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Potential of R-Squared Regimen in Treating Follicular Lymphoma

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew Lunning, DO, University of Nebraska Medical Center; John M. Pagel, MD, PhD, Swedish Cancer Institute; Pier Luigi Zinzani, MD, PhD, University of Bologna
Published: Tuesday, Sep 03, 2019



Transcript: 

Ian W. Flinn, MD, PhD: We’re going to talk about R2 [lenalidomide-rituximab] in depth now.

There’s the RELEVANCE data, from the frontline setting, that showed a large international randomized trial that was designed to be superior. The R2 [lenalidomide-rituximab] was to be chemotherapy. It turns out that it was basically equivalent. I know that in some people in the US, I’ve heard some people get up and say, “Well, that’s my standard frontline therapy.” There’s the AUGMENT data that show, as you mentioned, that it was in the rituximab-sensitive patients comparing R2 [lenalidomide-rituximab] to R [rituximab]. Well, what won? It sounds like most of us are still using chemoimmunotherapy as frontline. But is anybody using R2 [lenalidomide-rituximab] standardly as frontline therapy at this time?

Matthew Lunning, DO: No.

John M. Pagel, MD, PhD: No, I’m not. But I will say, it’s an appealing option in the right patients in the frontline. I think you know that if you do have a patient population who’s perhaps a little more frail and unfit, you would normally treat with rituximab alone. And based on the RELEVANCE trial, that even though it didn’t show any advantage to giving R2 [lenalidomide-rituximab] over chemoimmunotherapy, it showed that R2 [lenalidomide-rituximab] is probably just as good, and the data were quite impressive in that way. And so I ask myself a lot of times, if I’m going to give single-agent rituximab in that setting, in the frontline setting in particular here, do I have a reason that I’m not going to add lenalidomide to it or not?

I will say that you have to really step back and say that these rashes can be very problematic. I mean, I think we all see that or other problems that can happen with the Revlimid. It’s not for everybody just because you can do it, right? We have to recognize, this is not a curative regimen. We’re talking about for people who are in their 70s or 80s, perhaps…. And so what’s the bang for the buck, so of speak? What are we really going to get out of it? Sometimes I think it’s very, very reasonable to do, and other times I think it’s not as reasonable to do.

Matthew Lunning, DO: I think cost can factor into that when there’s not a survival advantage, you know. It’s very similar, and I believe it was 18 months of lenalidomide. It’s not 6 months of lenalidomide.

Pier Luigi Zinzani, MD, PhD: Yes, and it’s more than 1 year, so it’s a long time.

John M. Pagel, MD, PhD: Let’s not ever forget co-pays on patients. It’s something that we don’t really absorb and think about, but it’s something we should be paying attention to.

Ian W. Flinn, MD, PhD: So maybe for the select patient, but not for every patient frontline. But Pier Luigi, you brought up something about it in the second line. You’re quite taken with the AUGMENT data, the randomized trial?

Pier Luigi Zinzani, MD, PhD: Yeah. The data really—as I said before, R2 [lenalidomide-rituximab], for relapsed-refractory patients, is a very good chemotherapy-free regimen; it’s very important. The first time there is an advent of chemotherapy-free regimen with an immunomodulator, lenalidomide, and an anti-CD20 monoclonal, rituximab. These are really good in terms of clinical response with a very low toxicity and could be, and I think it will be the best of second-line treatment for our patients with follicular lymphoma.

As I said before, in Europe we are waiting only for the EMA [European Medicines Agency] official indication, because we are 6, 8 months later than FDA, as usual. But I think it is a really good combination, and probably in the future we can try to combine it with another drug, like a triplet, to increase the clinical response; the efficacy without any kind of cumulative toxicity. Why not with other new biological agents? There are several other phase I, phase II studies concerning whether to include another agent too.

Ian W. Flinn, MD, PhD: Matt, you brought up a really important point about the design of the AUGMENT trial, which was basically, you had to be appropriate for single-agent rituximab to be entered on for that trial. There’s a population of patients that you’re probably not going to want to use that in, right?

Matthew Lunning, DO: Yeah. You know the people who can’t get access to it because they can’t afford the up-front cost to get on to lenalidomide I think would be the first population. Having used it in the maintenance setting in multiple myeloma, I’m not too afraid of the DVT [deep vein thrombosis] risks. I think there’s something to say about having a steroid plus lenalidomide from that standpoint. But I think it is an investment in potential; you know rash does come out. The cytopenias are definitely there, and I think you have to be on guard for dose reductions and dose holds. You know the cytopenias are very responsive to growth factor and dosing holds. But respect those and don’t press the envelope in a disease where you know the goal is quality of life for as long as possible, rather than push through at doses that they’re not necessarily...

