Rationale and Use of BTK Inhibitors as Initial Treatment for CLL

Tara Graff, DO, MS: BTK stands for Bruton tyrosine kinase. It’s critical for the propagation of B-cell-receptor signaling, and it’s upregulated, so it’s overexpressed in a CLL [chronic lymphocytic leukemia] cell compared with a normal cell. By blocking that signal, you’re decreasing B-cell proliferation and, essentially, cancer cell proliferation. This is where the target is for BTK inhibitors.

Ibrutinib was the first BTK inhibitor. It was the first generation. It targeted the BTK selectively, but it has more off-target inhibition as well. Then came acalabrutinib, which is a second-generation BTK inhibitor. It has very strong inhibition at the Bruton tyrosine kinase receptor, but also less off-target inhibition compared with ibrutinib. Therein lies what we see with certain adverse effects and things like that. We have those 2 drugs, and now we have zanubrutinib as well. That’s come into the fold. Those are the 3 drugs we’re using to inhibit the BTK.

We’re learning that there’s a sustained PFS [progression-free survival], overall survival, overall response rate, and tolerability as time goes on with the BTK inhibitors. The RESONATE-2 trial is looking at ibrutinib. It has the 7-year long-term follow-up data. It showed sustained PFS and overall survival; PFS was 61% at 7 years vs 9%. For chlorambucil, which it was compared with in that trial, overall survival was 78% and overall response rate remained 92%. Hypertension and atrial fibrillation—commonly seen as cardiovascular adverse effects with ibrutinib—persisted, but as time went on, they didn’t get worse. Patients actually appeared to tolerate the medication better. From 5 years on, patients did well. There was a low discontinuation rate from that point on. It continued to show efficacy and tolerability over time, which is impressive when you’re talking about an oral medication.

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