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Highlights from ASH 2017: Mantle Cell Lymphoma

Panelists: Alexey V. Danilov, MD, PhD, Oregon Health & Science University; Andre Goy, MD, Hackensack University Medical Center; John P. Leonard, MD, New York-Presbyterian/Weill Cornell Medical Center; John M. Pagel, MD, PhD, DSc, Swedish Medical Center Seattle and Issaquah; Stephen J. Schuster, MD, The University of Pennsylvania
Published: Monday, Feb 12, 2018



Transcript: 

John P. Leonard, MD: We’ve just come from the 2017 ASH Annual Meeting. We’ve had several days of new data, excitement, and discussions. I want to go down the list and ask everyone to share their key take-home points from ASH. What new things that you learned do people at home, in their offices, need to know about as they approach patients? Tell me about things that you’re excited about, going forward, in mantle cell lymphoma. What are your thoughts?

Alexey V. Danilov, MD, PhD: For me, the excitement is around novel therapies. I think we are entering a new era where novel therapies potentially might even replace chemotherapy agents, or DNA damaging agents, in certain subtypes of lymphoma. I think the follow up to ibrutinib data looks very interesting. The new acalabrutinib data looks very good. In the future, we need to figure out how to use those drugs, combined with chemotherapy, in an upfront setting. Or, use combinations in relapsed/refractory mantle cell lymphoma. And, do we need to use them indefinitely, or can we stop at MRD? There are going to be a lot of questions to be answered through clinical trials. I think it is important to enroll patients with mantle cell lymphoma on clinical trials, like John said. This is a rare disease and we need answers.

John P. Leonard, MD: Steve?

Stephen J. Schuster, MD: There were 2 strong messages that I got from this meeting. One was that in mantle cell lymphoma, progression-free survival is important. And, it tends to correlate with overall survival. I know the data can be criticized as being retrospective, and there was some heterogeneity between those that got transplants and those who didn’t, etcetera. The bottom line is, it’s one of a number of studies that showed that in mantle cell lymphoma, PFS can translate into OS. That’s not what you see, for example, in many of the follicular lymphoma studies. So, at least outside of the setting of clinical trials, even using the older chemotherapeutic approaches, they’re intensive and may or may not use an autologous transplant. It’s important to try to get to as deep as remission as possible. That will lead to the longest PFS. And, again, as we move forward into the era of novel agents, we can exploit them.

The second message is, once you’ve had that long remission, your next treatment should probably not be chemotherapy. For patients who have more than 1 chemotherapy exposure, when they go on to a kinase inhibitor, they have a markedly inferior duration of response. So, I think you have to look at ibrutinib, acalabrutinib, outside the setting of a clinical trial as your next step. I don’t think there are long-term solutions for the relapsed patient. Hopefully, someday, it will move up front to a non-DNA damaging regimen. We’ll have even longer PFS rates and we won’t be in that situation.

John P. Leonard, MD: Yes. I was very much struck by how BTK-centric the meeting was. Mantle cell lymphoma is moving in that direction. We’ve got more and more data with ibrutinib. We now have acalabrutinib. There are a few other agents out there which may or may not have important differentiating features. But, it seems likely that more people are going to get a BTK inhibitor, up front. Relapsed—it’s certainly moving up. These combinations are coming along. And then, BTK resistance is going to be a crucial thing in determining what will work in those patients with resistance. I think that’s something, with respect to mantle cell lymphoma, that really struck me as being important. We need to keep working on, “How do we use these drugs most effectively?” “How do we stop them if patients can go into a treatment-free interval?” But, also, “How do we combine them?” Perhaps, a shorter duration, in combination, will lead to treatment-free intervals?

Andre Goy, MD: The mere fact that we are having all of this excitement and new data is actually thanks to clinical trials. So, we definitely encourage our audience to refer patients and participate in clinical trials to answer these questions. My take-home message from ASH—I have great optimism in mantle cell lymphoma. We are in a bit of a transition. We are starting to learn how to combine, or try to combine with chemotherapy. We are starting to do a window before chemotherapy. I’m convinced, as I alluded to before, that we’re going to do combinations, particularly with small molecules and venetoclax, and, obviously, BTK inhibitors, that seem to really give a high response rate and the molecular complete response that might allow us to start to develop non-chemotherapy options in that setting.

What’s going to also be really important is trying to identify mechanisms of resistance, so that we can identify the best sequence and alternate some of these biological agents, until we reach a deep enough response and have a durable outcome. One caveat, though, that I just want to highlight is, we tend to think that chemotherapy is over. I think it took us 20 years to make some progress in mantle cell lymphoma. So, we’re not just throwing it away, immediately. We just want to make sure that we have the proper combination. And then, finally, immunotherapy—this was a big thing at ASH, and it will definitely also apply in mantle cell lymphoma.

