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Follicular Lymphoma: Consolidation and Maintenance

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Published: Tuesday, Jan 17, 2017



Transcript:

Krishna V. Komanduri, MD:
Well, you brought up the notion of maintenance, and I think that we’re seeing an increasing role of both consolidation and maintenance therapies in a number of diseases that we’re going to be talking about today. I want to turn to John and ask, what do you think, in this era, is the optimal role of consolidation and maintenance therapy? And, in particular, we have an exciting plenary presentation that’s going to be presented at this ASH 2016 meeting on the role of obinutuzumab in both induction and maintenance therapy. I wonder if you could talk about that.

John P. Leonard, MD: Traditionally, or at least most recently, we’ve referred to maintenance largely in relationship to rituximab treatment. And I think there are 2 real settings that we have data on that are more robust. The first is the PRIMA study, which takes patients, led by Gilles Salles, who were treated with either R-CHOP or R-CVP, who went into remission, and then were randomized to observation or 2 years of rituximab maintenance, showing that there was a progression-free survival benefit but not an overall survival benefit. And I explain that to patients, that PFS benefit helps about 15% of patients and for the other 85% it doesn’t make a big difference. So, that’s how I try to frame it when I speak with patients. You can decide if that’s important or not with respect to PFS. We also have the RESORT study, which looked at single-agent rituximab, that Leo referenced. It randomized patients to observation or maintenance, and showed that re-treatment is just as good as maintenance. And so, that questioned in some people’s mind, in that setting, is there value of maintenance versus re-treatment?

On the other hand, we don’t have any real solid data on whether or not you need maintenance after bendamustine in follicular lymphoma, or what’s the relative risk-benefit of that. That’s an unknown, and many people have adopted maintenance after bendamustine based on the PRIMA study. But, others have said, “No, it’s a PFS benefit, not an overall survival benefit.” So, that’s the state of maintenance. And I would say one-third of patients don’t get maintenance, one-third do, and one-third might, depending on the preferences of the doctor and patient. This is how I think of it, and people may skew that a little bit differently.

So, now we have a new version of rituximab: obinutuzumab, a novel anti-CD20 antibody that has various enhanced properties that seem to make it a better antibody in some settings, make it a little bit more toxic with respect to infusion reactions in some settings. We have CLL data, that we’ll come to at some point later, showing that it seems to be better than rituximab in that setting, and I think those are pretty clear data, but others will comment when we get there.

We have data in large cell lymphoma presented at this meeting suggesting that with R-CHOP, substituting in obinutuzumab doesn’t help that much. And then, we have follicular lymphoma, which is our topic. In follicular lymphoma, single-agent comparisons of the new antibody are not that impressive versus rituximab. But, in the GALLIUM study, patients getting R-chemotherapy, or I’ll call it ‘O-chemotherapy’ for obinutuzumab, were randomized to one of those approaches and then had 2 years of maintenance with whatever they got. So, if they got R-chemotherapy, they continued with R maintenance, ‘O-chemotherapy’ continued with ‘O-maintenance’ for 2 years. And the net of that was that there was a progression-free survival benefit, which is the main feature of that.

So, I think it’s clearly a positive study from that endpoint. In my mind, there will be people that will be using it and there’s some value to progression-free survival benefit. However, on the flip side, it’s PFS, it’s not overall survival benefit. The toxicity will matter, and the question is, is it sufficiently different that it will stop people from using it or sufficiently minor that will let people say, “Go ahead, it’s not a big deal, adopt a new antibody”? And, I think, my sense is that the antibody-related toxicities are probably not a huge issue for most patients.

And then, there are some interesting things about how this will change practice and will everybody get the new antibody. Will certain subsets get the new antibody? What about the chemotherapy that was chosen, and did we learn anything from that? And if I didn’t use maintenance before, am I now going to use it on the basis of this study? So, there are a lot of questions. It’s good for patients that we have things that are helping them. But, I think that despite the fact that this will be a positive phase III trial, there are still some things that make this, if you get into the details of the data, perhaps not so clear-cut that everybody now is going to get this approach.

Krishna V. Komanduri, MD: The authors did suggest that this should be the new standard of care on the basis of their data.

John P. Leonard, MD: I think they said “a new standard,” which I think everyone around the table likes to use as, and I would agree with them that it is a standard, but not the standard. The question will be for which patients. Our community is going to have to decide that, and I think if you practice correctly, you probably should talk about these things with your patients, too, and make them understand their preference because, again, it is PFS, it’s not overall survival. So, I think there is wiggle room for patients, and to use maintenance in this strategy, you’re automatically taking perhaps a 4- to 6-month treatment and now making it a 2.5-year treatment. And that may just be fine if there’s benefit, but for some people, that may not work out as being quite so optimal.

Leo I. Gordon, MD: A couple things. John mentioned the RESORT study, which I think is an important trial, a 600 or so patient trial that really focused on a group of patients that, by definition, didn’t require treatment. These are patients with a very low bulk, asymptomatic disease. They were then treated. Actually, they were randomized between 4 doses of Rituxan alone and Rituxan life-time as maintenance, and there was no difference in overall survival. There was a little bit more toxicity, but obviously we would have expected that in the maintenance group. But, what it tells me, even though it’s an important study, is if you take a group of patients that didn’t do treatment, more isn’t better. And so, I’m not surprised. I think it’s hard to know what major question it answers in terms of making decisions about maintenance therapy.

You did point out, it’s interesting, that despite the lack of data on bendamustine or bendamustine in maintenance, it was adopted as standard in the GALLIUM study. So, it’s interesting that they extrapolated right to it.

John P. Leonard, MD: And I think we’ll see some fairly robust data on that arm of the study, or that group of patients treated on the study, that hopefully will be informative as to how that approach goes for patients.

