to manage it with medications. For most of my patients, the only way I could get the hypertension to get under good control was to get them off the BTK inhibitor. I just couldn’t overcome it with antihypertensives, even adding in a second class of drugs, sometimes the third class. I’ve even gone to 4 classes of antihypertensives and still struggled to get the hypertension under good control. I would caution people to be aware of the hypertension risk. You may have to discontinue your BTK inhibitor if your patient develops significant hypertension.

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