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Other Promising Strategies in CLL

Panelists: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center; Steven Coutre, MD, Stanford University Medical Center; Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute; Nicole Lamanna, MD, Columbia University Medical Center; Shuo Ma, MD, PhD, Robert H. Lurie Comprehensive Cancer Center
Published: Monday, Feb 19, 2018



Transcript: 

William G. Wierda, MD, PhD: In terms of other interesting therapeutic targets for patients with CLL, there are other drugs under development. Maybe, Matt, you can comment on some of the other interesting targets that we should be looking out for, for a potentially next approval.

Matthew S. Davids, MD, MMSc: So, we’ve hit some of them already. I think one other target within the B-cell receptor pathway to mention is SYK, the spleen tyrosine kinase. There’s a drug, entospletinib, we’ve seen some additional data here at the ASH meeting. Nothing too different from what we’ve seen before. It’s clearly an active agent. We do see some of the immune-mediated toxicities as well, although not to the same degree as what we’ve seen with the delta PI3-kinase inhibitors.

One thing to bear in mind with the apoptosis pathway is that BCL-2 is not the only potential target. And in fact, as we selectively target BCL-2, we do worry that we may see upregulation of other anti-apoptotic proteins. So, there are now MCL-1 inhibitors that have entered the clinic. And it’s possible we’ll see BCXL inhibitors in the future. Eventually, we may have a whole toolkit of agents to target the apoptotic pathway, which is exciting. CAR T-cell therapy has been very successful in lymphoma. There certainly have been some promising responses in CLL as well, but the data are more early there, and I think we need to see more data in CAR T cells before that’s going to become more of a routine part of our CLL practice. So, those will be some of the more interesting targets I can think of.

William G. Wierda, MD, PhD: You’ve done a lot of work with the BH3 profiling, etc. Your understanding of venetoclax resistance, mechanism of venetoclax resistance, maybe you can comment on that.

Matthew S. Davids, MD, MMSc: Yes. I think with ibrutinib, it was pretty clear early on that these BTK mutations developed and it was a very clear pathway for resistance. Unfortunately, we haven’t seen a similar story evolving yet with venetoclax. We did see some abstracts presented at this meeting that looked at mutational profiles in a more limited number of patient samples, and there was no clear answer as to what the cause of resistance was. It’s not like we saw BCL-2 mutations or anything like this. So, I think it remains a bit of an unknown. I think from this functional perspective, we can imagine these other antiapoptotic proteins being upregulated—MCL-1, BCXL—but we don’t have a lot of data yet in patients to prove that.

William G. Wierda, MD, PhD: And targeting those?

Matthew S. Davids, MD, MMSc: Targeting those, I think, is a very promising approach, but the drugs really have just entered the clinic so whether that’s even a safe approach, we don’t know yet.

William G. Wierda, MD, PhD: So, Shuo, maybe you can comment on the checkpoint inhibitors. What’s our understanding of the activity of checkpoint inhibitors in CLL, and where are we going with those?

Shuo Ma, MD, PhD: Right. The Mayo Clinic presented their interesting study enrolling patients with relapsed/refractory CLL, as well as Richter transformation, with pembrolizumab. So, their observation is very interesting in that the CLL patient actually did not respond to the T-1 antibody. However, the diffused large B-cell lymphoma component, at the Richter transformation, responded 40% of overall response rate among those patients. And even in those patients, their CLL component did not respond. Their large-cell lymphoma component responded. So, I think definitely that raises the question whether we can cover the PD-1 blockade, too, as combination therapy with something else to treat Richter transformation, which is an area of huge unmet medical need.

William G. Wierda, MD, PhD: So, Nicole, there are now 3 approved CD20 antibodies. We have rituximab—which was the initial drug that we had and clearly showed improved in outcomes with chemotherapy in patients with CLL—ofatumumab, and we have obinutuzumab, which appears to be better when combined with chlorambucil than rituximab. Ublituximab is another one that we’ve seen some data about. Can you maybe comment on different CD20 antibodies where they may be useful? Is there a difference in effectiveness?

