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Follicular Lymphoma: Novel Approaches With Rituximab

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Jan 29, 2018



Transcript: 

Ian W. Flinn, MD, PhD: There is another regimen that we should probably spend some time talking about, and that’s the R-squared regimen: rituximab and lenalidomide. There are data now in a variety of different settings with this combination. Where do you see this fitting in, either frontline, second line, or third line? What about the toxicities associated with this? Are you a believer?

Loretta J. Nastoupil, MD: That’s a really great question, and I think we struggle a lot with this. As Peter has mentioned, the microenvironment in follicular lymphoma is critically important. How we target that—there are probably various mechanisms—and whether we use a combination of approaches is something that’s currently under investigation. The beauty of this combination, in my opinion, is that you’re targeting T cells and NK cells, and the combination is probably much more important than single agents such that you can enhance the T cells and NK cells and then potentially direct them at the tumor in the microenvironment signaling.

That being said, we know that it appears to be effective in phase II studies, and now we’re all eagerly awaiting these randomized phase III studies that will tell us where the appropriate use of this treatment is. Now, as we’ve all been involved in drug development in follicular lymphoma, when something looks good in the relapsed setting we rapidly move it into the frontline setting. Right now, we have randomized studies in the frontline setting for patients with untreated follicular lymphoma, who are of high tumor burden, looking at R-squared, or lenalidomide plus rituximab, versus R-chemotherapy. It’s a little bit different than the GALLIUM study schema in that you could choose your chemotherapy, as a physician, according to patient characteristics. So, that might tease out a little bit differently, but we’re all eagerly awaiting those data.

In the relapsed setting, we have the AUGMENT study, which is a randomized trial looking at R-squared versus R-monotherapy. And then, we’ve all heard preliminary data from the MAGNIFY trial, which looked at an induction of 12 months of R-squared therapy in relapsed indolent and mantle cell lymphomas, followed by a maintenance randomization. The randomization, in my opinion, of that study is probably less important other than that it might answer questions about the duration of therapy. But all of these studies suggest that we’re excited about the potential efficacy of this combination. Toxicity appears to be manageable and maybe not that much different from chemotherapy. But again, how will we implement this new regimen? Whether it’s frontline in the relapsed setting, whether you wait until you fail 2 lines of chemotherapy and then introduce it, or whether you introduce it in those early relapsers–because there are some data out of the MAGNIFY study that look quite promising–I think we don’t know the answer yet.

Ian W. Flinn, MD, PhD: When will the RELEVANCE trial read out? There’s sort of a joke in academic circles that you have to be an early assistant professor to begin a career in follicular lymphoma because these timelines are so long. Is there going to be an early readout in that study that will have a hint of what’s going on?

Loretta J. Nastoupil, MD: Yes, we’re anticipating that. This is a good example of us needing earlier readouts and endpoints in frontline follicular lymphoma because we’re going to have a study that’s going to read out where the standard of care may no longer be the standard of care. And what I mean by that is, we have the GALLIUM data now that says obinutuzumab plus chemotherapy might be the current standard of care in frontline follicular lymphoma.

That being said, there is a novel endpoint in the RELEVANT study looking at a complete response rate at 30 months. That was generated out of a chemotherapy-based database. So, whether or not it’s truly a surrogate marker for PFS in a nonchemotherapy-treated patient population is still unknown. But we are anticipating a potential early readout later this month or next month.

Ian W. Flinn, MD, PhD: Peter, you’ve used R-squared a lot. Your group has used this regimen in a variety of different histologies. Do you have any tips on patient selection? With their adverse events, there could be risk of thrombosis. There’s rash. Who’s the ideal patient for this?

Peter Martin, MD, MS: Yes, Sam Yamshon, actually a student at Cornell, is going to present data tomorrow looking at the risk of thrombosis with lenalidomide in lymphoma patients. Interestingly, it doesn’t seem to be the same as multiple myeloma. I’ll just put that out there. Maybe it’s because we’re doing a better job now of preventing it in all of our prospective trials, but it may not be the same as multiple myeloma.
In all of follicular lymphoma, there’s patient selection going on. We all make the decisions. I’ll say that in general, my bias until recently has been to treat patients with less bulky tumor. Some of that may just be a little bit of a lack of experience, right? If somebody has a big bulky tumor, you sort of want to get a response pretty quickly. If they’re really symptomatic, you want to get a response quickly. We know that chemotherapy does that.

