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Induction Therapy for 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: Tuesday, Jan 09, 2018



Transcript: 

John P. Leonard, MD: So, now we get into therapy, and this is something that I think we all know: if we were consulting with an individual patient, we could be in the room for an hour. We can’t allocate an hour to talk about upfront therapy. But I’m going to start. We’ll kind of walk down the list and highlight differences within our panel. So, I’ll get John to start. I’m going to give you a hypothetical 60-year-old patient who is fit and is newly diagnosed with mantle cell lymphoma. The other is a hypothetical 75-year-old patient, maybe with some comorbidities, who is newly diagnosed with mantle cell lymphoma. We’ll say that both need treatment. How do you decide what to do? Obviously, there’s a lot of nuance to this.

John M. Pagel, MD, PhD, DSc: Right. When you introduced me, John, you said that I’m from Seattle. So, that means we transplant every patient. Of course, that’s a stretch and a joke, but you know that’s a common approach, to consolidate patients with aggressive treatment in many cases. I’m not sure it’s always the right thing to do. But typically, an approach that many of us are still employing, at least, I would say, in the Pacific Northwest, is to get people to a good remission, a very deep complete remission. How you get there, of course, is very controversial. We can talk more about that if it’s a younger patient, maybe hyper-CVAD. In an older patient, maybe bendamustine and rituximab (BR). I typically tend to be very aggressive with patients based on what they can tolerate. Then, it’s not uncommon to consider an autologous transplant for those patients in first remission. So, for the 60-year-old patient who is fit, that’s an approach I probably am going to take. I’m not crazy about hyper-CVAD, even in a 60-year-old. But getting them to good remission with bendamustine/rituximab, or an abbreviated course of hyper-CVAD is what I might desire to do. And then, to collect stem cells and go to transplant.

The 75-year-old is a little more controversial, obviously. Does transplant really help somebody who’s already in their mid-70s? Usually, in that kind of case, I’m going to stay away from transplant and try and maintain them as long as I can with a good remission, perhaps even with some of the newer drugs that we’ll end up talking about.

John P. Leonard, MD: Is that someone you typical would use BR with?

John M. Pagel, MD, PhD, DSc: I probably would. I think bendamustine/rituximab is very well tolerated in most patients. One of the most important things that we have to remember with bendamustine is that it’s very myelosuppressive. There’s no rule that says you have to give 6 cycles of the regimen. I typically might assess a patient after just 3 cycles or so. And not uncommonly, if I think the risk is relatively low, I’ll just stop there. I know I could give a little bit more in the future, although I’m not a fan of coming back to more bendamustine repeatedly.

Alexey V. Danilov, MD, PhD: John, do you ever consider bendamustine/rituximab for patients for whom you potentially could then perform an autologous stem cell transplant?

John M. Pagel, MD, PhD, DSc: That’s difficult. We have published data that shows that you can collect stem cells after people have had bendamustine. We even published a paper on the use of bendamustine as a mobilization tool. It wasn’t highly successful, but it can be done. At the end of the day, for me, now, with the use of Mozobil (plerixafor), and the ability to mobilize stem cells with these new agents, it’s not typically a factor. In fact, it’s very rare not to be able to collect stem cells in somebody who’s had prior bendamustine now.

John P. Leonard, MD: Andre, I’m guessing your approach is similar? Is there anything different about your strategy? Younger patient, BR-based therapy; older patient, more intensive therapy? Do you typically use hyper-CVAD, or something else for the new person?

Andre Goy, MD: The key philosophy in treating mantle cell lymphoma is that I think it’s one of the diseases where patients become chemotherapy-resistant all the time. Achieving a deep response, or an early response, impacts the outcome.

If a patient is dose intensive, fit, and is treated with hyper-CVAD followed by transplant, I don’t think there’s a big difference. There was actually an abstract at the 2017 ASH Annual Meeting that we can refer to. It reviewed a large population, almost 1200 patients, and looked at the impact of high-dose therapy consolidation for a complete response. There’s really a bias because it’s a retrospective analysis on the complete response patients. But clearly, the dose-intense strategies have really pushed the progression-free survival. And that’s where we have a median PFS well in excess of 5 years. Even in the real world, it is up to at least 7 years. In the original hyper-CVAD, that’s always a problem, in the trials. The trials always have an easier picture than the real world. Ten years is still 52% of the patients who still have not relapsed. So, in a younger patient, that only becomes an option.

