Frontline Treatment Approaches in CLL


Drs Alexey Danilov and Anthony Mato review treatment options available for newly diagnosed chronic lymphocytic leukemia and describe decisions for monotherapy vs combination therapy.

Alexey Danilov, MD, PhD: Let’s start talking a little about frontline therapy options that we have in CLL [chronic lymphocytic leukemia]. In my mind, we have 2½ options. One would be a combination of a BTK inhibitor with CD20 antibody or a BTK inhibitor alone. The other would be venetoclax and obinutuzumab. The third option would be chemoimmunotherapy, which we already discussed to a certain extent. Of those 3 options, do you have a favorite?

Anthony Mato, MD, MSCE: That’s a good question. No, I don’t have a favorite. I often have an impartial discussion about BTK inhibitors and venetoclax. I weigh the pros and cons, much like that slide that gets circulated with the scales of justice weighing 1 vs the other. There are pros and cons to both. I don’t think any of the sequencing data that we or anybody else have put together has strongly suggested what you have to start with to get the best outcome long-term in terms of PFS2 [second progression-free survival] 2 or PFS3 [third progression-free survival], or however you want to think about that concept of noncurative, sequential therapies.

I don’t have a strong opinion at this particular moment. I’m exploring both for each patient. Of course, if somebody has a comorbidity that’s restrictive of a BTK inhibitor or venetoclax, then there’s only 1 option available to patients, and I offer 1 option. We need comparative trials. We need trials that have clinically relevant controls and not straw man controls. Until we have that, I’m not prepared to declare a winner in my practice.

Alexey Danilov, MD, PhD: I completely agree. Until we have those comparisons, it’s going to be hard to know. You’re right: we care about overall survival and progression-free survival following the subsequent regimen and which sequencing approach is better. That often becomes a discussion with a patient where it’s a choice between fixed-duration strategies, such as venetoclax-obinutuzumab, which many patients like. It’s based on the CLL14 study, which randomized patients doing venetoclax-obinutuzumab vs chlorambucil-obinutuzumab. For all comers in that study, the 4-year progression-free survival is still at 75% and median PFS hasn’t been reached. That’s where patients receive therapy for only 1 year. I consider that a very impressive data set.

On the other hand, as far as indefinite therapy with BTK inhibitors, great data have recently come out following the ELEVATE-TN study publication, in which acalabrutinib was compared with chemoimmunotherapy and resulted in a very impressive progression-free survival. That’s where the conversation typically ends. Plus, on 1 hand, there are the typical adverse effects that we discussed regarding BTK inhibition with atrial fibrillation and hypertension. On the other hand, with venetoclax-obinutuzumab, the inconvenience of laboratory testing and potential risks of neutropenia aren’t necessarily associated with higher risk of infections. I agree that it’s difficult to say that 1 is better than another. It becomes a choice in my clinic based on patient preference, comorbidities, quality of life, and lifestyle. If you decide to go with a BTK inhibitor—to make it a little more complicated, let’s say acalabrutinib—do you combine it with a CD20 antibody, or do you use it by itself?

Anthony Mato, MD, MSCE: It’s the same answer as earlier about the discussion. The ELEVATE-TN data are intriguing, and I’ve certainly incorporated the data for the combination vs monotherapy into the discussion. In our practice, we have a clinical trial looking at acalabrutinib-obinutuzumab as a time-limited therapy. Patients are very eager to have a BTK inhibitor with the ease of starting a BTK inhibitor without the ramp-up and having the potential to stop. Our study allows everybody to stop by 24 months, but you can stop as early as 12 months. We’ve used that regimen in that context more than 20 times already in the last year.

Standard of care more often ends up being acalabrutinib monotherapy, and the combination on clinical trial for the time-limited approach. But there have been some circumstances where I’ve brought in obinutuzumab to acalabrutinib a little later. If I thought the response was suboptimal, I’ve had patients linger with counts of about 400,000 or 500,000 for a couple of months with the lymphocytosis that starts to get a little scary after awhile. I have to debulk them a bit with the obinutuzumab, especially in light of those data. That’s where I am. If those curves separate again at the next update, that will largely shift me toward using the combination. What do you think about that? There were a lot of naysayers when Jeff Sharman presented that at 24 months. They said the curves were going to come together and they didn’t, so now people are starting to think harder about this choice.

Alexey Danilov, MD, PhD: It’s interesting. To remind the audience, Anthony is talking about the ELEVATE-TN study, where there was a separation of curves in progression-free survival. A combination of acalabrutinib and obinutuzumab looked somewhat better by roughly 10% at the latest follow-up compared with acalabrutinib alone, and both looked a little better than chemoimmunotherapy control. The study wasn’t necessarily powered to detect that difference. If you put it in context of prior studies, such as the Alliance study, which compared ibrutinib plus rituximab vs ibrutinib alone and saw no difference whatsoever in progression-free survival, or The University of Texas MD Anderson Cancer Center study, which used ibrutinib with or without rituximab without any difference in progression-free survival, I do question that.

However, I recognize that obinutuzumab is a different antibody. It’s a second-generation glycoengineered antibody, which I believe has better efficacy in chronic lymphocytic leukemia, so it’s highly possible that these data are real. However, the combination was also associated with slightly more frequent adverse effects, including infections and infusion-related reactions, so I’m always cautious about using it for everybody. I would still use acalabrutinib alone for the majority of patients, but I’m excited about the study that you guys have where you’re planning to use this as time-limited therapy. If it truly works so well, this should be the approach for acalabrutinib and obinutuzumab. I wish there were such an arm in ELEVATE-TN.

Transcript edited for clarity.

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