William Wierda, MD, PhD: We talked about first-line therapy and what drives selection of first-line therapy. Patients do well for many years, but some of them do relapse or progress on treatment. Therefore, therapeutic sequencing is an important concept. There are not a lot of data around therapeutic sequencing. I wonder, Dr Allan, if I could ask you to give us your thoughts on the major concepts regarding therapeutic sequencing. For example, if we start with a BTK [Bruton tyrosine kinase] inhibitor, what do we do next if a patient progresses, and where are we trying to get that patient for long-term disease control? If we start with a BCL2 small-molecule inhibitor, what is the sequencing strategy in that case?

John Allan, MD: That’s a great topic and a hot topic, but we don’t quite know the answer to whether there is a best sequence for our patients. The only way to find the answer is to start patients on 1 therapy and have a long-term study that then follows patients switching to another therapy upon progression. Because these patients do so well and following that PFS [progression-free survival] too, depending on your sequence, a study with a long-term follow-up would be the only way to truly identify the best sequence. That’s never going to happen because it requires a large number of patients and long-term follow-up. Therefore, we’re left looking at studies that have been performed, where 1 of the inclusion criteria is exposure as a prior therapy to say a BTK inhibitor or a BCL2 inhibitor.

The only prospective clinical trial that’s been designed and reported and published in that manner is looking at true ibrutinib progressors in patients with a BTK inhibitor intolerance and salvaging them with venetoclax. This was a smaller phase 2 study that enrolled patients with true progression and/or intolerance. This study had close to 100 or so patients, of which the vast majority—close to 60%—had progression on BTK inhibitors.

Mind you, patients in this study are heavily pretreated with relapsed/refractory CLL [chronic lymphocytic leukemia] from the era of the earlier BTK use, which is where we’re hopefully emerging from, so we won’t be treating these types of patients anymore. But we found that venetoclax has great salvage abilities, and response rates were close to 70%. CR [complete response] rates were relatively high in the patient population with refractory CLL. Peripheral blood MRD [minimal residual disease] rates were in the 40% range, which didn’t necessarily translate to deep bone marrow disease negativity. Not a lot of patients had deep bone marrow disease negativity, so that’s a little unknown.

We found and have shown that if you can get patients in an MRD-negative state, those patients had a PFS that wasn’t met at the time—they had reported it and never had another follow-up. But overall, patients had a PFS of about 2 years when they get venetoclax-based salvage therapy. In this case, again, patients were highly refractory and had previous progression on BTK inhibitors, so that is typically the classic standard of care.

If you start a BTK inhibitor, we then flip to a venetoclax or a BCL2 inhibitor–based treatment. Whether you add an anti-CD20 monoclonal antibody or you do fixed-duration therapy is based on MURANO data. Though it is important to remember that in the MURANO study, only a small number of patients of the total patient population had prior BTK inhibitor exposure. Therefore, we didn’t get our answer from that study. Ultimately, though, you typically do some venetoclax-based treatment.

Based on some real-world evidence, personal experience, and cross-study comparisons, we know that switching to another B-cell receptor antagonist like a PI3K inhibitor after a BTK inhibitor, progression is probably not going to MRD negativity. If you come off a BTK inhibitor for intolerance, PI3K inhibitors can have some activity and get you to MRD negativity, but they have their own issues with intolerance and toxicities. As we said, venetoclax is a very well-tolerated drug. Patients do well on venetoclax. We can salvage these patients who are tough to treat because we know that if they’re progressing on a BTK inhibitor, disease biology is saying something.

That typically indicates 17p deletion. There is a small subset of patients who don’t have a BTK mutation, but they are common among patients who truly progress. They need a switch out of the treatment pathway, so to speak, and fortunately, we have venetoclax to do that. The flip side of this is now that the CLL14 study is around, and many people are adopting and are attracted to this fixed-duration therapy, we’re getting a new wave of patients who’ve been BTK inhibitor naïve. We don’t have current prospective clinical data of true patients being salvaged with BTK inhibitors post-venetoclax progression or relapse.

Fortunately with time, we’ve gotten some real-world data from collaborating groups around the world to be able to put enough patients in relapsed/refractory settings who had been BTK inhibitor naïve. We now have relatively significant numbers in real-world settings to where we can see response rates resemble what we see when you use a BTK inhibitor in a patient who is BTK inhibitor naïve even though they progress and relapse on venetoclax.

That data provide some encouragement from the community and from providers. It allows us to at least educate our patients that it doesn’t matter so much which drug you use first. You will be salvaged regardless of which drug you use, and it makes sense. These are completely different mechanisms of action. They don’t have cross-talk too much and the mechanisms of resistance with a venetoclax or BCL2 inhibitor are very different from the mechanisms of resistance we see with a BTK inhibitor–based treatment.

Fortunately, we know that the sequence doesn’t seem to matter too much. You can tailor therapy a little, but classically, you’re staying in a BTK pathway then a BCL2 pathway or the opposite. You’re not typically doing a B-cell receptor or a BTK inhibitor staying within the B-cell receptor antagonism and going to a PI3K and then to a venetoclax, because it is probably not going to get you to MRD negativity. That’s typically my practice. Depending on which class of drugs you use first, you use the other class second.

We don’t know if there is a frontline impact on long-term survival, so we don’t know if there is a best first-line treatment. Those head-to-head studies haven’t been done. We’re getting that, but the studies have all been combinations vs monotherapies. It is an exciting time, but using 1 pathway and then the other has typically been my practice. When talking to my colleagues and other people in the community, that’s the train of thought currently in therapeutic sequencing.

Transcript Edited for Clarity