Moving the Dial on CLL Management: Sequencing Strategies and Unmet Needs

Brad S. Kahl, MD: In relapse/refractory CLL [chronic lymphocytic leukemia], the landscape has changed quite a bit in the last few years. Previously, patients entering the relapsed/refractory space had had immunochemotherapy. Nowadays, a lot of our patients who are coming in with relapsed/refractory disease have already been exposed to a novel agent. It’s very much a moving target. We’ve learned from a number of trials in the relapsed space that, in general, the targeted agents like the BTK [Bruton tyrosine kinase] inhibitors are better than immunochemotherapy.

In the MURANO trial, venetoclax-rituximab performed much better than bendamustine-rituximab. Acalabrutinib performed better than idelalisib or bendamustine-rituximab in the ASCEND trial. Ibrutinib performed better than immunochemotherapy in the RESONATE trial, so that’s well established. Now the question is how do you manage a patient that’s failing a BTK inhibitor? Alternatively, if the patient received venetoclax, let’s say, a BCL2 inhibitor in the front line, where it’s approved to be given for 12 months. And let’s say they get some period of remission, but now they’re progressing again and they need a second-line treatment. What’s the best way to manage that patient? That’s where we’re lacking a lot of data. We certainly believe you can re-treat these patients with venetoclax-based therapy.

For me, that decision would depend a lot on how long that first remission lasted. If somebody received venetoclax-obinutuzumab for a year and then stopped it, and then 1 year later they’re progressing again, that’s a disappointing result to me. I probably wouldn’t go back to venetoclax-based therapy. I’d be much more likely to go to a BTK inhibitor like acalabrutinib. But what if your patient received venetoclax-obinutuzumab for 12 months and then stopped, and they go 4 more years in remission off-therapy? It might be perfectly reasonable to re-treat that patient with venetoclax-rituximab as was given in the MURANO regimen, and that’s a 2-year fixed-duration strategy. This is an area where we’re just starting to get data, starting to sort this out.

But I’ll admit, there are a lot of unknowns about optimal sequencing. It’s going to get even more complicated in the next few years because we know we’re getting data now for novel-novel combinations in the front line, like time limited. We recently saw results from the CAPTIVATE study and the GLOW study looking at a 12-month fixed duration of ibrutinib and venetoclax. Presumably that 2-drug regimen will get an approval relatively soon, and I’m sure that will get usage. What do you do with those patients who had ibrutinib-venetoclax for 12 months? How are you going to treat them in the second line? It’s going to depend on the quality of that first remission, but we just don’t have much data to guide us. It’s probably going to get more complicated for the next few years in terms of sequencing of treatments because we’re going to have more approvals and more options. The good news is they’re all very good options. There aren’t many bad options here, so these are good problems to have when you have all these effective therapies.

TRANSCRIPT EDITED FOR CLARITY