Future Directions Treating CLL With Novel Therapy-Based Regimens

Anthony Mato, MD, MSCE: Because we’re talking about combinations, the world is leaning toward the novel-novel combinations or the triplets. Where do you stand on where ibrutinib-venetoclax will fit into your treatment landscape, given that it may likely be an option in the near future? Will you use it? Who will you use it for? I’m curious.

Alexey Danilov, MD, PhD: This is a very interesting question. I still haven’t made up my mind on this. The most obvious population that could be a good candidate for this doublet-doublet therapy is patients with high-risk CLL [chronic lymphocytic leukemia] or patients with deletion 17p or TP53 mutations. We know that the venetoclax-obinutuzumab combination is associated with inferior efficacy in this particular group of patients as opposed to the whole CLL cohort. For patients with high-risk CLL with TP53 abnormalities, the median PFS [progression-free survival] has been reached, and it stands at about 4 years. That’s still a very impressive result for a time-limited therapy; nevertheless, it’s less effective.

On the other hand, we also know that BTK inhibitors are likely less effective in this group of patients as well based on the PFS data that we have. This will be the first group of patients where I’d be interested in using this regimen, in particular with patients who are interested in time-limited therapy. The question will then become what to use next after these patients progress and have already been exposed to the 2 most effective classes of drugs that we have in this situation for deletion 17p disease.

My answer is that it depends on the mode of progression. If I find a BTK mutation, then maybe next would be something like pirtobrutinib or repeated venetoclax. If we find a BCL2 mutation, then the next approach will be BTK inhibitor or the CAR [chimeric antigen receptor] T-cell approach, which is emerging. It’s still not approved for therapy of CLL, but hopefully we’ll have that as standard of care at some point. A clinical trial is still available. In regard to patients who have standard-risk CLL, I’m still not certain. What this regimen provides is an all-oral combination treatment. In my practice, it might replace BTK inhibitor single-agent because of this opportunity for time-limited therapy. I’m not sure which patients would be the best candidate. What do you think, Anthony?

Anthony Mato, MD, MSCE: I’m similar in thinking to you. My major issue with the novel-novel combinations is the comparisons. I’ve learned this term recently about relative contributions and how to assess them. When individual drugs are better than the control arm, I don’t know how to judge the combination, so that’s my major concern. What will limit my adaptation of the regimen is essentially that, relatively speaking, the comparison is placebo. The other concern I have is what you just brought up: the resistance pattern. Right now, I’m working with a younger patient who’s under 30 who’s being treated with triplet therapy in the context of a clinical trial and is progressing. I’m trying to sort out what to do next. It’s complex, particularly because the relapse is mostly nodal and it’s hard to assess what you asked for—the BCL2 and BTK mutations—to make that decision in real time outside getting a lymph node out. We’re starting to grapple with these questions in practice. It’s not only theoretical, so that’s a bit of a concern.

Regarding the deletion 17p population, I agree that the data look good, although there were fewer than 30 patients treated with the deletion 17p on the CAPTIVATE fixed-duration trial. The comparison in my mind is the CLL14 results with deletion 17p, where only 17 patients were treated. We’re dealing with tiny numbers of patients and trying to make these broad conclusions about which would be better. I’d use it only in a 17p deleted patient who absolutely mandated a fixed-duration schedule. Otherwise, a continuous BTK inhibitor is still a reasonable option.

Alexey Danilov, MD, PhD: I completely agree. Of the therapies that we have that have been tested extensively, BTK inhibitors are probably the most extensively tested effective option and remain a very appropriate therapy for these patients. You mentioned triplet therapy. Do you think that has legs, or do you think that’s not the future? I found it a bit difficult in terms of tolerability in older patients of mine.

Anthony Mato, MD, MSCE: I don’t think it’s the future, and I don’t think the current trials comparing triplet therapies in the United States with ibrutinib-obinutuzumab are going to be very informative. The data I’ve seen so far from OSU [Ohio State University] on IVO [ibrutinib, venetoclax, obinutuzumab] look about as effective as ibrutinib-venetoclax but with more adverse effects, so I haven’t been a widespread promoter of triplet trials. I believe there’s a trial—maybe you can correct me on this—where acalabrutinib-venetoclax is being compared with AVO [acalabrutinib, venetoclax, obinutuzumab] vs chemoimmunotherapy. If that’s the case, it might be helpful to have that information when it’s finally published. It seems as if the acalabrutinib team are good about comparing the contribution of the CD20 vs not, so that will be very helpful.

Alexey Danilov, MD, PhD: I agree. That will be a great study in combination with your trial that compares acalabrutinib-venetoclax vs venetoclax-obinutuzumab. That’s a randomized study as well. Those 2 studies will help us answer a lot of questions. What’s the right approach to frontline therapy of CLL? That’s interesting. Because we started the conversation with prognostic markers, while the CAPTIVATE regimen, or the doublet therapy with novel-novel, hasn’t been approved, is BTK inhibitor your go-to regimen for the majority of patients with TP53 abnormalities? Or do you still consider venetoclax?

Anthony Mato, MD, MSCE: I still consider both, largely because the venetoclax data for deletion 17p are based on CLL14, with only 17 patients in that arm. It’s too small of a number for me to give up on a particular therapy that has generally been excellent for patients, so I’m not willing to do that. The long-term follow-up data from NCI [National Cancer Institute] with deletion 17p look really good. But at the same time, that’s a highly select patient population who are able to participate in a trial there. We need studies comparing these modalities—either BTK vs BCL2 in that population or fixed duration vs continuous therapy—to give us the answer about what to do. I still offer both on and off study.

Transcript edited for clarity.