Second-Line Therapy in CLL: RESONATE Trial Data


Daniel Wojenski, PharmD, discusses the long-term data on ibrutinib use in patients with relapsed/refractory CLL from the RESONATE trial.

Katie Culos, PharmD, BCOP: What is there left to talk about in the second-line therapy? And what are our approved options for those patients? We know that in CLL [chronic lymphocytic leukemia] at this point, most patients will relapse and receive subsequent therapies, except maybe those people in the FCR [fludarabine, cyclophosphamide, rituximab] patient population who were out to 10 years, which is impressive. What are our options and the data supporting the second-line therapies in CLL?

Daniel Wojenski, PharmD, BCPS, BCOP: In the second-line options, this is the million-dollar question. We have all these options, and now the sequencing is our big challenge. How are we going to sequence all these options, and what are the data behind it? Similar to the first-line setting, where I mentioned we have BTK inhibitors such as acalabrutinib and ibrutinib, we also have venetoclax in this setting. But then we also are looking at our PI3K inhibitors idelalisib and duvelisib. We have a number of options, and we’re looking at all those. We’re just going to try to figure out what the best sequence is.

We still see patients coming in who have chemoimmunotherapy that they’ve received in the first-line setting, especially because a lot of these data that we’ve talked about emerged within the last 2 to 5 years. But most of the newer patients we’re seeing are receiving chemotherapy-free options in that frontline setting. Now we’re going to be looking at how to go ahead and sequence these and what data we have.

I’m just going to start by talking about ibrutinib and venetoclax and the information we have in the second-line setting for those. Starting with the phase 3 RESONATE trial, we showed that with ibrutinib that the updated data presented by Dr [Talha] Munir and colleagues in 2019 showed improved efficacy for single-agent ibrutinib in the relapsed setting over ofatumumab in patients with relapsed/refractory CLL or SLL [small lymphocytic leukemia].

I know that everyone is looking at me when I said ofatumumab, but we have to remember that this study was enrolling in 2012, and that therapy was more commonly used at that time. Although I agree that in this day and age, we would not be using ofatumumab here. This study did also include high-risk features when they were treating patients. There were 195 patients who received ibrutinib and 196 received ofatumumab in this study. The median follow-up on this report in 2019 was 65.3 months, and median progression-free survival remained significantly longer for patients randomized to ibrutinib vs ofatumumab. That was 44.1 months vs 8.1 months.

Progression-free survival benefits with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with deletion 17p, TP53 mutation, deletion 11q, and/or mutated IGHV status, which was very impressive. This represented more than 82% of the patients who were enrolled in this trial. Only 16% of the patients discontinued ibrutinib after adverse events, and that was reassuring. That still seems like a high number, but there are studies that were higher than that, especially with such long-term follow-up, that a majority of patients were still able to tolerate their ibrutinib therapy. We saw some wiggle room in terms of what we can do to mitigate some of those toxicity strategies, but certainly that’s something that we can continue to work on.

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