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Ibrutinib + Venetoclax for 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: We talked a little bit about, or a lot about, BTK [Bruton tyrosine kinase]-inhibitor-based therapy with CD20 antibodies. I wonder if you can give us your opinion on BCL2 [B-cell lymphoma 2 protein] inhibitor, or venetoclax-based therapy, and CD20 antibody and if we think that’s important.

Stephen Opat, MBBS: If you compare the monotherapy venetoclax, so most of these studies we’re talking about are in relapsed disease. But if you compare the MURANO study with the monotherapy studies, there are some subtle differences of adding an antibody to venetoclax-based therapy. First of all, bulky adenopathy, which was adverse in the monotherapy, was no longer adverse when you’re combining it with Rituxan [rituximab]. And secondly, if you look at the depth of response there are much higher rates of…MRD [minimal residual disease]-negativity. And so, while there’s been a number of retrospective cross-trial comparisons, they can’t prove there’s a benefit, there’s been no head-to-head venetoclax with an antibody versus venetoclax single agent.

I think it’s likely that if you’re getting more disease clearance, if you accept minimal residual disease-negativity as an end point, it’s likely to translate into improved progression-free survival. I also think the fact that bulky lymphadenopathy is no longer adverse in the MURANO study is compelling that the combination is perhaps better than monotherapy. But can I say, hand on my heart, it’s better though there’s been no trial.

Shuo Ma, MD, PhD: I can add 2 points. One is that we have done a multivariate analysis comparing, we did a stage Ib study of rituximab plus venetoclax, so comparing that data with the phase I study of venetoclax alone. On the multivariate analysis, adding rituximab seemed to improve the CR rate, complete remission rate. That’s 1 thing.

The second thing is in the Gazyva, obinutuzumab plus venetoclax combination, the starting of obinutuzumab is also a debulking strategy trying to reduce your tumor burden by the time you’re starting venetoclax, and therefore reducing, downgrading your TLS [tumor lysis syndrome] risk category. So I think adding the anti-CD28 antibody probably has not only debulking effect, but also potentially deepens your response.

William Wierda, MD, PhD: Which is important again for venetoclax, which is generally thought of as a fixed-duration treatment.

Shuo Ma, MD, PhD: Especially for fixed-duration therapy, the depth of response and achieving MRD is much more important compared to indefinite therapy.

Jacqueline Barrientos, MD: Yes, that’s one of the things that I’ve liked from this ASH [American Society of Hematology annual meeting], that with longer follow-up we continue to see that achieving undetectable MRD correlates with better time in remission.

Transcript Edited for Clarity

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Transcript:

William Wierda, MD, PhD: We talked a little bit about, or a lot about, BTK [Bruton tyrosine kinase]-inhibitor-based therapy with CD20 antibodies. I wonder if you can give us your opinion on BCL2 [B-cell lymphoma 2 protein] inhibitor, or venetoclax-based therapy, and CD20 antibody and if we think that’s important.

Stephen Opat, MBBS: If you compare the monotherapy venetoclax, so most of these studies we’re talking about are in relapsed disease. But if you compare the MURANO study with the monotherapy studies, there are some subtle differences of adding an antibody to venetoclax-based therapy. First of all, bulky adenopathy, which was adverse in the monotherapy, was no longer adverse when you’re combining it with Rituxan [rituximab]. And secondly, if you look at the depth of response there are much higher rates of…MRD [minimal residual disease]-negativity. And so, while there’s been a number of retrospective cross-trial comparisons, they can’t prove there’s a benefit, there’s been no head-to-head venetoclax with an antibody versus venetoclax single agent.

I think it’s likely that if you’re getting more disease clearance, if you accept minimal residual disease-negativity as an end point, it’s likely to translate into improved progression-free survival. I also think the fact that bulky lymphadenopathy is no longer adverse in the MURANO study is compelling that the combination is perhaps better than monotherapy. But can I say, hand on my heart, it’s better though there’s been no trial.

Shuo Ma, MD, PhD: I can add 2 points. One is that we have done a multivariate analysis comparing, we did a stage Ib study of rituximab plus venetoclax, so comparing that data with the phase I study of venetoclax alone. On the multivariate analysis, adding rituximab seemed to improve the CR rate, complete remission rate. That’s 1 thing.

The second thing is in the Gazyva, obinutuzumab plus venetoclax combination, the starting of obinutuzumab is also a debulking strategy trying to reduce your tumor burden by the time you’re starting venetoclax, and therefore reducing, downgrading your TLS [tumor lysis syndrome] risk category. So I think adding the anti-CD28 antibody probably has not only debulking effect, but also potentially deepens your response.

William Wierda, MD, PhD: Which is important again for venetoclax, which is generally thought of as a fixed-duration treatment.

Shuo Ma, MD, PhD: Especially for fixed-duration therapy, the depth of response and achieving MRD is much more important compared to indefinite therapy.

Jacqueline Barrientos, MD: Yes, that’s one of the things that I’ve liked from this ASH [American Society of Hematology annual meeting], that with longer follow-up we continue to see that achieving undetectable MRD correlates with better time in remission.

Transcript Edited for Clarity
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