Now that we’ll have the ability to integrate novel therapies, maybe we’ll talk a bit more in detail about p53 and how it can change the picture. The next question is, in a non-intensive therapy patient, an older patient, the BR data are not necessarily that impressive, I would argue. It was proven, in a trial, to be slightly better than R-CHOP. It offered a platform to combine with other agents. So, we’re waiting for the results. The same thing has been noted with acalabrutinib.

John P. Leonard, MD: I’m a big fan of BR, both in younger and older patients. I think BR with rituximab maintenance, which has been kind of an indirect—we’ll come back to maintenance in a minute—is something that I commonly use. Briefly, Steve, what are your thought on blastoid mantle cell lymphoma, upfront? If a patient comes in with blastoid mantle cell lymphoma, how do you treat that patient?

Stephen J. Schuster, MD: I’m less influenced by morphology than I am by genetics. There tends to, however, be a correlation between morphology, Ki-67 score, and cytogenetics. You’re much more likely to see a blastoid patient with a high Ki-67 score, a p53 mutation, and more of an aggressive clinical presentation. So, again, it’s not 100%. I mentioned the one outlier that had an ugly morphology, but he did well for years.

Anyway, I would echo with what Andre and John said. I think that in a patient that needs treatment, obviously I’m setting aside the approach to somebody that’s p53-mutated. Chemotherapy, in those patients, is not going to give, alone, very long success. And certainly, with mantle cell lymphoma, once you’ve been treated and you progress, the prognosis becomes, unlike other small B-cell lymphomas, guarded. It’s really the relapsed mantle cell patient that has a bad prognosis. And first remissions, if you do it right, can be quite durable and beneficial. If you’re using chemotherapy, you want to get into as deep remission as possible. I like AraC (cytarabine) as part of the cytoreduction, in younger patients, under the age of 60, and then autologous transplant. We’ve been using DHAP, or DHAP-alternating with R-CHOP and autologous transplant in those kinds of patients.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: So, now we get into therapy, and this is something that I think we all know: if we were consulting with an individual patient, we could be in the room for an hour. We can’t allocate an hour to talk about upfront therapy. But I’m going to start. We’ll kind of walk down the list and highlight differences within our panel. So, I’ll get John to start. I’m going to give you a hypothetical 60-year-old patient who is fit and is newly diagnosed with mantle cell lymphoma. The other is a hypothetical 75-year-old patient, maybe with some comorbidities, who is newly diagnosed with mantle cell lymphoma. We’ll say that both need treatment. How do you decide what to do? Obviously, there’s a lot of nuance to this.

John M. Pagel, MD, PhD, DSc: Right. When you introduced me, John, you said that I’m from Seattle. So, that means we transplant every patient. Of course, that’s a stretch and a joke, but you know that’s a common approach, to consolidate patients with aggressive treatment in many cases. I’m not sure it’s always the right thing to do. But typically, an approach that many of us are still employing, at least, I would say, in the Pacific Northwest, is to get people to a good remission, a very deep complete remission. How you get there, of course, is very controversial. We can talk more about that if it’s a younger patient, maybe hyper-CVAD. In an older patient, maybe bendamustine and rituximab (BR). I typically tend to be very aggressive with patients based on what they can tolerate. Then, it’s not uncommon to consider an autologous transplant for those patients in first remission. So, for the 60-year-old patient who is fit, that’s an approach I probably am going to take. I’m not crazy about hyper-CVAD, even in a 60-year-old. But getting them to good remission with bendamustine/rituximab, or an abbreviated course of hyper-CVAD is what I might desire to do. And then, to collect stem cells and go to transplant.

The 75-year-old is a little more controversial, obviously. Does transplant really help somebody who’s already in their mid-70s? Usually, in that kind of case, I’m going to stay away from transplant and try and maintain them as long as I can with a good remission, perhaps even with some of the newer drugs that we’ll end up talking about.

John P. Leonard, MD: Is that someone you typical would use BR with?

