Novel Therapies for CLL: Sequencing Strategies

William Wierda, MD, PhD: Let’s talk about sequencing. It’s a tough subject. Anthony, can you comment? It’s a complicated topic. There aren’t data that say 1 strategy over another is better in terms of starting with a BTK [Bruton tyrosine kinase] vs starting with BCL2. Can you summarize some of the general concepts around sequencing? If you start with a BTK, do you treat to progression and then switch to a BCL2? Also, comment on where chemoimmunotherapy would be in that sequence.

Anthony Mato, MD, MSCE: I agree that there are no data to support 1 strategy over another. But if you start with a covalent BTK inhibitor, there are 2 options. You’ll treat to progress. If they progress, they’re generally resistant. That takes covalent BTK inhibitors off the table because of the known mechanism of resistance, or you’ll discontinue because of an adverse event [AE]. That’s a relatively common event with ibrutinib, less common with acalabrutinib and zanubrutinib. If you discontinue because of an adverse event, you could think about what the AE was. There’s a strong rationale to switch and stay within class to another covalent BTK inhibitor, like switching from ibrutinib to acalabrutinib.

Upon progression from a covalent BTK inhibitor, the standard of care is venetoclax-based therapy, time-limited with venetoclax re-treatment as the next most reasonable line of therapy. BTK to BTK to venetoclax to venetoclax is 4 different lines of therapy before you need to do anything experimental or consider a PI3K. If you start with venetoclax, everybody gets a year and then stops. That’s what happens for most people when it’s given with obinutuzumab.

And then the question is whether you do venetoclax again or a BTK inhibitor. Most people think about venetoclax again, particularly if the remission duration was long. You would do venetoclax, venetoclax re-treatment, switch to a covalent BTK inhibitor, and then treat to progress or do the same strategy regarding intolerance if possible. You can stretch the BTK and BCL2 inhibitors over 2 to 4 lines of therapy and then consider PI3K vs experimental therapies like noncovalents. That’s how I think about sequencing. That being said, no matter which strategy you pick, on average, you get 10 to 12 years of median progression-free survival [PFS]. That’s pretty good going from monotherapy to monotherapy.

William Wierda, MD, PhD: I agree. Nicole, do you do anything different from what Anthony said, in a patient with deletion 17p, realizing that’s 5% to 8% of frontline patients?

Nicole Lamanna, MD: We have longer data in the front line, particularly for ibrutinib, because the BTKs were the first to market. As mentioned earlier, about the progression-free survival of the patients with 17p appear, compared to venetoclax-obinutuzumab, appear longer. We have some nice data, over 5 to 6 years, on some of those patients with 17p or TP53 mutation, and it seems that the PFS curves are longer. For high-risk patients, I tend to continue monotherapy.

When we talk about the combination of a BTK plus venetoclax, will that be an advantage for high-risk patients? I’m looking forward to some of the data from the SEQUOIA study to see if that will be better in our high-risk-patient population so we can truncate their therapy vs continuous, which is what I’m currently doing on my high-risk individuals: giving continuous BTK for the 17p population until we see data.

I agree with Anthony that we just have more data because the BTKs were used first. We know we can sequence patients when they relapse to venetoclax, and patients do well. We have emerging and mounting data for the patients who might have gotten venetoclax-obinutuzumab in the front line and then can be salvaged with a BTK in the opposite fashion, and whether those responses will be as robust over time. From the IV [intravenous] combinations, there are certain patients who, if they’re multiple relapsed and have a BTK plus venetoclax, their responses aren’t as good. This speaks to the fact that these multiple-relapsed patients are going to be trickier to salvage. We’ll need other therapies, which I’m sure we’re going to touch on shortly, to salvage some of those guys whose PFS and overall survival will be shorter in that setting.

Anthony Mato, MD, MSCE: I’ve been thinking about this a lot with the 17p’s. There’s no obvious reason why a patient has to have a BTK inhibitor. The median PFS for venetoclax-obinutuzumab is about 40 months for 17p.

Catherine Callaghan Coombs, MD: It’s 49.

Anthony Mato, MD, MSCE: If you get half as good a remission out of re-treatment, which is a general rule of thumb with chemotherapy, you’re looking at a 70-month median progression-free survival. That will rival any BTK inhibitor for that patient population. To me it’s a wash.

Nicole Lamanna, MD: It could be. We need to see, right? That’s what we hope, but we just need to see those data. Unfortunately, there’s a lag. That doesn’t mean it won’t be that way.

Anthony Mato, MD, MSCE: We already know we get 49 months.

Nicole Lamanna, MD: Agreed.

Anthony Mato, MD, MSCE: I would argue that we make decisions to use, let’s say, ibrutinib as a standard of care for del(17p) based on like a handful of patients treated at NCI [National Cancer Institute] with the longest-term follow-up. The data are just as scanty for BTK inhibitors as they are for venetoclax. They’re both completely fine. I’m spicing it up now on the OncLive® debate, but it’s a wash. I don’t think there’s an obvious strategy for which is better.

William Wierda, MD, PhD: I agree. We need data. One thing we would all agree on is no genotoxic therapy—ie, chemotherapy—for patients with 17p or mutated TP53.

Transcript edited for clarity.