John P. Leonard, MD: John?

John M. Pagel, MD, PhD, DSc: I’ll extrapolate from what we’ve learned about the use of CAR [chimeric antigen receptor] T cells in large cell lymphoma at this meeting, and where that will play in for mantle cell lymphoma. I am very enthusiastic about this. Steve’s data is incredibly impressive. I thought the data presented by Dr Jeremy Abramson on his large cell lymphoma patients was quite encouraging for using CAR T cells from 2 standpoints. First, was the difficult patients getting complete remissions that are durable. And, the cytokine release syndrome rates, as well as the neurotoxicity rates being much more manageable and acceptable. And then, the future of this as a potential outpatient therapy, of course, can be critically important. I don’t think there’s any reason for which we can’t think that these kind of great, exciting results in large cell disease won’t get translated to mantle cell lymphoma.

Andre Goy, MD: They do apply.

John M. Pagel, MD, PhD, DSc: I think that’s incredibly exciting. I hope that next year, when we do this, we’re talking a little more about the data from mantle cell lymphoma with CAR T cells.

John P. Leonard, MD: I think we want to also emphasize the news for patients. This is great news for patients. I was impressed by what you said earlier—that anything that we talk about, or any of the long-term data, ends up being retrospective. Basically, anything with 3 or 4 years of follow-up is really a study that’s reporting a regimen that we don’t use anymore. I say that to patients all the time. “Anything you read about your prognosis in mantle cell lymphoma doesn’t take into account what has happened just in the last year.” It’s incredibly challenging for people in practice to keep up with it. It’s hard for us to keep up with it.

Stephen J. Schuster, MD: And, for patients, there’s a lot of negative stuff on the internet, which is dangerous.

John P. Leonard, MD: I think it really highlights the fact that there is a lot of progress happening. There is a lot of optimism. Mantle cell lymphoma is not what it used to be for patients, regarding prognosis. Hopefully, we can continue to make progress and have patients have better and better outcomes.

I want to thank all of you for joining us today. This has really been a great discussion—a great recap. I always love hearing different people’s perspectives. I think we agree on a lot of things, but we disagree on a lot of things. And, we always learn. I think that’s a reflection of the disease. It’s a reflection of mantle cell lymphoma, in general. For the audience, I hope that this has really been a kind of state-of-the-art discussion on mantle cell lymphoma biology, treatment, and outcomes, in 1 session. It’s been a nice program. So, thank you all, very much. On behalf of our panel, we thank you very much for joining us for this Peer Exchange® discussion.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: We’ve just come from the 2017 ASH Annual Meeting. We’ve had several days of new data, excitement, and discussions. I want to go down the list and ask everyone to share their key take-home points from ASH. What new things that you learned do people at home, in their offices, need to know about as they approach patients? Tell me about things that you’re excited about, going forward, in mantle cell lymphoma. What are your thoughts?

Alexey V. Danilov, MD, PhD: For me, the excitement is around novel therapies. I think we are entering a new era where novel therapies potentially might even replace chemotherapy agents, or DNA damaging agents, in certain subtypes of lymphoma. I think the follow up to ibrutinib data looks very interesting. The new acalabrutinib data looks very good. In the future, we need to figure out how to use those drugs, combined with chemotherapy, in an upfront setting. Or, use combinations in relapsed/refractory mantle cell lymphoma. And, do we need to use them indefinitely, or can we stop at MRD? There are going to be a lot of questions to be answered through clinical trials. I think it is important to enroll patients with mantle cell lymphoma on clinical trials, like John said. This is a rare disease and we need answers.

John P. Leonard, MD: Steve?

Stephen J. Schuster, MD: There were 2 strong messages that I got from this meeting. One was that in mantle cell lymphoma, progression-free survival is important. And, it tends to correlate with overall survival. I know the data can be criticized as being retrospective, and there was some heterogeneity between those that got transplants and those who didn’t, etcetera. The bottom line is, it’s one of a number of studies that showed that in mantle cell lymphoma, PFS can translate into OS. That’s not what you see, for example, in many of the follicular lymphoma studies. So, at least outside of the setting of clinical trials, even using the older chemotherapeutic approaches, they’re intensive and may or may not use an autologous transplant. It’s important to try to get to as deep as remission as possible. That will lead to the longest PFS. And, again, as we move forward into the era of novel agents, we can exploit them.

The second message is, once you’ve had that long remission, your next treatment should probably not be chemotherapy. For patients who have more than 1 chemotherapy exposure, when they go on to a kinase inhibitor, they have a markedly inferior duration of response. So, I think you have to look at ibrutinib, acalabrutinib, outside the setting of a clinical trial as your next step. I don’t think there are long-term solutions for the relapsed patient. Hopefully, someday, it will move up front to a non-DNA damaging regimen. We’ll have even longer PFS rates and we won’t be in that situation.