John M. Pagel, MD, PhD, DSc: I probably would. I think bendamustine/rituximab is very well tolerated in most patients. One of the most important things that we have to remember with bendamustine is that it’s very myelosuppressive. There’s no rule that says you have to give 6 cycles of the regimen. I typically might assess a patient after just 3 cycles or so. And not uncommonly, if I think the risk is relatively low, I’ll just stop there. I know I could give a little bit more in the future, although I’m not a fan of coming back to more bendamustine repeatedly.

Alexey V. Danilov, MD, PhD: John, do you ever consider bendamustine/rituximab for patients for whom you potentially could then perform an autologous stem cell transplant?

John M. Pagel, MD, PhD, DSc: That’s difficult. We have published data that shows that you can collect stem cells after people have had bendamustine. We even published a paper on the use of bendamustine as a mobilization tool. It wasn’t highly successful, but it can be done. At the end of the day, for me, now, with the use of Mozobil (plerixafor), and the ability to mobilize stem cells with these new agents, it’s not typically a factor. In fact, it’s very rare not to be able to collect stem cells in somebody who’s had prior bendamustine now.

John P. Leonard, MD: Andre, I’m guessing your approach is similar? Is there anything different about your strategy? Younger patient, BR-based therapy; older patient, more intensive therapy? Do you typically use hyper-CVAD, or something else for the new person?

Andre Goy, MD: The key philosophy in treating mantle cell lymphoma is that I think it’s one of the diseases where patients become chemotherapy-resistant all the time. Achieving a deep response, or an early response, impacts the outcome.

If a patient is dose intensive, fit, and is treated with hyper-CVAD followed by transplant, I don’t think there’s a big difference. There was actually an abstract at the 2017 ASH Annual Meeting that we can refer to. It reviewed a large population, almost 1200 patients, and looked at the impact of high-dose therapy consolidation for a complete response. There’s really a bias because it’s a retrospective analysis on the complete response patients. But clearly, the dose-intense strategies have really pushed the progression-free survival. And that’s where we have a median PFS well in excess of 5 years. Even in the real world, it is up to at least 7 years. In the original hyper-CVAD, that’s always a problem, in the trials. The trials always have an easier picture than the real world. Ten years is still 52% of the patients who still have not relapsed. So, in a younger patient, that only becomes an option.

Now that we’ll have the ability to integrate novel therapies, maybe we’ll talk a bit more in detail about p53 and how it can change the picture. The next question is, in a non-intensive therapy patient, an older patient, the BR data are not necessarily that impressive, I would argue. It was proven, in a trial, to be slightly better than R-CHOP. It offered a platform to combine with other agents. So, we’re waiting for the results. The same thing has been noted with acalabrutinib.

John P. Leonard, MD: I’m a big fan of BR, both in younger and older patients. I think BR with rituximab maintenance, which has been kind of an indirect—we’ll come back to maintenance in a minute—is something that I commonly use. Briefly, Steve, what are your thought on blastoid mantle cell lymphoma, upfront? If a patient comes in with blastoid mantle cell lymphoma, how do you treat that patient?

Stephen J. Schuster, MD: I’m less influenced by morphology than I am by genetics. There tends to, however, be a correlation between morphology, Ki-67 score, and cytogenetics. You’re much more likely to see a blastoid patient with a high Ki-67 score, a p53 mutation, and more of an aggressive clinical presentation. So, again, it’s not 100%. I mentioned the one outlier that had an ugly morphology, but he did well for years.

Anyway, I would echo with what Andre and John said. I think that in a patient that needs treatment, obviously I’m setting aside the approach to somebody that’s p53-mutated. Chemotherapy, in those patients, is not going to give, alone, very long success. And certainly, with mantle cell lymphoma, once you’ve been treated and you progress, the prognosis becomes, unlike other small B-cell lymphomas, guarded. It’s really the relapsed mantle cell patient that has a bad prognosis. And first remissions, if you do it right, can be quite durable and beneficial. If you’re using chemotherapy, you want to get into as deep remission as possible. I like AraC (cytarabine) as part of the cytoreduction, in younger patients, under the age of 60, and then autologous transplant. We’ve been using DHAP, or DHAP-alternating with R-CHOP and autologous transplant in those kinds of patients.

Transcript Edited for Clarity 
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