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Investigational Treatment in 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: Thursday, Feb 08, 2018



Transcript: 

John P. Leonard, MD: Alexey, there are a lot of new drugs being explored in mantle cell lymphoma. I think we can give a symposium over several hours on all of them, given all of the data. We have lenalidomide, ibrutinib, acalabrutinib, and bortezomib, which are all approved. Then, we have novel anti-CD20 monoclonal antibodies. We have venetoclax. We have some data with phosphoinositide 3-kinase inhibitors, although that’s been more limited, I would say, in mantle cell lymphoma. There are cyclin D–dependent kinase 4/6 inhibitors. I’m going to get to Steve and chimeric antigen receptor T cells in a second, because I want to hear his experience there. But, as far as other types of agents, tell us what you think are some of the more promising things that people need to know about? Perhaps, if they have access to a clinical trial, they may want to pursue that option for their patients?

Alexey V. Danilov, MD, PhD: Absolutely. It’s becoming a very exciting field. Certainly, ibrutinib resistance is one issue, and I think we are making some headway there in addressing that. Venetoclax, as you mentioned, has now been approved in chronic lymphocytic leukemia with deletion 17p. So, it’s a BH3 mimetic. It’s not a kinase inhibitor (for a change), which is an exciting mechanism of action. It has been studied in mantle cell lymphoma, and there’s close to a several dozen patients enrolled on the study. The data in heavily pretreated disease looks fairly similar to what ibrutinib does with progression-free survival—over a year. And, there are complete response rates of over 60%. So, we have a different mechanism with very exciting data. There’s data in CLL that demonstrates that venetoclax works post-ibrutinib. So, the expectation is that it would work post-ibrutinib in mantle cell lymphoma. John mentioned combination trials. I think combination trials are the way to go in this disease.

In terms of PI3-kinase inhibitors, the study with the single agent was somewhat underwhelming. Response rates were 40%, and duration of response was about 3, 4 months. However, PI3-kinase inhibition is very important in lymphoma. There is a lot of preclinical data from Weill Cornell, and from other centers that demonstrates that ibrutinib resistance is actually dependent on PI3K signaling, in many cases. I think it’s still a promising field, and there are several agents in the field—the PI3K-delta inhibitor, idelalisib; a PI3K-delta and PI3K-gamma dual inhibitor, duvelisib; and then, umbralisib, which is a PI3K delta inhibitor that also concurrently inhibits CK1. There are also studies of therapies in combination with ibrutinib run by the Dana-Farber Cancer Institute. So, this is still a very exciting field.

In terms of palbociclib, the CDK4/6 inhibitor, from a scientific perspective, one would think that it would work great in mantle cell lymphoma. However, single agent responses are fairly underwhelming—under 20%. But, again, there is very good preclinical data that suggests that it might abrogate some of the resistance pathways to ibrutinib. One area where it would be nice to have a dedicated drug is NF-kappa B signaling. Ibrutinib resistance, in part, relies on NF-kappa B. There are BRK3 mutations, TRAF2 mutations all within the NF-kappa B pathway, and then abnormalities on PIM1 kinase and ERBB4. So, all part of the NF-kappa B pathway. It would be very good to have a dedicated NF-kappa B inhibitor, but that has been quite elusive so far.

Stephen J. Schuster, MD: Get to the end of the pathway.

John P. Leonard, MD: Steve, you were part of our study that Jia Ruan, MD, PhD, presented—lenalidomide/rituximab as upfront therapy. With all of these agents, do you think that we are approaching a chemotherapy-free sort of strategy (which is more of a technical descriptive term than anything)? You espouse the intensive approach?