John P. Leonard, MD: Yes. I was very much struck by how BTK-centric the meeting was. Mantle cell lymphoma is moving in that direction. We’ve got more and more data with ibrutinib. We now have acalabrutinib. There are a few other agents out there which may or may not have important differentiating features. But, it seems likely that more people are going to get a BTK inhibitor, up front. Relapsed—it’s certainly moving up. These combinations are coming along. And then, BTK resistance is going to be a crucial thing in determining what will work in those patients with resistance. I think that’s something, with respect to mantle cell lymphoma, that really struck me as being important. We need to keep working on, “How do we use these drugs most effectively?” “How do we stop them if patients can go into a treatment-free interval?” But, also, “How do we combine them?” Perhaps, a shorter duration, in combination, will lead to treatment-free intervals?

Andre Goy, MD: The mere fact that we are having all of this excitement and new data is actually thanks to clinical trials. So, we definitely encourage our audience to refer patients and participate in clinical trials to answer these questions. My take-home message from ASH—I have great optimism in mantle cell lymphoma. We are in a bit of a transition. We are starting to learn how to combine, or try to combine with chemotherapy. We are starting to do a window before chemotherapy. I’m convinced, as I alluded to before, that we’re going to do combinations, particularly with small molecules and venetoclax, and, obviously, BTK inhibitors, that seem to really give a high response rate and the molecular complete response that might allow us to start to develop non-chemotherapy options in that setting.

What’s going to also be really important is trying to identify mechanisms of resistance, so that we can identify the best sequence and alternate some of these biological agents, until we reach a deep enough response and have a durable outcome. One caveat, though, that I just want to highlight is, we tend to think that chemotherapy is over. I think it took us 20 years to make some progress in mantle cell lymphoma. So, we’re not just throwing it away, immediately. We just want to make sure that we have the proper combination. And then, finally, immunotherapy—this was a big thing at ASH, and it will definitely also apply in mantle cell lymphoma.

John P. Leonard, MD: John?

John M. Pagel, MD, PhD, DSc: I’ll extrapolate from what we’ve learned about the use of CAR [chimeric antigen receptor] T cells in large cell lymphoma at this meeting, and where that will play in for mantle cell lymphoma. I am very enthusiastic about this. Steve’s data is incredibly impressive. I thought the data presented by Dr Jeremy Abramson on his large cell lymphoma patients was quite encouraging for using CAR T cells from 2 standpoints. First, was the difficult patients getting complete remissions that are durable. And, the cytokine release syndrome rates, as well as the neurotoxicity rates being much more manageable and acceptable. And then, the future of this as a potential outpatient therapy, of course, can be critically important. I don’t think there’s any reason for which we can’t think that these kind of great, exciting results in large cell disease won’t get translated to mantle cell lymphoma.

Andre Goy, MD: They do apply.

John M. Pagel, MD, PhD, DSc: I think that’s incredibly exciting. I hope that next year, when we do this, we’re talking a little more about the data from mantle cell lymphoma with CAR T cells.

John P. Leonard, MD: I think we want to also emphasize the news for patients. This is great news for patients. I was impressed by what you said earlier—that anything that we talk about, or any of the long-term data, ends up being retrospective. Basically, anything with 3 or 4 years of follow-up is really a study that’s reporting a regimen that we don’t use anymore. I say that to patients all the time. “Anything you read about your prognosis in mantle cell lymphoma doesn’t take into account what has happened just in the last year.” It’s incredibly challenging for people in practice to keep up with it. It’s hard for us to keep up with it.

Stephen J. Schuster, MD: And, for patients, there’s a lot of negative stuff on the internet, which is dangerous.

John P. Leonard, MD: I think it really highlights the fact that there is a lot of progress happening. There is a lot of optimism. Mantle cell lymphoma is not what it used to be for patients, regarding prognosis. Hopefully, we can continue to make progress and have patients have better and better outcomes.

I want to thank all of you for joining us today. This has really been a great discussion—a great recap. I always love hearing different people’s perspectives. I think we agree on a lot of things, but we disagree on a lot of things. And, we always learn. I think that’s a reflection of the disease. It’s a reflection of mantle cell lymphoma, in general. For the audience, I hope that this has really been a kind of state-of-the-art discussion on mantle cell lymphoma biology, treatment, and outcomes, in 1 session. It’s been a nice program. So, thank you all, very much. On behalf of our panel, we thank you very much for joining us for this Peer Exchange® discussion.

Transcript Edited for Clarity 
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