Management of Chronic Lymphocytic Leukemia in 2020 - Episode 13

Combinations for Relapsed or Refractory CLL


William Wierda, MD, PhD: We talked a little bit in the frontline setting about the combination targeted therapy. There’s work also that’s been done in the relapsed setting and has been reported at this meeting and earlier meetings. What are your thoughts on combination strategies in the relapsed setting?

Carolyn Owen, MD: I think that certainly we’re talking combination with antibody, the MURANO study with the finite duration included an antibody. And I don’t think anybody is questioning that you want to use the venetoclax with the rituximab. What is more interesting is all of the new combinations of BCL2 [B-cell lymphoma 2 protein] inhibitor with BTK [Bruton tyrosine kinase], and it depends on which BTK. And there’s PI3 kinase inhibitor combination studies. I think that all of those studies are very exciting. The MRD [minimal residual disease]-negativity rates can be quite impressive in the different studies, but at this point, we really don’t have any evidence that tells us that trying to put everything together in the relapsed setting is going to be better than giving sequential access to the agents in the way that the phase III studies have now been done.

We know that BTK inhibitors work very well in the vast majority of relapsed patients who haven’t obviously been exposed to a BTK inhibitor before, and then the same for venetoclax and rituximab in the MURANO study. Most of those patients had only had 1 prior line of therapy, which was usually chemoimmunotherapy, and response rates were excellent and very impressive and durable.

Although the combination of ibrutinib and venetoclax, or acalabrutinib and venetoclax, obinutuzumab, these combinations, they look very impressive, I think that the data are really too short at this time to be able to tell us that those strategies are better. And I would say that the choice currently should be between a BTK inhibitor and venetoclax and rituximab for patients who’ve received chemoimmunotherapy in relapse. The difficulty is that obviously if you have had a BTK inhibitor as your first-line therapy, then really if you’re looking at BCL2-based therapy, there’s not a lot of choice at that point. We don’t know how well it will work and whether finite-duration therapy is as good an approach. We’ll just have to wait and see.

William Wierda, MD, PhD: Do you have a different overall strategy for relapsed deletion 17p than relapsed non-17p?

Carolyn Owen, MD: I’ve heard a lot of debate, and I think like most people, I think Jackie had even mentioned before when she was talking about choices for frontline, I agree that I feel more comfortable with the idea of indefinite duration of therapy in a patient with a TP53 mutation or deletion 17p. But there really aren’t any data that strongly tell us that that is necessary. Venetoclax-based therapy works very well in that population of patients, and some patients can even get deep remissions. We don’t know whether continuing the agent would actually have led to a better overall survival later, rather than having the fixed duration and then re-treating, expecting that probably re-treatment would occur earlier than in a lower-risk patient.

You really need to look at both strategies in a clinical trial, and I think that there’s a lot of nervousness, so I’m not sure if the uptake of a study of that nature would be as brisk as some other clinical trials. But I think there’s a lot of willingness to try venetoclax-based therapy with a finite duration in those patients. And so, although that’s not going to be in a prospective comparative fashion, I think we will get data. Certainly, the CLL14 study frontline didn’t exclude patients with deletion 17p. The MURANO study saw patients with deletion 17p, so there are those patients out there who we’ll be able to look at and see how they do. There are going to be cross-trial comparisons to see patient outcomes. But I don’t think the question is answered, although I agree, I favor a continuous therapy at this point.

Stephen Opat, MBBS: Can I add from the MURANO study, I think that patients with 17p, their chance of achieving MRD-negativity is less, and even if they do, I think there is an emerging signal that perhaps the durability is not as good. But having said that, there are still patients with 17p who were treated on the MURANO study who achieved MRD-negativity in the long treatment-free interval. So, it’s not completely out of the question. I just think it’s probably less likely.

William Wierda, MD, PhD: I think from my perspective, the thing that I worry about in a relapsed 17p patient is that time off treatment may be short because they tend to be more proliferative. I don’t really trust them to go long periods off treatment. And the median progression-free survival on the M13-982 trial, which was venetoclax monotherapy in the relapsed 17p population, was about 2 years, and that’s about the same as it is with a BTK inhibitor-based therapy. I think of them still as high risk. I don’t like to have them off treatment, and I worry about resistance in those patients.

Transcript Edited for Clarity