Nicole Lamanna, MD: Certainly. The clinical data have shown that obinutuzumab in some of the randomized studies—when it has been compared to rituximab, whether that be with chlorambucil in particular—there’s no doubt that there were improved responses and even some MRD negativity in that study as compared to the chlorambucil/rituximab arm. So, there’s no doubt that I think we’re seeing a clearer signal that obinutuzumab gives higher response rates. Is that all across the board? Hard to know. There are a lot of head-to-head randomized data, but certainly there is some.

I think that’s why there has been a lot more studies involving the combination of venetoclax or another agent with obinutuzumab. Certainly, we still have those combinations with rituximab. Now you have ublituximab, which is very similar to obinutuzumab in mechanism, and certainly those data look promising as well. I guess the question that always arises in my head is, how many monoclonal CD20 antibodies do we need? I don’t mean to be mean or negative. I guess the point being is that we have cost issues to deal with and so there’s that that we have to face. If it’s clearly dramatically better, I think that we should push to use one particular antibody versus what we’re doing, which is a smattering in the United States.

Rituximab is still the most widely used monoclonal antibody. I think there will be reimbursement issues or it depends on the hospital and the formularies of which antibodies they will pay for. And then there are biosimilars and then subcutaneous rituximab. So, how that will be incorporated is another thing. So, I think that there are lots of CD20 monoclonal antibodies. I think clearly there are some that are probably more potent. But the question is, in practice, how will we incorporate them remains to be seen.

William G. Wierda, MD, PhD: And what about toxicities? Is there a difference?

Nicole Lamanna, MD: There’s more infusion-related toxicities with the more potent antibodies, but generally, if you get somebody through that first infusion, they’re well tolerated. So, you up the ante on the antihistamines and the steroids. And most people do fine and you split the dose. You can work around it once they get through that first infusion, but certainly, we do see a little bit more of that, a little bit more neutropenia. But those are manageable.

Shuo Ma, MD, PhD: One interesting observation from the combination study is that when you’re combining with ibrutinib, there seem to be less infusion reaction with obinutuzumab.

Nicole Lamanna, MD: Certainly, that has come out with some of the data.

Shuo Ma, MD, PhD: Although that’s not here yet, still in the clinical trial phase.

Matthew S. Davids, MD, MMSc: I can speak to that briefly since I’m presenting a poster tonight at the ASH meeting where we did a randomization actually, and we treated one group of patients with obinutuzumab alone followed by combination with ibrutinib, the second group with ibrutinib first alone followed by the combination, and in the third group, we started both simultaneously. And we actually saw that 63% of the patients in that first arm where they started with the antibody alone had infusion reactions. And only 1 out of the 16 patients in the other 2 arms had reactions. So, it does seem to help to start the ibrutinib first, or at least simultaneously, with the antibody.

William G. Wierda, MD, PhD: Any other topics we should cover before…

Steven Coutre, MD: Well, one thing I think to bring up is to remind ourselves that when we’re looking at data or here listening to presentations of big trials is to also focus on the quality of life issues. Really important components of all of our trials. How do our patients tolerate these?

Nicole Lamanna, MD: We didn’t talk about the patient-reported outcomes.

Steven Coutre, MD: Yes, the patient-reported outcomes. We have some data from this meeting looking at those in the context of our novel therapy trials. There’s a really interesting publication just very recently in Blood Advances that was a survey tool that was used to send the patients asking them what’s important to them. Is it oral versus IV, a side effect profile, efficacy? I refer colleagues to look at that carefully. It’s pretty revealing. I think it shows that they want to see that their cancer is controlled for the longest time possible, and they’re willing to tolerate some side effects in exchange, but not too many. So, it’s really, really important as we develop these new therapies and the combinations. You mentioned the ibrutinib/venetoclax. Very, very well tolerated, so that’s an important finding.

Nicole Lamanna, MD: Yes, and it as very good. The presentation Dr. Robak presented involved the patient-reported outcomes. Even long-term monotherapy with ibrutinib is very tolerated and most patients report very good quality of life in addition to the efficacy and their hematologic parameters improve, but their quality of life is improving, too. So, we have to keep that in mind because that’s just monotherapy.

