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Combining Targeted Therapies in CLL

Panelists: Jacqueline Barrientos, MD, Zucker School of Medicine at Hofstra/Northwell; Stephen Opat, MBBS, Monash Health; Carolyn Owen, MD, University of Calgary; Shuo Ma, MD, PhD, Feinberg School of Medicine at Northwestern Medicine; William Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center
Published: Friday, Feb 21, 2020



Transcript:

William Wierda, MD, PhD: Moving on into additional combinations, there are data that were presented here, and last year, and then updates that our group from The University of Texas MD Anderson Cancer Center reported on combinations of BTK [Bruton tyrosine kinase] plus BCL2 [B-cell lymphoma 2 protein]. The CAPTIVATE trial was updated here at ASH [the American Society of Hematology annual meeting], so maybe Jacqueline you can give us a summary on what’s happening with combination therapy, combination targeted therapy, and where we think that’s going.

Jacqueline Barrientos, MD: Yes. Nitin Jain, MD, from MD Anderson presented the longer follow-up on patients treated with ibrutinib and venetoclax, ibrutinib being used as a debulking agent. And then you add on venetoclax. What we see with longer follow-up is that you can achieve deeper responses. And so at this moment there are some people who are still not able to achieve an undetectable level of MRD [minimal residual disease], and the study is considering modifying the protocol to extend them to give them another year, kind of like an MRD-driven practice, to see if they can get a deeper remission, and with that, a longer remission duration once you stop both drugs. And in terms of patients who have stopped this therapy, many of them are still in remission, which is something that is very encouraging. And we see that supported by the data presented by Constantine Tam, MD, MBBS from the CAPTIVATE trial follow-up from the last year, when you presented the initial presentation.

Currently that study is a combination with a fixed-duration dosing. The presentation also shows that patients can achieve lower TLS [tumor lysis syndrome] risk with the debulking at the time of reassessment when the venetoclax is going to be administered and initiated. Patients can achieve a deeper remission in terms of MRD depth achievement, and also there’s no higher risk of toxicity other than what we would expect from single agents. So there’s no new sickness, and that’s also very encouraging. I think it’s possible that in the future instead of using a BTK with a monoclonal antibody, we may be choosing to use a BCL2 agent, but at this moment the Intergroup studies are for BTK plus monoclonal antibody, obinutuzumab, plus or minus venetoclax. So we’re still going to have to wait a little bit longer for American data for that.

William Wierda, MD, PhD: So combination BTK, BCL2, and not standard of care, being studied in phase III trials. Are you optimistic about that strategy?

Jacqueline Barrientos, MD: I am very optimistic from the data that have been presented.

William Wierda, MD, PhD: And fixed duration you think is important....

Jacqueline Barrientos, MD: That’s one of the questions that was posted in the session. Would you use an approach where you tell everyone, use 15 months of combinational therapy, or would you do MRD-driven? I don’t think at this moment we can answer that. I may agree with the presenter saying that from a population perspective, it might be easier in the community to just do fixed-duration regimen instead of MRD-driven, because it might be too complicated.

William Wierda, MD, PhD: MRD monitoring by blood, bone marrow biopsy, how do you think about those things?

Jacqueline Barrientos, MD: From what I’m seeing, the concomitant rate is very similar. I think from the data from the CLL14 trial, you can just go by the peripheral blood. But I don’t know how my colleagues feel, if you feel strongly that you have to pursue a bone marrow biopsy.
             
Stephen Opat, MBBS: I’ll take a step back. I guess interpreting all these studies, it’s really important to determine what’s the most important end point, and is it progression-free survival, is it overall survival? Is it better to give the drugs concurrently or sequentially? All these questions are yet to be answered. On the specific question of a bone marrow biopsy in the setting of the clinical trial, it seems that sequentially if you’ve cleared the MRD from the peripheral blood, you could potentially do a bone marrow biopsy on those patients, which is a small number of patients; you may find a slight difference, it’s less than a log or half a log difference in the levels of MRD between peripheral blood and bone marrow. It’s higher with chemotherapy and less with novel agents. But I think outside of a clinical trial, I don’t think for the individual patient there’s any indication to monitor MRD at this stage.
                            
Shuo Ma, MD, PhD: I think it depends on the regimen. The concordance between peripheral blood MRD versus bone marrow MRD, for example, the venetoclax plus obinutuzumab combination, the concordance is close to 90%, which is pretty good. Whereas for example, the ibrutinib plus venetoclax study, the peripheral blood MRD undetectable rate was almost 100% versus 68% when you’re doing it in the bone marrow. So there’s still a big difference.

