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Venetoclax for CLL After Progression on 1 Prior Therapy

Panelists: Matthew S. Davids, MD, MMSc Dana-Farber Cancer Institute; Naval G. Daver, MD The University of Texas MD Anderson Cancer Center; Daniel A. Pollyea, MD, MS University of Colorado School of Medicine
Published: Tuesday, Jan 15, 2019

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Transcript: 

Matthew S. Davids, MD, MMSc:
So, the BCL2 inhibitor of venetoclax was initially granted accelerated approval in CLL [chronic lymphocytic leukemia] for patients who had deletion 17p and had progressed on at least 1 therapy. But recently, a confirmatory phase III trial, the MORANO trial, read out. This was a comparison of venetoclax with rituximab versus a standard of care for relapsed disease, bendamustine and rituximab, and showed very significant progression-free and overall survival benefits of the venetoclax regimen. So, more recently, this led to the full approval of venetoclax for patients with CLL who have progressed on at least 1 prior therapy, and I think this is a very important new option for patients with CLL. An advantage of this regimen is that it’s designed as a time-limited regimen with about a 2-year treatment course, and that I think compares favorably to patients who need to receive continuous therapies.

B-cell receptor signaling in CLL is one of the critical pathways that keep CLL cells alive. It allows CLL cells to proliferate and to cause issues in terms of growth and causing infiltration of the bone marrow, causing enlarging lymph nodes. And so…interrupting the B-cell receptor pathway, either through BTK inhibition, pI3 kinase inhibition, or by other mechanisms…has proved to be an extremely effective strategy for treating this disease.

So, right now, the question of using venetoclax on its own versus venetoclax in combination with rituximab is one that we’re unlikely to see explored in a clinical trial setting, so we need to extrapolate from the existing data sets we have from the early phase clinical trials of venetoclax, when it was used as a monotherapy in comparison with the more recent data sets we have of venetoclax in combination with rituximab. My sense is that the combination with rituximab does induce deeper responses, both in terms of complete remission, as well as, perhaps even more importantly, in MRD negativity rates.

And so, therefore, I do lean toward using the venetoclax/rituximab regimen, as I think there is a potential there for time-limited therapy, which is certainly a major advance for our patients with CLL.

So the venetoclax/rituximab regimen is highly active for patients who have high-risk CLL, including deletion 17p. The response rates in that high-risk population are equivalent to that seen in the lower-risk CLL patients. What remains to be seen is whether the durability will be as long. We saw with the single-agent venetoclax studies that the durability of response was shorter in those patients who have deletion 17p. So far, the follow-up is shorter in the rituximab/venetoclax combination studies, but the results certainly look very promising for those patients with deletion 17p at this time point.

Yes, so my personal experience in treating venetoclax patients with the rituximab combination has been quite positive. I find that using this combination is a little bit challenging to initiate because we need to monitor the patients very closely for tumor lysis syndrome. However, once patients get through that initial period of risk, the drug is extremely well tolerated, and we need to monitor for neutropenia, and some patients can have some lingering gastrointestinal adverse effects. But in the long term, these patients can tolerate venetoclax therapy quite well and stay on the drug for a very long time.


Transcript Edited for Clarity
 
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Transcript: 

Matthew S. Davids, MD, MMSc:
So, the BCL2 inhibitor of venetoclax was initially granted accelerated approval in CLL [chronic lymphocytic leukemia] for patients who had deletion 17p and had progressed on at least 1 therapy. But recently, a confirmatory phase III trial, the MORANO trial, read out. This was a comparison of venetoclax with rituximab versus a standard of care for relapsed disease, bendamustine and rituximab, and showed very significant progression-free and overall survival benefits of the venetoclax regimen. So, more recently, this led to the full approval of venetoclax for patients with CLL who have progressed on at least 1 prior therapy, and I think this is a very important new option for patients with CLL. An advantage of this regimen is that it’s designed as a time-limited regimen with about a 2-year treatment course, and that I think compares favorably to patients who need to receive continuous therapies.

B-cell receptor signaling in CLL is one of the critical pathways that keep CLL cells alive. It allows CLL cells to proliferate and to cause issues in terms of growth and causing infiltration of the bone marrow, causing enlarging lymph nodes. And so…interrupting the B-cell receptor pathway, either through BTK inhibition, pI3 kinase inhibition, or by other mechanisms…has proved to be an extremely effective strategy for treating this disease.

So, right now, the question of using venetoclax on its own versus venetoclax in combination with rituximab is one that we’re unlikely to see explored in a clinical trial setting, so we need to extrapolate from the existing data sets we have from the early phase clinical trials of venetoclax, when it was used as a monotherapy in comparison with the more recent data sets we have of venetoclax in combination with rituximab. My sense is that the combination with rituximab does induce deeper responses, both in terms of complete remission, as well as, perhaps even more importantly, in MRD negativity rates.

And so, therefore, I do lean toward using the venetoclax/rituximab regimen, as I think there is a potential there for time-limited therapy, which is certainly a major advance for our patients with CLL.

So the venetoclax/rituximab regimen is highly active for patients who have high-risk CLL, including deletion 17p. The response rates in that high-risk population are equivalent to that seen in the lower-risk CLL patients. What remains to be seen is whether the durability will be as long. We saw with the single-agent venetoclax studies that the durability of response was shorter in those patients who have deletion 17p. So far, the follow-up is shorter in the rituximab/venetoclax combination studies, but the results certainly look very promising for those patients with deletion 17p at this time point.

Yes, so my personal experience in treating venetoclax patients with the rituximab combination has been quite positive. I find that using this combination is a little bit challenging to initiate because we need to monitor the patients very closely for tumor lysis syndrome. However, once patients get through that initial period of risk, the drug is extremely well tolerated, and we need to monitor for neutropenia, and some patients can have some lingering gastrointestinal adverse effects. But in the long term, these patients can tolerate venetoclax therapy quite well and stay on the drug for a very long time.


Transcript Edited for Clarity
 
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