Transcript Edited for Clarity 

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Transcript: 

William G. Wierda, MD, PhD: In terms of other interesting therapeutic targets for patients with CLL, there are other drugs under development. Maybe, Matt, you can comment on some of the other interesting targets that we should be looking out for, for a potentially next approval.

Matthew S. Davids, MD, MMSc: So, we’ve hit some of them already. I think one other target within the B-cell receptor pathway to mention is SYK, the spleen tyrosine kinase. There’s a drug, entospletinib, we’ve seen some additional data here at the ASH meeting. Nothing too different from what we’ve seen before. It’s clearly an active agent. We do see some of the immune-mediated toxicities as well, although not to the same degree as what we’ve seen with the delta PI3-kinase inhibitors.

One thing to bear in mind with the apoptosis pathway is that BCL-2 is not the only potential target. And in fact, as we selectively target BCL-2, we do worry that we may see upregulation of other anti-apoptotic proteins. So, there are now MCL-1 inhibitors that have entered the clinic. And it’s possible we’ll see BCXL inhibitors in the future. Eventually, we may have a whole toolkit of agents to target the apoptotic pathway, which is exciting. CAR T-cell therapy has been very successful in lymphoma. There certainly have been some promising responses in CLL as well, but the data are more early there, and I think we need to see more data in CAR T cells before that’s going to become more of a routine part of our CLL practice. So, those will be some of the more interesting targets I can think of.

William G. Wierda, MD, PhD: You’ve done a lot of work with the BH3 profiling, etc. Your understanding of venetoclax resistance, mechanism of venetoclax resistance, maybe you can comment on that.

Matthew S. Davids, MD, MMSc: Yes. I think with ibrutinib, it was pretty clear early on that these BTK mutations developed and it was a very clear pathway for resistance. Unfortunately, we haven’t seen a similar story evolving yet with venetoclax. We did see some abstracts presented at this meeting that looked at mutational profiles in a more limited number of patient samples, and there was no clear answer as to what the cause of resistance was. It’s not like we saw BCL-2 mutations or anything like this. So, I think it remains a bit of an unknown. I think from this functional perspective, we can imagine these other antiapoptotic proteins being upregulated—MCL-1, BCXL—but we don’t have a lot of data yet in patients to prove that.

William G. Wierda, MD, PhD: And targeting those?

Matthew S. Davids, MD, MMSc: Targeting those, I think, is a very promising approach, but the drugs really have just entered the clinic so whether that’s even a safe approach, we don’t know yet.

William G. Wierda, MD, PhD: So, Shuo, maybe you can comment on the checkpoint inhibitors. What’s our understanding of the activity of checkpoint inhibitors in CLL, and where are we going with those?

Shuo Ma, MD, PhD: Right. The Mayo Clinic presented their interesting study enrolling patients with relapsed/refractory CLL, as well as Richter transformation, with pembrolizumab. So, their observation is very interesting in that the CLL patient actually did not respond to the T-1 antibody. However, the diffused large B-cell lymphoma component, at the Richter transformation, responded 40% of overall response rate among those patients. And even in those patients, their CLL component did not respond. Their large-cell lymphoma component responded. So, I think definitely that raises the question whether we can cover the PD-1 blockade, too, as combination therapy with something else to treat Richter transformation, which is an area of huge unmet medical need.

William G. Wierda, MD, PhD: So, Nicole, there are now 3 approved CD20 antibodies. We have rituximab—which was the initial drug that we had and clearly showed improved in outcomes with chemotherapy in patients with CLL—ofatumumab, and we have obinutuzumab, which appears to be better when combined with chlorambucil than rituximab. Ublituximab is another one that we’ve seen some data about. Can you maybe comment on different CD20 antibodies where they may be useful? Is there a difference in effectiveness?

