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Venetoclax in Chronic Lymphocytic Leukemia

Panelists:Alessandra Ferrajoli, MD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, Weill Cornell Medical College; Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine, Susan M. O’Brien, MD, UC Irvine Health; William G. Wierda, MD, PhD, University of Texas MD Anderson Cancer Center
Published: Thursday, Apr 14, 2016


Transcript:

William G. Wierda, MD, PhD:
Venetoclax is a drug that's not yet approved by the FDA for treatment of CLL. There's more and more data that we're hearing about. There's quite a bit of data, I think, that's being reported here at ASH 2015. I know, Dr. Ma, you've had a lot of experience and you have an abstract that you're updating at this meeting. I wonder if you could comment first on the mechanism of action of venetoclax and then perhaps give us a summary of your updated data that you're presenting here.

Shuo Ma, MD, PhD: Venetoclax is BCL-2 inhibitor. BCL-2 is an important anti-apoptotic protein that's overexpressed in many cancer cells that allows the cancer cells to survive. So by blocking the BCL-2, you can induce the apoptosis initiation. And venetoclax is an orally available selected BCL-2 inhibitor that has been studied previously and reported in relapse refractory CLL patients, that has a very high response rate.

In this ASH meeting 2015, there are two interesting studies. One is venetoclax as a single agent in 17p-deletion CLL patients—that's a relapse refractory group. So, in this phase II study, the overall response rate was reported to be 80% and the complete response rate was 10%. The 12-month progression-free survival was 72%. So, you can see that monotherapy with venetoclax can induce a deep and durable response.

And then I'm going to report an updated analysis on our phase Ib study in combination of venetoclax with rituximab. So, this is also in a group of patients with relapse and refractory CLL. In this group of patients, we have noticed an overall response rate of 86%, with a complete response of 47%. And more importantly, 55% of all patients achieved an MRD-negative bone marrow response. So a very deep response. And we have also looked at the progression-free survival and overall survival. So at a 24-month analysis, about 86% of patients are free from progression of disease.

Another interesting phenomena is that when you look at the duration of response based on MRD analysis, none of the MRD-negative patients actually have progressed at an 18-month mark. Whereas with MRD-positive patients, about 75% of the patients are free from progression. This is regardless of the quality of response. If you have an MRD-negative partial response, you can also be free from progression at 18-month analysis.

In this study another interesting thing is, for oral agents, as we have talked about with the BCR inhibitors, is advice for patient to continue having continuous treatment. But with a very deep response we're achieving with venetoclax therapy, we're asking the question, can patients actually stop treatment and still maintain a response? So far we’ve had 11 patients who have stopped venetoclax therapy after achieving either a CR or MRD-negative PR. And only two of those patients have progressed after 24-months off therapy. And both of those patients were MRD-positive patients. I think the bottom line is that achieving MRD-negative, your deep response does seem to allow the patient the chance to get off the treatment and still remain in remission.

Thomas J. Kipps, MD, PhD: And I think it's very important. I mean, some of those patients were our patients, and I think that the idea that if you can stop the drug, having the patient do well after stopping the drug is actually very exciting for many patients. Having a limited finite course of treatment may be possible, if you obtain a deep remission. We had discussions with patients, and obviously someone who had achieved either an MRD-negative response or just a deep CR, who wished to consider going off treatment, and followed them longer than they've been on therapy, and they still are doing very well. So, that's encouraging because it may indicate that we don't have to continually treat patients with these agents, and we may devise regimens that could be a shorter-term reaction. We're now addressing the question about some of these patients who are now just beginning to show some progression after being observed for years now, whether they can be retreated with the drug and whether they can achieve a very good response next go-around. I think they will be able to.

William G. Wierda, MD, PhD: As we finish up, maybe Dr. Ferrajoli, you can comment just on the issue of tolerability and what the side effects are that we've worried about with venetoclax, and how are we addressing this.

Alessandra Ferrajoli, MD: The main concern for venetoclax is actually very different from the one of the small molecule inhibitor we talked about before. There has to be great attention to the risk for tumor lysis syndrome. Patients need to be undergoing prophylaxis for tumor lysis syndrome. They need to be hydrated, and their laboratory values need to be monitored very closely because of the risk of life-threatening hyperkalemia related to this agent. Another toxicity that venetoclax has is myelosuppression. We do see myelosuppression often, mostly neutropenia. It's a neutropenia that does respond to treatment with growth factor. However, if present, it can be persisting, and to some extent there is also thrombocytopenia.