We don’t necessarily know how quickly lenalidomide is going to work in those patients, but as we get more experience with it we may change that. In general, my bias has been to use it in people who maybe don’t need immediate responses. And then, as Loretta said, if they’ve been refractory to chemotherapy I’m not going to go back and use it. R-squared makes a lot of sense in that setting.

Ian W. Flinn, MD, PhD: We had patients on the RELEVANCE trial, the frontline study that Loretta described, and it was incredibly popular because the thought of having a chemotherapy-free regimen was very attractive to patients. So, I think there are a lot of people who are going to be interested in seeing what the results of this frontline trial are. And then, we’ll have yet another issue to deal with on how to sequence therapies beyond that, if it turns out to be positive.

Peter Martin, MD, MS: I wondered about that. What if it’s equivalent, for example. If it’s still as good as chemotherapy and would be a reasonable option in certain settings, even if doesn’t beat chemotherapy but does well, there are patients who would probably choose that over chemotherapy.

Ian W. Flinn, MD, PhD: I suspect there are a lot of patients, and it probably does come down to the details about the adverse events. We think of it as being a chemotherapy-free regimen, but it’s not without its own set of adverse events.

Peter Martin, MD, MS: Yes. Some of that is due to the duration of therapy too, right? The clinical trials that Nathan and you did at MD Anderson, and the one we did through the CALGB (Cancer and Leukemia Group B), used 1 year of therapy and that was it. All of the registrational trials are longer durations of Revlimid (lenalidomide), and that may impact tolerability. We’ll see. Those data will come out and we’ll have a look at it.

Ian W. Flinn, MD, PhD: Do you have any experience with any of the rituximab biosimilars? Even if you don’t, how would you incorporate that into your practice?

Peter Martin, MD, MS: I have no experience with any of the biosimilars, but I’ve actually had discussions with European colleagues who now have a lot of experience with them. What they’ve told me is they’re not often the ones making the decisions. It’s the hospital administrators who told them to. The clinical trials that have been done that I’ve seen have suggested that they’re pretty equivalent, and I accept that. I don’t think we need to see a lot more data.

Grzegorz S. Nowakowski, MD: Yes, those are usually considered on the totality of evidence. There’s a structure similarity, there are some preclinical studies that showed similar activity. And then, there are usually much smaller studies that are done clinically, too, to compare efficacy and toxicity, but they’re not necessarily fully powered to recapitulate official findings with the original drug.

Anas Younes, MD: Right. But the issue is really extrapolation, right? What we learned from obinutuzumab we cannot extrapolate now for all diseases. Would it work well for follicular lymphoma? It didn’t work better than rituximab for large B-cell lymphomas. The question then is, is this the same for biosimilars? I see it probably should be similar pattern, and that’s the concern here. In one way, because they’re biosimilars, the bar is too low. You show that they’re relatively similar, but you’re not required to repeat every single trial to show that they’re still similar in certain diseases. So, it brings up the issue of when these agents are not tested in the curable diseases, which I can understand why they didn’t do that. I don’t know. We’ll see how they will play out. I think for non-curable cancers, it’s perfectly fine. There are a lot of similarities. I would feel very comfortable using them. For a curable intent, I’d like to see more data before I make a switch.

Ian W. Flinn, MD, PhD: Yes, I feel the same way. I think the bar for incorporating them into the follicular lymphoma regimen is a lot lower than in patients with large-cell lymphoma, where you could really do some damage if the drug wasn’t as absolutely equal to rituximab.

Grzegorz S. Nowakowski, MD: If you look at some countries with limited resources though, it definitely did expand the access. We see quite a broad use of biosimilars, for example, in Asia, or even in Europe as well.