Nicole Lamanna, MD: Certainly. The clinical data have shown that obinutuzumab in some of the randomized studies—when it has been compared to rituximab, whether that be with chlorambucil in particular—there’s no doubt that there were improved responses and even some MRD negativity in that study as compared to the chlorambucil/rituximab arm. So, there’s no doubt that I think we’re seeing a clearer signal that obinutuzumab gives higher response rates. Is that all across the board? Hard to know. There are a lot of head-to-head randomized data, but certainly there is some.

I think that’s why there has been a lot more studies involving the combination of venetoclax or another agent with obinutuzumab. Certainly, we still have those combinations with rituximab. Now you have ublituximab, which is very similar to obinutuzumab in mechanism, and certainly those data look promising as well. I guess the question that always arises in my head is, how many monoclonal CD20 antibodies do we need? I don’t mean to be mean or negative. I guess the point being is that we have cost issues to deal with and so there’s that that we have to face. If it’s clearly dramatically better, I think that we should push to use one particular antibody versus what we’re doing, which is a smattering in the United States.

Rituximab is still the most widely used monoclonal antibody. I think there will be reimbursement issues or it depends on the hospital and the formularies of which antibodies they will pay for. And then there are biosimilars and then subcutaneous rituximab. So, how that will be incorporated is another thing. So, I think that there are lots of CD20 monoclonal antibodies. I think clearly there are some that are probably more potent. But the question is, in practice, how will we incorporate them remains to be seen.

William G. Wierda, MD, PhD: And what about toxicities? Is there a difference?

Nicole Lamanna, MD: There’s more infusion-related toxicities with the more potent antibodies, but generally, if you get somebody through that first infusion, they’re well tolerated. So, you up the ante on the antihistamines and the steroids. And most people do fine and you split the dose. You can work around it once they get through that first infusion, but certainly, we do see a little bit more of that, a little bit more neutropenia. But those are manageable.

Shuo Ma, MD, PhD: One interesting observation from the combination study is that when you’re combining with ibrutinib, there seem to be less infusion reaction with obinutuzumab.

Nicole Lamanna, MD: Certainly, that has come out with some of the data.

Shuo Ma, MD, PhD: Although that’s not here yet, still in the clinical trial phase.

Matthew S. Davids, MD, MMSc: I can speak to that briefly since I’m presenting a poster tonight at the ASH meeting where we did a randomization actually, and we treated one group of patients with obinutuzumab alone followed by combination with ibrutinib, the second group with ibrutinib first alone followed by the combination, and in the third group, we started both simultaneously. And we actually saw that 63% of the patients in that first arm where they started with the antibody alone had infusion reactions. And only 1 out of the 16 patients in the other 2 arms had reactions. So, it does seem to help to start the ibrutinib first, or at least simultaneously, with the antibody.

William G. Wierda, MD, PhD: Any other topics we should cover before…

Steven Coutre, MD: Well, one thing I think to bring up is to remind ourselves that when we’re looking at data or here listening to presentations of big trials is to also focus on the quality of life issues. Really important components of all of our trials. How do our patients tolerate these?

Nicole Lamanna, MD: We didn’t talk about the patient-reported outcomes.

Steven Coutre, MD: Yes, the patient-reported outcomes. We have some data from this meeting looking at those in the context of our novel therapy trials. There’s a really interesting publication just very recently in Blood Advances that was a survey tool that was used to send the patients asking them what’s important to them. Is it oral versus IV, a side effect profile, efficacy? I refer colleagues to look at that carefully. It’s pretty revealing. I think it shows that they want to see that their cancer is controlled for the longest time possible, and they’re willing to tolerate some side effects in exchange, but not too many. So, it’s really, really important as we develop these new therapies and the combinations. You mentioned the ibrutinib/venetoclax. Very, very well tolerated, so that’s an important finding.

Nicole Lamanna, MD: Yes, and it as very good. The presentation Dr. Robak presented involved the patient-reported outcomes. Even long-term monotherapy with ibrutinib is very tolerated and most patients report very good quality of life in addition to the efficacy and their hematologic parameters improve, but their quality of life is improving, too. So, we have to keep that in mind because that’s just monotherapy.

Transcript Edited for Clarity 
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