Transcript Edited for Clarity
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Transcript:

William G. Wierda, MD, PhD:
Venetoclax is a drug that's not yet approved by the FDA for treatment of CLL. There's more and more data that we're hearing about. There's quite a bit of data, I think, that's being reported here at ASH 2015. I know, Dr. Ma, you've had a lot of experience and you have an abstract that you're updating at this meeting. I wonder if you could comment first on the mechanism of action of venetoclax and then perhaps give us a summary of your updated data that you're presenting here.

Shuo Ma, MD, PhD: Venetoclax is BCL-2 inhibitor. BCL-2 is an important anti-apoptotic protein that's overexpressed in many cancer cells that allows the cancer cells to survive. So by blocking the BCL-2, you can induce the apoptosis initiation. And venetoclax is an orally available selected BCL-2 inhibitor that has been studied previously and reported in relapse refractory CLL patients, that has a very high response rate.

In this ASH meeting 2015, there are two interesting studies. One is venetoclax as a single agent in 17p-deletion CLL patients—that's a relapse refractory group. So, in this phase II study, the overall response rate was reported to be 80% and the complete response rate was 10%. The 12-month progression-free survival was 72%. So, you can see that monotherapy with venetoclax can induce a deep and durable response.

And then I'm going to report an updated analysis on our phase Ib study in combination of venetoclax with rituximab. So, this is also in a group of patients with relapse and refractory CLL. In this group of patients, we have noticed an overall response rate of 86%, with a complete response of 47%. And more importantly, 55% of all patients achieved an MRD-negative bone marrow response. So a very deep response. And we have also looked at the progression-free survival and overall survival. So at a 24-month analysis, about 86% of patients are free from progression of disease.

Another interesting phenomena is that when you look at the duration of response based on MRD analysis, none of the MRD-negative patients actually have progressed at an 18-month mark. Whereas with MRD-positive patients, about 75% of the patients are free from progression. This is regardless of the quality of response. If you have an MRD-negative partial response, you can also be free from progression at 18-month analysis.

In this study another interesting thing is, for oral agents, as we have talked about with the BCR inhibitors, is advice for patient to continue having continuous treatment. But with a very deep response we're achieving with venetoclax therapy, we're asking the question, can patients actually stop treatment and still maintain a response? So far we’ve had 11 patients who have stopped venetoclax therapy after achieving either a CR or MRD-negative PR. And only two of those patients have progressed after 24-months off therapy. And both of those patients were MRD-positive patients. I think the bottom line is that achieving MRD-negative, your deep response does seem to allow the patient the chance to get off the treatment and still remain in remission.

Thomas J. Kipps, MD, PhD: And I think it's very important. I mean, some of those patients were our patients, and I think that the idea that if you can stop the drug, having the patient do well after stopping the drug is actually very exciting for many patients. Having a limited finite course of treatment may be possible, if you obtain a deep remission. We had discussions with patients, and obviously someone who had achieved either an MRD-negative response or just a deep CR, who wished to consider going off treatment, and followed them longer than they've been on therapy, and they still are doing very well. So, that's encouraging because it may indicate that we don't have to continually treat patients with these agents, and we may devise regimens that could be a shorter-term reaction. We're now addressing the question about some of these patients who are now just beginning to show some progression after being observed for years now, whether they can be retreated with the drug and whether they can achieve a very good response next go-around. I think they will be able to.

William G. Wierda, MD, PhD: As we finish up, maybe Dr. Ferrajoli, you can comment just on the issue of tolerability and what the side effects are that we've worried about with venetoclax, and how are we addressing this.

Alessandra Ferrajoli, MD: The main concern for venetoclax is actually very different from the one of the small molecule inhibitor we talked about before. There has to be great attention to the risk for tumor lysis syndrome. Patients need to be undergoing prophylaxis for tumor lysis syndrome. They need to be hydrated, and their laboratory values need to be monitored very closely because of the risk of life-threatening hyperkalemia related to this agent. Another toxicity that venetoclax has is myelosuppression. We do see myelosuppression often, mostly neutropenia. It's a neutropenia that does respond to treatment with growth factor. However, if present, it can be persisting, and to some extent there is also thrombocytopenia.

Transcript Edited for Clarity
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