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Future Therapy: Bruton's TKI Containing Combinations in MCL

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: That brings us to the new drugs in mantle cell lymphoma. There are so many things coming along—so many new drugs. We have these contrasts of intensive therapy, which we’re moving away from.  Perhaps, toward the end, we will talk about CAR T cells. It’s relatively limited in mantle cell lymphoma so far, although there are studies going on. And no doubt, there have been some impressive responses. But, there are a lot of other drugs that are being explored in mantle cell lymphoma—upfront, in combination, and in the relapsed setting, in combination. We have this interesting scenario where these remain non-curable disorders, for the most part, at this point. As you add 2 oral drugs (as opposed to 1 oral drug), obviously you’re going to get more toxicity. For patients who are on these drugs long-term, quality of life becomes an issue. I don’t think we do a great job of measuring that. And then obviously, as Andre alluded to, we have to consider the cost of adding in these drugs. Do we use them all together? Do we use them in sequence?

John, there are a number of different clinical trials using drugs that we’ve talked about, like ibrutinib, acalabrutinib, and venetoclax, which we haven’t gotten to. They are being explored in clinical trials. Can you give us a sense of the landscape—not so much yet about their use in clinical practice, but where we’re going? Perhaps we’ll hear more about the role of these new drugs in combination, upfront, at upcoming meetings in the next year or so.

John M. Pagel, MD, PhD, DSc: Right. I think the Bruton’s tyrosine kinase inhibitors are being looked at in every scenario you can imagine, in this setting. They are being looked at in combination with chemotherapy-immunotherapy, and in combination with other novel agents. There’s a very interesting combination being explored, using ibrutinib in combination with the BCL-2 inhibitor, venetoclax. In an early trial, it has shown activity in mantle cell lymphoma. There’s certainly benefit to, perhaps, that combination or sequencing. These are questions that we have to ask. And then, of course, these agents are all being looked at in combination with chemotherapy-immunotherapy. There’s an acalabrutinib combination trial with bendamustine/rituximab (BR) in the frontline setting, that’s also been looked at in relapsed patients. And, ibrutinib in combination with R-CHOP and BR, as well.

This is all exciting, but the patients that we have today want to know how to do this. What they’re commonly asking is, how do we get away from chemotherapy? And, will we be able to do these things as chemotherapy-free regimens in the first-line setting? And then, there is the conundrum about back to transplant, and what to do with these patients. Now we have newer agents that could put off a transplant, especially an allogeneic transplant that has significant risk for early death. I think we have to do more trials. We have to, of course, do a better job in this disease. We have to get more people on a study. The problem is, there’s just not enough patients to continue to treat off of trials. Because of that, if we do that, we won’t learn. I love the combinations. We need to get people on trial. I hope the audience understands that it is critically important for us, in advancing the treatments.

John P. Leonard, MD: Andre, how do you see this shaking out? It seems to me that there’s no question—if you take a bendamustine/rituximab backbone, and you add to it ibrutinib, or venetoclax, or acalabrutinib, I would expect progression-free survival to be better. Many things improve PFS in mantle cell lymphoma. Overall survival may or may not be different. Toxicity is going to be more, no doubt. How do you think this is all going to shake out? And, from the standpoint of long-term management, is it going to be better for a patient to get, let’s say—and I’m just throwing out a scenario—BR with ibrutinib? Or, BR, and then ibrutinib when they progress? Obviously, we need studies. But, at the end of the day, when trying to figure this out, with just PFS as the endpoint, what’s the value of these combinations?

Andre Goy, MD: That’s a really good question. That’s where the real-world data really matters, as well as having large databases where we look at the impact of the sequence of care. This is true in myeloma, where there are so many therapies now. But, in mantle cell lymphoma, this is going to become an issue. Now we have the new endpoint in mantle cell lymphoma—molecular complete response, MRD [minimal residual disease] negativity. With these combinations, we should have the same approach. This is simplistic—to think that we’re going to have a deeper response, frontline, with a combination of rituximab plus XY and Z. It’s early, but there’s an ongoing study at The University of Texas MD Anderson Cancer Center looking at ibrutinib/rituximab leading as a window and in combination with venetoclax. The molecular complete response rate is so impressive that for the patient who actually is MRD-negative, the proposal of the current trial is to actually stop and not do consolidation chemotherapy. And, for the patients who are not MRD-negative, it is proposed to continue on a short course of hyper-CVAD [fractioned cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone]. I think that’s where the field is going. I think that there is an opportunity in trying to combine these novel agents to try to get a deep response. That goes around the issues of the dose intensity—the ability to tolerate dose intensive therapy. That’s what I would do. And then, build on the platform with the biological agent, try to achieve a molecular complete response, and consolidate with chemotherapy, if needed, at that time.

