Management of Chronic Lymphocytic Leukemia in 2020 - Episode 17

Sequencing Strategies for CLL


William Wierda, MD, PhD: There were a couple of abstracts presented here on new and novel strategies. One of the impressive presentations I think was given by Anthony Mato, MD, with the LOXO-305, which is a reversible inhibitor. You were giving us some thoughts and discussion about irreversible inhibitors and mechanisms of resistance. Maybe you can review for us, since you chaired that session, the abstract that was presented on LOXO-305, which is a reversible inhibitor of BTK [Bruton tyrosine kinase].

Shuo Ma, MD, PhD: The LOXO-305 study that was presented by Dr Mato at ASH [the American Society of Hematology annual meeting] 2019 is the first-in-human phase I study in B-cell malignancies, so not only CLL [chronic lymphocytic leukemia] but it also included other B-cell lymphomas, and is a dose ramp-up study, so a 3+3 design. And so far, there’s no dose-limiting toxicity observed. And the efficacy is looking very impressive, even with the first lowest dose, starting dose. They’re able to see some interesting responses. They included patients who have been either intolerant to ibrutinib or resistant to ibrutinib, and they’re seeing responses across the board.

I think the most interesting finding is that even for patients who harbor not only the BTK mutation but also the PLC-gamma-2 mutation were able to show clinical response to the LOXO-305. I think that’s a very interesting observation because it’s a little bit initially counterintuitive to me, I always think PLC-gamma-2 mutation is downstream, so how can you actually overcome that? Apparently, it’s not an absolute, so that activation mutation may not be 100% effective, and if you’re able to have stronger inhibition in the BTK pathway, you can still potentially overcome that mutation. So, it’s a very promising next-generation BTK inhibitor that can potentially overcome the known resistance.

William Wierda, MD, PhD: Anthony also gave a presentation on real-world experience and venetoclax-based therapy. I don’t know, Carolyn, if you saw that presentation and what your thoughts are.

Carolyn Owen, MD: It was a lovely presentation to start with. It was just based on real-world data, obviously investigators around the world, but many American centers, sharing the data on the patients they have treated with venetoclax, either on clinical trial or off, who then after progression or discontinuation of venetoclax were treated with a BTK inhibitor [BTKi], or PI3 kinase was also investigated. I think it really provides the necessary comfort for the question that has been percolating around since venetoclax, the BCL2 [B-cell lymphoma 2 protein] inhibitor, became available, which is we know that venetoclax works after ibrutinib, but we don’t know that ibrutinib works after venetoclax.

And although biologically there was no reason to think that one order or another would have more efficacy, we didn’t know. And now I think based on this data, we do know that the responses were excellent and very durable in the report. Obviously, it’s only a small group of patients but put together, 300 and some patients in that series I think, it was very reassuring. So if the plan is to provide somebody with VEN-R [venetoclax, rituximab] second-line therapy or VEN-O [venetoclax, obinutuzumab] as first-line therapy, there’s no reason to think you wouldn’t to be able to provide them a BTK inhibitor at relapse and get the same response you would have been expecting today when you give a different patient a BTK inhibitor.

William Wierda, MD, PhD: I wonder if, Stephen, you can comment on your experience and your group’s experience down in Australia in terms of sequencing and if you’ve had the opportunity to treat patients post-venetoclax with a BTK inhibitor.

Stephen Opat, MBBS: The experience is very limited in that combination. I know that if you look at the early phase venetoclax trials, prior BTK inhibitor was recognized as a factor for suboptimal response. But the problem is that it’s confounded by the number of lines of therapy, so people who’ve had 6, 7, heavily pretreated patients don’t tend to respond well to whatever you do. I think we really need more contemporary data, so patients who’ve maybe had 1 line with a BTK and then had venetoclax. I’m not sure how much we can learn from looking at patients who’ve failed multiple lines of therapy, then they failed ibrutinib, and then you give the next line, seventh or eighth line, I think they all tend to do quite poorly.

Carolyn Owen, MD: I think ultimately though, it’s about how long patients live. If you get a lesser response to ibrutinib if given after venetoclax, but you get a better response to venetoclax because it was given earlier. In general, subsequent lines of therapy have a less durable response than lines of therapy given earlier. If your venetoclax response is not as long if it’s given after a BTKi, or the other way around, if the patients in the end get the same duration of life and remission, then it doesn’t matter which one of the agents you’ve used. So you really do need to look, like you’re saying, in both orders.

Stephen Opat, MBBS: And you’re selecting for the poor responders because the patients doing well aren’t needing the next treatment. You’re selecting the worst players and you’re re-exposing. So how much is due to the biology versus the exposures? It’s a difficult question. And the question is, is it better to give them all together or give them sequentially? So, there’s still a lot of work to keep us busy.

Transcript Edited for Clarity