Ian W. Flinn, MD, PhD: I wonder about the comment earlier that it’s probably more the administration that’s going to make some of these decisions—I worry about that a lot—rather than the individual physicians in the individual application.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: There is another regimen that we should probably spend some time talking about, and that’s the R-squared regimen: rituximab and lenalidomide. There are data now in a variety of different settings with this combination. Where do you see this fitting in, either frontline, second line, or third line? What about the toxicities associated with this? Are you a believer?

Loretta J. Nastoupil, MD: That’s a really great question, and I think we struggle a lot with this. As Peter has mentioned, the microenvironment in follicular lymphoma is critically important. How we target that—there are probably various mechanisms—and whether we use a combination of approaches is something that’s currently under investigation. The beauty of this combination, in my opinion, is that you’re targeting T cells and NK cells, and the combination is probably much more important than single agents such that you can enhance the T cells and NK cells and then potentially direct them at the tumor in the microenvironment signaling.

That being said, we know that it appears to be effective in phase II studies, and now we’re all eagerly awaiting these randomized phase III studies that will tell us where the appropriate use of this treatment is. Now, as we’ve all been involved in drug development in follicular lymphoma, when something looks good in the relapsed setting we rapidly move it into the frontline setting. Right now, we have randomized studies in the frontline setting for patients with untreated follicular lymphoma, who are of high tumor burden, looking at R-squared, or lenalidomide plus rituximab, versus R-chemotherapy. It’s a little bit different than the GALLIUM study schema in that you could choose your chemotherapy, as a physician, according to patient characteristics. So, that might tease out a little bit differently, but we’re all eagerly awaiting those data.

In the relapsed setting, we have the AUGMENT study, which is a randomized trial looking at R-squared versus R-monotherapy. And then, we’ve all heard preliminary data from the MAGNIFY trial, which looked at an induction of 12 months of R-squared therapy in relapsed indolent and mantle cell lymphomas, followed by a maintenance randomization. The randomization, in my opinion, of that study is probably less important other than that it might answer questions about the duration of therapy. But all of these studies suggest that we’re excited about the potential efficacy of this combination. Toxicity appears to be manageable and maybe not that much different from chemotherapy. But again, how will we implement this new regimen? Whether it’s frontline in the relapsed setting, whether you wait until you fail 2 lines of chemotherapy and then introduce it, or whether you introduce it in those early relapsers–because there are some data out of the MAGNIFY study that look quite promising–I think we don’t know the answer yet.

Ian W. Flinn, MD, PhD: When will the RELEVANCE trial read out? There’s sort of a joke in academic circles that you have to be an early assistant professor to begin a career in follicular lymphoma because these timelines are so long. Is there going to be an early readout in that study that will have a hint of what’s going on?

Loretta J. Nastoupil, MD: Yes, we’re anticipating that. This is a good example of us needing earlier readouts and endpoints in frontline follicular lymphoma because we’re going to have a study that’s going to read out where the standard of care may no longer be the standard of care. And what I mean by that is, we have the GALLIUM data now that says obinutuzumab plus chemotherapy might be the current standard of care in frontline follicular lymphoma.

That being said, there is a novel endpoint in the RELEVANT study looking at a complete response rate at 30 months. That was generated out of a chemotherapy-based database. So, whether or not it’s truly a surrogate marker for PFS in a nonchemotherapy-treated patient population is still unknown. But we are anticipating a potential early readout later this month or next month.

Ian W. Flinn, MD, PhD: Peter, you’ve used R-squared a lot. Your group has used this regimen in a variety of different histologies. Do you have any tips on patient selection? With their adverse events, there could be risk of thrombosis. There’s rash. Who’s the ideal patient for this?

Peter Martin, MD, MS: Yes, Sam Yamshon, actually a student at Cornell, is going to present data tomorrow looking at the risk of thrombosis with lenalidomide in lymphoma patients. Interestingly, it doesn’t seem to be the same as multiple myeloma. I’ll just put that out there. Maybe it’s because we’re doing a better job now of preventing it in all of our prospective trials, but it may not be the same as multiple myeloma.
In all of follicular lymphoma, there’s patient selection going on. We all make the decisions. I’ll say that in general, my bias until recently has been to treat patients with less bulky tumor. Some of that may just be a little bit of a lack of experience, right? If somebody has a big bulky tumor, you sort of want to get a response pretty quickly. If they’re really symptomatic, you want to get a response quickly. We know that chemotherapy does that.

