BTK Inhibitors in Relapsed/Refractory CLL


William Wierda, MD, PhD: Dr Burke, in terms of BTK [Bruton tyrosine kinase] inhibitor–based therapy, what can we expect in the relapsed setting in general? We talked about first-generation versus second-generation compounds. What can we expect if we put a patient who’s been previously treated, maybe with BR [bendamustine, rituximab], on a BTK inhibitor–based therapy? Most trials that have been done in the relapsed setting enrolled patients who’d had prior chemoimmunotherapy. In that setting, what can we expect with a BTK inhibitor–based therapy as relapsed treatment?

John Burke, MD: If you look to the data, the original study that we have the longest follow-up with is RESONATE, which compared ibrutinib with ofatumumab in patients previously treated with chemoimmunotherapy. The long-term follow-up was published last year, and they reported a median PFS [progression-free survival] with ibrutinib of 44 months, just under 4 years. The median overall survival was a little over 5 years. I think the RESONATE study is the best long-term follow-up data we have with ibrutinib.

With acalabrutinib, we have the ASCEND trial that compared acalabrutinib with the control arm, which was a mix of either bendamustine-rituximab or idelalisib-rituximab. We saw improved PFS with acalabrutinib in that trial. For patients who have been treated previously with chemotherapy, a BTK inhibitor or the venetoclax-rituximab combination therapy is the way to go over salvage chemotherapy. I saw a patient not that long ago who had previously been treated with fludarabine-based chemotherapy and then relapsed and saw a doctor who recommended BR.

I cringed because we now have data that suggest that patient would be better served by either a BTK inhibitor or venetoclax-rituximab. That’s the key point practitioners need to know—those are the standard approaches now for second-line therapy after previous chemoimmunotherapy. Median PFSs are in the range of 4 years.

William Wierda, MD, PhD: In the relapse setting, what population of patients worry you? Are you still worried about 17p deletion, even though we know that the targeted therapies have activity in patients who are 17p deletion mutated?

John Burke, MD: We know that those 17p and TP53 aberrancies still fare less well than those who do not have those in the relapsed setting. Most of the other gene mutations seem to have less prognostic importance, which is true in the untreated setting as well. In the previously untreated setting, there was a publication in Blood just 2 months ago based on the CLL14 study showing that venetoclax seems to overcome some of the adverse prognostic implications of, say, deletion 11q. The only FISH [fluorescence in situ hybridization] abnormality that conferred a less favorable prognosis with up-front therapy with venetoclax-bendamustine was 17p or TP53 aberrancies.

It’s true that these targeted agents are overcoming a lot of the other adverse prognostic and genetic factors but not 100% overcoming the 17p problem.

Transcript Edited for Clarity

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