Then, comes the question of maintenance. Will the maintenance matter as much in that setting? That adds a layer of complexity. A patient from the LyMa trial, who had MRD negativity, who you would expect would not necessarily benefit from maintenance, is still benefiting from the maintenance because the MRD reflects the PBL [peripheral blood lymphocytes] in the blood and in the bone marrow. The bone marrow was more important than the blood, but they still benefitted. It shows that there are some potentially residual cells elsewhere, that you can’t measure. So, all of these are still open questions. Back to what John said, the clinical trials will be really important. But, to answer your question, our combination with a biological agent achieves a deep response. Those patients may not need to have chemotherapy. And then, moving away from chemotherapy. Then, the other is consolidation chemotherapy.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: That brings us to the new drugs in mantle cell lymphoma. There are so many things coming along—so many new drugs. We have these contrasts of intensive therapy, which we’re moving away from.  Perhaps, toward the end, we will talk about CAR T cells. It’s relatively limited in mantle cell lymphoma so far, although there are studies going on. And no doubt, there have been some impressive responses. But, there are a lot of other drugs that are being explored in mantle cell lymphoma—upfront, in combination, and in the relapsed setting, in combination. We have this interesting scenario where these remain non-curable disorders, for the most part, at this point. As you add 2 oral drugs (as opposed to 1 oral drug), obviously you’re going to get more toxicity. For patients who are on these drugs long-term, quality of life becomes an issue. I don’t think we do a great job of measuring that. And then obviously, as Andre alluded to, we have to consider the cost of adding in these drugs. Do we use them all together? Do we use them in sequence?

John, there are a number of different clinical trials using drugs that we’ve talked about, like ibrutinib, acalabrutinib, and venetoclax, which we haven’t gotten to. They are being explored in clinical trials. Can you give us a sense of the landscape—not so much yet about their use in clinical practice, but where we’re going? Perhaps we’ll hear more about the role of these new drugs in combination, upfront, at upcoming meetings in the next year or so.

John M. Pagel, MD, PhD, DSc: Right. I think the Bruton’s tyrosine kinase inhibitors are being looked at in every scenario you can imagine, in this setting. They are being looked at in combination with chemotherapy-immunotherapy, and in combination with other novel agents. There’s a very interesting combination being explored, using ibrutinib in combination with the BCL-2 inhibitor, venetoclax. In an early trial, it has shown activity in mantle cell lymphoma. There’s certainly benefit to, perhaps, that combination or sequencing. These are questions that we have to ask. And then, of course, these agents are all being looked at in combination with chemotherapy-immunotherapy. There’s an acalabrutinib combination trial with bendamustine/rituximab (BR) in the frontline setting, that’s also been looked at in relapsed patients. And, ibrutinib in combination with R-CHOP and BR, as well.

This is all exciting, but the patients that we have today want to know how to do this. What they’re commonly asking is, how do we get away from chemotherapy? And, will we be able to do these things as chemotherapy-free regimens in the first-line setting? And then, there is the conundrum about back to transplant, and what to do with these patients. Now we have newer agents that could put off a transplant, especially an allogeneic transplant that has significant risk for early death. I think we have to do more trials. We have to, of course, do a better job in this disease. We have to get more people on a study. The problem is, there’s just not enough patients to continue to treat off of trials. Because of that, if we do that, we won’t learn. I love the combinations. We need to get people on trial. I hope the audience understands that it is critically important for us, in advancing the treatments.

John P. Leonard, MD: Andre, how do you see this shaking out? It seems to me that there’s no question—if you take a bendamustine/rituximab backbone, and you add to it ibrutinib, or venetoclax, or acalabrutinib, I would expect progression-free survival to be better. Many things improve PFS in mantle cell lymphoma. Overall survival may or may not be different. Toxicity is going to be more, no doubt. How do you think this is all going to shake out? And, from the standpoint of long-term management, is it going to be better for a patient to get, let’s say—and I’m just throwing out a scenario—BR with ibrutinib? Or, BR, and then ibrutinib when they progress? Obviously, we need studies. But, at the end of the day, when trying to figure this out, with just PFS as the endpoint, what’s the value of these combinations?

Andre Goy, MD: That’s a really good question. That’s where the real-world data really matters, as well as having large databases where we look at the impact of the sequence of care. This is true in myeloma, where there are so many therapies now. But, in mantle cell lymphoma, this is going to become an issue. Now we have the new endpoint in mantle cell lymphoma—molecular complete response, MRD [minimal residual disease] negativity. With these combinations, we should have the same approach. This is simplistic—to think that we’re going to have a deeper response, frontline, with a combination of rituximab plus XY and Z. It’s early, but there’s an ongoing study at The University of Texas MD Anderson Cancer Center looking at ibrutinib/rituximab leading as a window and in combination with venetoclax. The molecular complete response rate is so impressive that for the patient who actually is MRD-negative, the proposal of the current trial is to actually stop and not do consolidation chemotherapy. And, for the patients who are not MRD-negative, it is proposed to continue on a short course of hyper-CVAD [fractioned cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone]. I think that’s where the field is going. I think that there is an opportunity in trying to combine these novel agents to try to get a deep response. That goes around the issues of the dose intensity—the ability to tolerate dose intensive therapy. That’s what I would do. And then, build on the platform with the biological agent, try to achieve a molecular complete response, and consolidate with chemotherapy, if needed, at that time.

Then, comes the question of maintenance. Will the maintenance matter as much in that setting? That adds a layer of complexity. A patient from the LyMa trial, who had MRD negativity, who you would expect would not necessarily benefit from maintenance, is still benefiting from the maintenance because the MRD reflects the PBL [peripheral blood lymphocytes] in the blood and in the bone marrow. The bone marrow was more important than the blood, but they still benefitted. It shows that there are some potentially residual cells elsewhere, that you can’t measure. So, all of these are still open questions. Back to what John said, the clinical trials will be really important. But, to answer your question, our combination with a biological agent achieves a deep response. Those patients may not need to have chemotherapy. And then, moving away from chemotherapy. Then, the other is consolidation chemotherapy.

Transcript Edited for Clarity 
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