Still the bone marrow MRD assessment is the golden standard in a clinical trial setting, but in the clinical practice I think it’s probably, the peripheral blood is a good parameter to monitor disease.

Transcript Edited for Clarity

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Transcript:

William Wierda, MD, PhD: Moving on into additional combinations, there are data that were presented here, and last year, and then updates that our group from The University of Texas MD Anderson Cancer Center reported on combinations of BTK [Bruton tyrosine kinase] plus BCL2 [B-cell lymphoma 2 protein]. The CAPTIVATE trial was updated here at ASH [the American Society of Hematology annual meeting], so maybe Jacqueline you can give us a summary on what’s happening with combination therapy, combination targeted therapy, and where we think that’s going.

Jacqueline Barrientos, MD: Yes. Nitin Jain, MD, from MD Anderson presented the longer follow-up on patients treated with ibrutinib and venetoclax, ibrutinib being used as a debulking agent. And then you add on venetoclax. What we see with longer follow-up is that you can achieve deeper responses. And so at this moment there are some people who are still not able to achieve an undetectable level of MRD [minimal residual disease], and the study is considering modifying the protocol to extend them to give them another year, kind of like an MRD-driven practice, to see if they can get a deeper remission, and with that, a longer remission duration once you stop both drugs. And in terms of patients who have stopped this therapy, many of them are still in remission, which is something that is very encouraging. And we see that supported by the data presented by Constantine Tam, MD, MBBS from the CAPTIVATE trial follow-up from the last year, when you presented the initial presentation.

Currently that study is a combination with a fixed-duration dosing. The presentation also shows that patients can achieve lower TLS [tumor lysis syndrome] risk with the debulking at the time of reassessment when the venetoclax is going to be administered and initiated. Patients can achieve a deeper remission in terms of MRD depth achievement, and also there’s no higher risk of toxicity other than what we would expect from single agents. So there’s no new sickness, and that’s also very encouraging. I think it’s possible that in the future instead of using a BTK with a monoclonal antibody, we may be choosing to use a BCL2 agent, but at this moment the Intergroup studies are for BTK plus monoclonal antibody, obinutuzumab, plus or minus venetoclax. So we’re still going to have to wait a little bit longer for American data for that.

William Wierda, MD, PhD: So combination BTK, BCL2, and not standard of care, being studied in phase III trials. Are you optimistic about that strategy?

Jacqueline Barrientos, MD: I am very optimistic from the data that have been presented.

William Wierda, MD, PhD: And fixed duration you think is important....

Jacqueline Barrientos, MD: That’s one of the questions that was posted in the session. Would you use an approach where you tell everyone, use 15 months of combinational therapy, or would you do MRD-driven? I don’t think at this moment we can answer that. I may agree with the presenter saying that from a population perspective, it might be easier in the community to just do fixed-duration regimen instead of MRD-driven, because it might be too complicated.

William Wierda, MD, PhD: MRD monitoring by blood, bone marrow biopsy, how do you think about those things?

Jacqueline Barrientos, MD: From what I’m seeing, the concomitant rate is very similar. I think from the data from the CLL14 trial, you can just go by the peripheral blood. But I don’t know how my colleagues feel, if you feel strongly that you have to pursue a bone marrow biopsy.
             
Stephen Opat, MBBS: I’ll take a step back. I guess interpreting all these studies, it’s really important to determine what’s the most important end point, and is it progression-free survival, is it overall survival? Is it better to give the drugs concurrently or sequentially? All these questions are yet to be answered. On the specific question of a bone marrow biopsy in the setting of the clinical trial, it seems that sequentially if you’ve cleared the MRD from the peripheral blood, you could potentially do a bone marrow biopsy on those patients, which is a small number of patients; you may find a slight difference, it’s less than a log or half a log difference in the levels of MRD between peripheral blood and bone marrow. It’s higher with chemotherapy and less with novel agents. But I think outside of a clinical trial, I don’t think for the individual patient there’s any indication to monitor MRD at this stage.
                            
Shuo Ma, MD, PhD: I think it depends on the regimen. The concordance between peripheral blood MRD versus bone marrow MRD, for example, the venetoclax plus obinutuzumab combination, the concordance is close to 90%, which is pretty good. Whereas for example, the ibrutinib plus venetoclax study, the peripheral blood MRD undetectable rate was almost 100% versus 68% when you’re doing it in the bone marrow. So there’s still a big difference.

Still the bone marrow MRD assessment is the golden standard in a clinical trial setting, but in the clinical practice I think it’s probably, the peripheral blood is a good parameter to monitor disease.

Transcript Edited for Clarity
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