Transcript Edited for Clarity

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Transcript:

Krishna V. Komanduri, MD:
Well, you brought up the notion of maintenance, and I think that we’re seeing an increasing role of both consolidation and maintenance therapies in a number of diseases that we’re going to be talking about today. I want to turn to John and ask, what do you think, in this era, is the optimal role of consolidation and maintenance therapy? And, in particular, we have an exciting plenary presentation that’s going to be presented at this ASH 2016 meeting on the role of obinutuzumab in both induction and maintenance therapy. I wonder if you could talk about that.

John P. Leonard, MD: Traditionally, or at least most recently, we’ve referred to maintenance largely in relationship to rituximab treatment. And I think there are 2 real settings that we have data on that are more robust. The first is the PRIMA study, which takes patients, led by Gilles Salles, who were treated with either R-CHOP or R-CVP, who went into remission, and then were randomized to observation or 2 years of rituximab maintenance, showing that there was a progression-free survival benefit but not an overall survival benefit. And I explain that to patients, that PFS benefit helps about 15% of patients and for the other 85% it doesn’t make a big difference. So, that’s how I try to frame it when I speak with patients. You can decide if that’s important or not with respect to PFS. We also have the RESORT study, which looked at single-agent rituximab, that Leo referenced. It randomized patients to observation or maintenance, and showed that re-treatment is just as good as maintenance. And so, that questioned in some people’s mind, in that setting, is there value of maintenance versus re-treatment?

On the other hand, we don’t have any real solid data on whether or not you need maintenance after bendamustine in follicular lymphoma, or what’s the relative risk-benefit of that. That’s an unknown, and many people have adopted maintenance after bendamustine based on the PRIMA study. But, others have said, “No, it’s a PFS benefit, not an overall survival benefit.” So, that’s the state of maintenance. And I would say one-third of patients don’t get maintenance, one-third do, and one-third might, depending on the preferences of the doctor and patient. This is how I think of it, and people may skew that a little bit differently.

So, now we have a new version of rituximab: obinutuzumab, a novel anti-CD20 antibody that has various enhanced properties that seem to make it a better antibody in some settings, make it a little bit more toxic with respect to infusion reactions in some settings. We have CLL data, that we’ll come to at some point later, showing that it seems to be better than rituximab in that setting, and I think those are pretty clear data, but others will comment when we get there.

We have data in large cell lymphoma presented at this meeting suggesting that with R-CHOP, substituting in obinutuzumab doesn’t help that much. And then, we have follicular lymphoma, which is our topic. In follicular lymphoma, single-agent comparisons of the new antibody are not that impressive versus rituximab. But, in the GALLIUM study, patients getting R-chemotherapy, or I’ll call it ‘O-chemotherapy’ for obinutuzumab, were randomized to one of those approaches and then had 2 years of maintenance with whatever they got. So, if they got R-chemotherapy, they continued with R maintenance, ‘O-chemotherapy’ continued with ‘O-maintenance’ for 2 years. And the net of that was that there was a progression-free survival benefit, which is the main feature of that.

So, I think it’s clearly a positive study from that endpoint. In my mind, there will be people that will be using it and there’s some value to progression-free survival benefit. However, on the flip side, it’s PFS, it’s not overall survival benefit. The toxicity will matter, and the question is, is it sufficiently different that it will stop people from using it or sufficiently minor that will let people say, “Go ahead, it’s not a big deal, adopt a new antibody”? And, I think, my sense is that the antibody-related toxicities are probably not a huge issue for most patients.

And then, there are some interesting things about how this will change practice and will everybody get the new antibody. Will certain subsets get the new antibody? What about the chemotherapy that was chosen, and did we learn anything from that? And if I didn’t use maintenance before, am I now going to use it on the basis of this study? So, there are a lot of questions. It’s good for patients that we have things that are helping them. But, I think that despite the fact that this will be a positive phase III trial, there are still some things that make this, if you get into the details of the data, perhaps not so clear-cut that everybody now is going to get this approach.

Krishna V. Komanduri, MD: The authors did suggest that this should be the new standard of care on the basis of their data.

John P. Leonard, MD: I think they said “a new standard,” which I think everyone around the table likes to use as, and I would agree with them that it is a standard, but not the standard. The question will be for which patients. Our community is going to have to decide that, and I think if you practice correctly, you probably should talk about these things with your patients, too, and make them understand their preference because, again, it is PFS, it’s not overall survival. So, I think there is wiggle room for patients, and to use maintenance in this strategy, you’re automatically taking perhaps a 4- to 6-month treatment and now making it a 2.5-year treatment. And that may just be fine if there’s benefit, but for some people, that may not work out as being quite so optimal.

Leo I. Gordon, MD: A couple things. John mentioned the RESORT study, which I think is an important trial, a 600 or so patient trial that really focused on a group of patients that, by definition, didn’t require treatment. These are patients with a very low bulk, asymptomatic disease. They were then treated. Actually, they were randomized between 4 doses of Rituxan alone and Rituxan life-time as maintenance, and there was no difference in overall survival. There was a little bit more toxicity, but obviously we would have expected that in the maintenance group. But, what it tells me, even though it’s an important study, is if you take a group of patients that didn’t do treatment, more isn’t better. And so, I’m not surprised. I think it’s hard to know what major question it answers in terms of making decisions about maintenance therapy.

You did point out, it’s interesting, that despite the lack of data on bendamustine or bendamustine in maintenance, it was adopted as standard in the GALLIUM study. So, it’s interesting that they extrapolated right to it.

John P. Leonard, MD: And I think we’ll see some fairly robust data on that arm of the study, or that group of patients treated on the study, that hopefully will be informative as to how that approach goes for patients.

Transcript Edited for Clarity
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