CLL: BTK Inhibitors in the R/R Setting

Nicole Lamanna, MD, provides an overview of Bruton's tyrosine kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL) in the relapsed/refractory (R/R) setting.

William Wierda, MD, PhD: I’m very optimistic about a lot of the new work being done with new and novel agents and cellular therapy, and how we have a lot of options for clinical trials for relapse disease. Fortunately, we have limited numbers of patients because they’re doing so well on the standard treatments. It’s been a little challenging to enroll patients on the newer trials, which require relapsed/ refractory patients, particularly to what standard of care it was.

Let’s turn to Nicole and the setting of relapsed disease. We have a lot of long-term data on BTK [Bruton tyrosine kinase] inhibitor–based therapy in the relapsed/refractory setting. That category of compounds was available before BCL2, so we do have some data on sequencing of BTK inhibitors in the relapsed and frontline settings, followed by BTK. We don’t have a lot of data for the reverse of that. Can you summarize your thoughts on BTK inhibitors in the relapsed setting if a patient has chemotherapy-immunotherapy in the front line? What the expectations are for outcomes with BTK inhibitor–based therapy in the relapsed setting?

Nicole Lamanna, MD: Obviously, because these agents were started in the relapsed/refractory setting, and that’s where we have the bulk of our experiences. When we think about the relapse, we’re typically thinking about what they had in their first line of therapy. What are their comorbidities? Have their disease characteristics changed? Have they acquired a TP53 mutation or any other complex karyotype? Have other risk factors have changed between their first therapy and subsequent lines of therapy? Now that they’re older and maybe more frail, do they have additional comorbidities that may play into it? We have to consider all this when we consider second-line or later therapies.

For patients who have gotten chemotherapy-immunotherapy, given the RESONATE study, which was ibrutinib vs obinutuzumab, we have very long-term and good PFS [progression-free survival] data for BTK inhibitors still supporting the use of ibrutinib in that setting. Many of the patients’ durations of response have been durable, greater than 3½ years or more after continuation of therapy. For the majority of the patients in that study, the median prior therapies was about 3. These are heavily pretreated patients. About 3½ years out, half the patients are still on ibrutinib therapy, so the patients are doing very well. That speaks to some of the durability that we have with patients who might have gotten chemotherapy-immunotherapies in the front line and are using ibrutinib, our BTK inhibitor, in the second line.

Similarly, the ASCEND study was looking at acalabrutinib vs investigator choice of either bendamustine-rituximab or idelalisib plus rituximab, favoring the use of acalabrutinib in that population as well. Durable responses are seen in that setting. We have a lot of experience with BTK inhibitors after chemotherapy-immunotherapy with durable responses. As you alluded to, we don’t have as much in the reverse setting with venetoclax in frontline therapy, although those data are obviously going to emerge as well.

In the relapsed setting after chemotherapy-immunotherapy, or maybe after BTK inhibitors, we have the MURANO data with venetoclax and rituximab. We have very nice data with the use of venetoclax-rituximab in the relapsed/refractory setting for patients with CLL [chronic lymphocytic leukemia] also showing very durable responses. That was the first time-limited approach with venetoclax in a 2-year fashion, different from the up-front setting with venetoclax-obinutuzumab, but durable responses were seen. We’re learning that even in that setting for patients who progress, for those who might have either genomic complexity or high-risk disease, the likelihood is that their PFS and undetectable MRD [minimal residual disease] status are lower in that setting. We’re also gaining longer follow-up about those individuals, which will be very helpful.

William Wierda, MD, PhD: There was a long-term follow up from the MURANO study that was recently reported. Who’s willing to comment on that outcome and what their thoughts are on the durability of responses we’re seeing in the relapsed setting with these venetoclax-rituximab data?

Jennifer Woyach, MD: I can comment. That was presented a few months ago, and the median progression-free survival has now been reached. It was around 53 or 54 months. That looks really promising for this regimen too. We’re also starting to see patients who were getting re-treated with venetoclax in that setting or went on to a BTK inhibitor following their venetoclax-rituximab therapy. It looks very promising that 100% of the people who went on to a BTK inhibitor had a response. We don’t know much about response duration because it’s a short follow-up. The postvenetoclax response rates were reported at being about 55%, although this reflects a lot of patients who had early progression. As we get patients who had longer remission durations before they progressed, we’ll probably see higher response rates in that setting.


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