We don’t necessarily know how quickly lenalidomide is going to work in those patients, but as we get more experience with it we may change that. In general, my bias has been to use it in people who maybe don’t need immediate responses. And then, as Loretta said, if they’ve been refractory to chemotherapy I’m not going to go back and use it. R-squared makes a lot of sense in that setting.

Ian W. Flinn, MD, PhD: We had patients on the RELEVANCE trial, the frontline study that Loretta described, and it was incredibly popular because the thought of having a chemotherapy-free regimen was very attractive to patients. So, I think there are a lot of people who are going to be interested in seeing what the results of this frontline trial are. And then, we’ll have yet another issue to deal with on how to sequence therapies beyond that, if it turns out to be positive.

Peter Martin, MD, MS: I wondered about that. What if it’s equivalent, for example. If it’s still as good as chemotherapy and would be a reasonable option in certain settings, even if doesn’t beat chemotherapy but does well, there are patients who would probably choose that over chemotherapy.

Ian W. Flinn, MD, PhD: I suspect there are a lot of patients, and it probably does come down to the details about the adverse events. We think of it as being a chemotherapy-free regimen, but it’s not without its own set of adverse events.

Peter Martin, MD, MS: Yes. Some of that is due to the duration of therapy too, right? The clinical trials that Nathan and you did at MD Anderson, and the one we did through the CALGB (Cancer and Leukemia Group B), used 1 year of therapy and that was it. All of the registrational trials are longer durations of Revlimid (lenalidomide), and that may impact tolerability. We’ll see. Those data will come out and we’ll have a look at it.

Ian W. Flinn, MD, PhD: Do you have any experience with any of the rituximab biosimilars? Even if you don’t, how would you incorporate that into your practice?

Peter Martin, MD, MS: I have no experience with any of the biosimilars, but I’ve actually had discussions with European colleagues who now have a lot of experience with them. What they’ve told me is they’re not often the ones making the decisions. It’s the hospital administrators who told them to. The clinical trials that have been done that I’ve seen have suggested that they’re pretty equivalent, and I accept that. I don’t think we need to see a lot more data.

Grzegorz S. Nowakowski, MD: Yes, those are usually considered on the totality of evidence. There’s a structure similarity, there are some preclinical studies that showed similar activity. And then, there are usually much smaller studies that are done clinically, too, to compare efficacy and toxicity, but they’re not necessarily fully powered to recapitulate official findings with the original drug.

Anas Younes, MD: Right. But the issue is really extrapolation, right? What we learned from obinutuzumab we cannot extrapolate now for all diseases. Would it work well for follicular lymphoma? It didn’t work better than rituximab for large B-cell lymphomas. The question then is, is this the same for biosimilars? I see it probably should be similar pattern, and that’s the concern here. In one way, because they’re biosimilars, the bar is too low. You show that they’re relatively similar, but you’re not required to repeat every single trial to show that they’re still similar in certain diseases. So, it brings up the issue of when these agents are not tested in the curable diseases, which I can understand why they didn’t do that. I don’t know. We’ll see how they will play out. I think for non-curable cancers, it’s perfectly fine. There are a lot of similarities. I would feel very comfortable using them. For a curable intent, I’d like to see more data before I make a switch.

Ian W. Flinn, MD, PhD: Yes, I feel the same way. I think the bar for incorporating them into the follicular lymphoma regimen is a lot lower than in patients with large-cell lymphoma, where you could really do some damage if the drug wasn’t as absolutely equal to rituximab.

Grzegorz S. Nowakowski, MD: If you look at some countries with limited resources though, it definitely did expand the access. We see quite a broad use of biosimilars, for example, in Asia, or even in Europe as well.

Ian W. Flinn, MD, PhD: I wonder about the comment earlier that it’s probably more the administration that’s going to make some of these decisions—I worry about that a lot—rather than the individual physicians in the individual application.

Transcript Edited for Clarity 
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