Stephen J. Schuster, MD: Well, no. I espouse getting people into as deep a remission as possible, upfront, because progression-free survival is important in this disease. In all of the studies that we’re talking about, by the time they’re able to be analyzed, they’re essentially going to be retrospective. We’ll have new agents when it comes to survival, for PFS. Now, with regard to Jia’s study, which I think is fantastic, I have a number of patients who are still on it 5 years later. That was very instructive. So, this was a study in mantle cell lymphoma where we treated patients, upfront, with lenalidomide and rituximab. We saw an astounding upfront complete response rate. Five years later, two-thirds of patients were still on therapy—not bad. And, I want to tell you that the patients I put on that trial were the same kinds of patients that I would have given chemotherapy to. They needed treatment. They had advanced disease. These were not indolent lymphomas.

So, how do I make sense of that result? I’m thinking that, again, this is theoretical. This is a genetically unstable disease. If you can postpone having to use cytotoxic chemotherapy agents and get them to respond, you may get a very durable response. And, of course, lenalidomide, by itself, is not mutageneic. Neither is Rituxan (rituximab). I think that these patients may have benefitted because we’ve not given them agents which, in the setting of unstable genome, lead to some mutation that turns out to be bad.

John P. Leonard, MD: I think it opens up the door for at least looking at these combinations—whether it’s a 2-drug, 3-drug, or a different 2-drug regimen.

Stephen J. Schuster, MD: Or, non-DNA damaging agents as first therapy for this disease.

Andre Goy, MD: It’s interesting. I think you had a subset of patients that had a molecular complete response as well?

John P. Leonard, MD: Yes.

Stephen J. Schuster, MD: It is astounding, and I think it also sets the world’s record for the number of oral presentations at the 2017 ASH Annual Meeting.

John P. Leonard, MD: Knowing your work in CAR T-cells, in a nutshell, where do we stand with CAR T cells in mantle cell lymphoma, at this point?

Stephen J. Schuster, MD: The CAR T cell I work with is the Novartis CAR T-cell, tisagenlecleucel. They licensed the technology. I’ve only treated a couple of patients, so I don’t have adequate follow-up to give you a big picture. You can achieve complete remission in patients. They were treated with extensive disease—spleens, impact on bone marrows. These were people in bad shape. So, it’s active. I know that Andre is running a trial as well. It’s follow up is probably still immature, but I’m sure he’s had the same observations?

Andre Goy, MD: We don’t have the data reported yet, but it will be submitted to ASCO. What I can say is that the complete response rates seem even more promising than in large cell lymphoma. So, this being said, we have some patients in whom we see the toxicity profile, that we know about CAR T cell for, now. I had one patient who did really well with grade 2—in complete response and doing well. We treated 4, 5, 6 patients, but one of the patients came with a blastoid variant. This is a poor guy who came from out of state. He had 1000 skin nodules, and had seen every drug, including ibrutinib, obviously. He responded, but it didn’t last. But, definitely, this is a proof of concept, and I think this is going to be part of the therapy in mantle cell lymphoma.

John P. Leonard, MD: John, before we wrap up this segment, what is your sense on maintenance and the future of mantle cell lymphoma? I think that with all of these oral agents, there’s going to be the ability to keep people on these drugs, long-term. Obviously, there are minor but chronic toxicities. Sometimes, they may be more severe. But, they are often nagging. Consider the expense, as well as other issues. Do you think that we will have defined durations of therapy? Do you think it will be that you achieve MRD, you go a little longer, you stop it, and then restart it? What do you see for the future of maintenance, as we start talking about the combined therapies?

John M. Pagel, MD, PhD, DSc: I think you hit on the most important thing. That is, how do we figure out when we can stop these agents and not necessarily continue them as maintenance, indefinitely? There are some patients for whom I think need it. We’ll figure that out. But, hopefully, we’ll find out that most patients can be stopped, at some point, based on some probable molecular evidence of MRD negativity. And then, we consider the fact that they could be retreated, perhaps, with the same agent once they relapse.

