Carolyn Owen, MD: As I was mentioning, targeted therapy has been in development for many years now. We have long-term data with ibrutinib, a BTK [Bruton tyrosine kinase] inhibitor-based therapy, which is continuous and indefinite. Maybe, Jacqueline, you can give us a little bit of a picture of what that entails—ibrutinib or BTK inhibitor-based therapy in the frontline setting. What can we expect? What’s the expectation for progression-free survival in that setting?

Jacqueline Barrientos, MD: There was recently an update on the long-term follow-up of the RESONATE trial. And that led to the full approval of ibrutinib in CLL [chronic lymphocytic leukemia] in relapsed/refractory disease. And what we’re seeing over time is that with a longer time on ibrutinib, the response rates go higher, as we had seen on the phase I and phase II trial. About 91% of the patients did achieve partial remission. Unfortunately, Steve, complete remissions, or MRD [minimal residual disease] attainment of undetectable disease are still very low compared to a drug such as venetoclax. But we know that the drug is safe.

Unfortunately, over time there are discontinuations and progressions. The discontinuations may be caused by toxicity from the drug. In particular, cardiac arrhythmias. Hypertension is a big thing. That may not be very well known in the community, but it happens over time and may be difficult to control with only 1 agent, and you might have to use a couple more agents.

Additionally, after 44 months on follow-up, about 46% of the patients are still taking the drug. Meaning a lot of the patients have either progressed or discontinued. And usually the people who do progress are the patients that we have characteristically thought of as higher risk for progression, including 17p deletion, TP53 mutations, and possibly with a complex karyotype. So, there is still an unmet need for these patients.

William Wierda, MD, PhD: We have seen over the last year, I can count them, 4 large randomized phase III clinical trials with BTK inhibitor-based therapy versus a spectrum of intensity for chemoimmunotherapy—chlorambucil-based, bendamustine-based, and FCR [fludarabine, cyclophosphamide, rituximab]. All of those trials are showing improvement in progression-free survival with a BTK inhibitor-based therapy with continuous and indefinite treatment. Three of the 4 were with ibrutinib. Recently there was a trial that was reported at this ASH [American Society of Hematology annual meeting] 2019, which is referred to as the ELEVATE-TN trial, with acalabrutinib, another irreversible inhibitor. Maybe Shuo, you can give us some insights on the use of different BTK inhibitors now that we have 2 approved drugs, in the frontline setting, and in the relapsed setting. And how you think about those 2 agents and select for any particular patient which 1 you’ll use.

Shuo Ma, MD, PhD: As we all know, ibrutinib has been compared to conventional immunochemotherapy in several very large randomized phase III clinical trials and has a very established record of efficacy, superior progression-free survival compared to conventional immunochemotherapy. For example, the ECOG 1912 study was comparing ibrutinib plus rituximab to the FCR [fludarabine, cyclophosphamide, rituximab] in the younger group of CLL patients as a frontline treatment. And so that has demonstrated a superior progression-free survival as well as some overall survival benefit, even though that’s small.

The Alliance study was studying the older patient population comparing ibrutinib. They are 3-arm studies. One arm is ibrutinib alone versus ibrutinib plus rituximab versus bendamustine plus rituximab. So that’s an older, relatively fit population of patients. For that population of patients, both ibrutinib and ibrutinib plus rituximab seemed to be superior to bendamustine, rituximab in terms of progression-free survival.

In another study, the iLLUMINATE study, that combined obinutuzumab with ibrutinib comparing to obinutuzumab plus chlorambucil. That is for elderly patients with comorbidities, unfit medical condition, and impaired renal function. So for that group of patients it also demonstrated that the ibrutinib-obinutuzumab combination is superior to the chlorambucil-obinutuzumab combination in progression-free survival.

So, these 3 very large randomized group of trials has definitely established ibrutinib as the frontline treatment to be superior to our previous standard of care for all patients, all comers. But as Jacqueline previously mentioned, for a subgroup of patients when you compare the IGVH-mutated patients who do not have the high-risk features, those patients in some of those trials actually have pretty similar progression-free survival. So, in that group of patients, immunochemotherapy is an option that has similar clinical outcomes. But if you think about the toxicity profile, I think you have to take that into consideration as well when you’re choosing therapy.

Transcript Edited for Clarity