So, maintenance is, in my mind, going to become less popular with indefinite therapy—as opposed to more popular as we move forward. That’s important for patients, too. They love their remission. They’re going to want to do whatever it takes to maintain it. But, if they also know they can maintain their remission and get off of the drug at some point, if they become MRD-negative, and understand that they can be successfully retreated, that’s got to be the strategy that we need to move forward with.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: Alexey, there are a lot of new drugs being explored in mantle cell lymphoma. I think we can give a symposium over several hours on all of them, given all of the data. We have lenalidomide, ibrutinib, acalabrutinib, and bortezomib, which are all approved. Then, we have novel anti-CD20 monoclonal antibodies. We have venetoclax. We have some data with phosphoinositide 3-kinase inhibitors, although that’s been more limited, I would say, in mantle cell lymphoma. There are cyclin D–dependent kinase 4/6 inhibitors. I’m going to get to Steve and chimeric antigen receptor T cells in a second, because I want to hear his experience there. But, as far as other types of agents, tell us what you think are some of the more promising things that people need to know about? Perhaps, if they have access to a clinical trial, they may want to pursue that option for their patients?

Alexey V. Danilov, MD, PhD: Absolutely. It’s becoming a very exciting field. Certainly, ibrutinib resistance is one issue, and I think we are making some headway there in addressing that. Venetoclax, as you mentioned, has now been approved in chronic lymphocytic leukemia with deletion 17p. So, it’s a BH3 mimetic. It’s not a kinase inhibitor (for a change), which is an exciting mechanism of action. It has been studied in mantle cell lymphoma, and there’s close to a several dozen patients enrolled on the study. The data in heavily pretreated disease looks fairly similar to what ibrutinib does with progression-free survival—over a year. And, there are complete response rates of over 60%. So, we have a different mechanism with very exciting data. There’s data in CLL that demonstrates that venetoclax works post-ibrutinib. So, the expectation is that it would work post-ibrutinib in mantle cell lymphoma. John mentioned combination trials. I think combination trials are the way to go in this disease.

In terms of PI3-kinase inhibitors, the study with the single agent was somewhat underwhelming. Response rates were 40%, and duration of response was about 3, 4 months. However, PI3-kinase inhibition is very important in lymphoma. There is a lot of preclinical data from Weill Cornell, and from other centers that demonstrates that ibrutinib resistance is actually dependent on PI3K signaling, in many cases. I think it’s still a promising field, and there are several agents in the field—the PI3K-delta inhibitor, idelalisib; a PI3K-delta and PI3K-gamma dual inhibitor, duvelisib; and then, umbralisib, which is a PI3K delta inhibitor that also concurrently inhibits CK1. There are also studies of therapies in combination with ibrutinib run by the Dana-Farber Cancer Institute. So, this is still a very exciting field.

In terms of palbociclib, the CDK4/6 inhibitor, from a scientific perspective, one would think that it would work great in mantle cell lymphoma. However, single agent responses are fairly underwhelming—under 20%. But, again, there is very good preclinical data that suggests that it might abrogate some of the resistance pathways to ibrutinib. One area where it would be nice to have a dedicated drug is NF-kappa B signaling. Ibrutinib resistance, in part, relies on NF-kappa B. There are BRK3 mutations, TRAF2 mutations all within the NF-kappa B pathway, and then abnormalities on PIM1 kinase and ERBB4. So, all part of the NF-kappa B pathway. It would be very good to have a dedicated NF-kappa B inhibitor, but that has been quite elusive so far.

Stephen J. Schuster, MD: Get to the end of the pathway.

John P. Leonard, MD: Steve, you were part of our study that Jia Ruan, MD, PhD, presented—lenalidomide/rituximab as upfront therapy. With all of these agents, do you think that we are approaching a chemotherapy-free sort of strategy (which is more of a technical descriptive term than anything)? You espouse the intensive approach?

Stephen J. Schuster, MD: Well, no. I espouse getting people into as deep a remission as possible, upfront, because progression-free survival is important in this disease. In all of the studies that we’re talking about, by the time they’re able to be analyzed, they’re essentially going to be retrospective. We’ll have new agents when it comes to survival, for PFS. Now, with regard to Jia’s study, which I think is fantastic, I have a number of patients who are still on it 5 years later. That was very instructive. So, this was a study in mantle cell lymphoma where we treated patients, upfront, with lenalidomide and rituximab. We saw an astounding upfront complete response rate. Five years later, two-thirds of patients were still on therapy—not bad. And, I want to tell you that the patients I put on that trial were the same kinds of patients that I would have given chemotherapy to. They needed treatment. They had advanced disease. These were not indolent lymphomas.

So, how do I make sense of that result? I’m thinking that, again, this is theoretical. This is a genetically unstable disease. If you can postpone having to use cytotoxic chemotherapy agents and get them to respond, you may get a very durable response. And, of course, lenalidomide, by itself, is not mutageneic. Neither is Rituxan (rituximab). I think that these patients may have benefitted because we’ve not given them agents which, in the setting of unstable genome, lead to some mutation that turns out to be bad.

John P. Leonard, MD: I think it opens up the door for at least looking at these combinations—whether it’s a 2-drug, 3-drug, or a different 2-drug regimen.

Stephen J. Schuster, MD: Or, non-DNA damaging agents as first therapy for this disease.

Andre Goy, MD: It’s interesting. I think you had a subset of patients that had a molecular complete response as well?

John P. Leonard, MD: Yes.

Stephen J. Schuster, MD: It is astounding, and I think it also sets the world’s record for the number of oral presentations at the 2017 ASH Annual Meeting.

John P. Leonard, MD: Knowing your work in CAR T-cells, in a nutshell, where do we stand with CAR T cells in mantle cell lymphoma, at this point?

Stephen J. Schuster, MD: The CAR T cell I work with is the Novartis CAR T-cell, tisagenlecleucel. They licensed the technology. I’ve only treated a couple of patients, so I don’t have adequate follow-up to give you a big picture. You can achieve complete remission in patients. They were treated with extensive disease—spleens, impact on bone marrows. These were people in bad shape. So, it’s active. I know that Andre is running a trial as well. It’s follow up is probably still immature, but I’m sure he’s had the same observations?

Andre Goy, MD: We don’t have the data reported yet, but it will be submitted to ASCO. What I can say is that the complete response rates seem even more promising than in large cell lymphoma. So, this being said, we have some patients in whom we see the toxicity profile, that we know about CAR T cell for, now. I had one patient who did really well with grade 2—in complete response and doing well. We treated 4, 5, 6 patients, but one of the patients came with a blastoid variant. This is a poor guy who came from out of state. He had 1000 skin nodules, and had seen every drug, including ibrutinib, obviously. He responded, but it didn’t last. But, definitely, this is a proof of concept, and I think this is going to be part of the therapy in mantle cell lymphoma.

John P. Leonard, MD: John, before we wrap up this segment, what is your sense on maintenance and the future of mantle cell lymphoma? I think that with all of these oral agents, there’s going to be the ability to keep people on these drugs, long-term. Obviously, there are minor but chronic toxicities. Sometimes, they may be more severe. But, they are often nagging. Consider the expense, as well as other issues. Do you think that we will have defined durations of therapy? Do you think it will be that you achieve MRD, you go a little longer, you stop it, and then restart it? What do you see for the future of maintenance, as we start talking about the combined therapies?

John M. Pagel, MD, PhD, DSc: I think you hit on the most important thing. That is, how do we figure out when we can stop these agents and not necessarily continue them as maintenance, indefinitely? There are some patients for whom I think need it. We’ll figure that out. But, hopefully, we’ll find out that most patients can be stopped, at some point, based on some probable molecular evidence of MRD negativity. And then, we consider the fact that they could be retreated, perhaps, with the same agent once they relapse.

So, maintenance is, in my mind, going to become less popular with indefinite therapy—as opposed to more popular as we move forward. That’s important for patients, too. They love their remission. They’re going to want to do whatever it takes to maintain it. But, if they also know they can maintain their remission and get off of the drug at some point, if they become MRD-negative, and understand that they can be successfully retreated, that’s got to be the strategy that we need to move forward with.

Transcript Edited for Clarity 
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