John M. Pagel, MD, PhD: Again, I think it comes back to what we said earlier. A lot of these people will do very well with great efficacy at lower doses. So I have a very low threshold to dose reduce. Frankly, I start patients at a lower dose because of those reasons.

Ian W. Flinn, MD, PhD: What about the group of people that are the early progressors, people that you’re particularly worried about, right? That you know maybe relapse within 6 or 9 months or a year after frontline therapy. John, are you going to use R2 [lenalidomide-rituximab] in those people? You probably wouldn’t give single-agent Rituxan.

John M. Pagel, MD, PhD: No, I’m not going to give them single-agent rituximab, but I am going to give them R2 [lenalidomide-rituximab]. I think the regimen is impressive in those patients, and I would say it’s not a home run. They’re still going to end up doing worse than somebody who has longer remissions from up-front therapy. But I like the idea of doing something that’s not nominally the same type of chemoimmunotherapy or close to it that they got before. I think R2 [lenalidomide-rituximab] is really going to become the major standard of care in second-line treatment even for more aggressive patients.

Matthew Lunning, DO: I’ll say that I would hope that they would potentially be at a center that had the SWOG study open, which has an arm which is obinutuzumab, lenalidomide in that patient in population, but I know that that’s not going to happen for everybody.

John M. Pagel, MD, PhD: But that’s a good point. I think we should really stress that. That’s something we haven’t talked about. And those kinds of patients, those are the patients we should be thinking about a clinical trial for especially, right? I mean, we all want to say everybody should be on a trial, but very few patients go on a trial. The ones who really need a trial are those, and we should never forget about that.

Pier Luigi Zinzani, MD, PhD: Yeah, and you have to remember that the historical data by Michael Wang concerning the role of R2 [lenalidomide-rituximab] also in diffuse large B-cell lymphoma. I mean, for aggressive follicular lymphoma, you can use R2 [lenalidomide-rituximab] because it’s quite active also in this setting of patients.

Matthew Lunning, DO: Actually there’s an abstract at ASH [the American Society of Hematology Annual Meeting & Exposition]. I mean, transformed follicular lymphoma has a pretty decent response rate. I know the PFS [progression-free survival] is quite short, but in that disease, it’s going to be a bridge to something.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: We’re going to talk about R2 [lenalidomide-rituximab] in depth now.

There’s the RELEVANCE data, from the frontline setting, that showed a large international randomized trial that was designed to be superior. The R2 [lenalidomide-rituximab] was to be chemotherapy. It turns out that it was basically equivalent. I know that in some people in the US, I’ve heard some people get up and say, “Well, that’s my standard frontline therapy.” There’s the AUGMENT data that show, as you mentioned, that it was in the rituximab-sensitive patients comparing R2 [lenalidomide-rituximab] to R [rituximab]. Well, what won? It sounds like most of us are still using chemoimmunotherapy as frontline. But is anybody using R2 [lenalidomide-rituximab] standardly as frontline therapy at this time?

Matthew Lunning, DO: No.

John M. Pagel, MD, PhD: No, I’m not. But I will say, it’s an appealing option in the right patients in the frontline. I think you know that if you do have a patient population who’s perhaps a little more frail and unfit, you would normally treat with rituximab alone. And based on the RELEVANCE trial, that even though it didn’t show any advantage to giving R2 [lenalidomide-rituximab] over chemoimmunotherapy, it showed that R2 [lenalidomide-rituximab] is probably just as good, and the data were quite impressive in that way. And so I ask myself a lot of times, if I’m going to give single-agent rituximab in that setting, in the frontline setting in particular here, do I have a reason that I’m not going to add lenalidomide to it or not?

I will say that you have to really step back and say that these rashes can be very problematic. I mean, I think we all see that or other problems that can happen with the Revlimid. It’s not for everybody just because you can do it, right? We have to recognize, this is not a curative regimen. We’re talking about for people who are in their 70s or 80s, perhaps…. And so what’s the bang for the buck, so of speak? What are we really going to get out of it? Sometimes I think it’s very, very reasonable to do, and other times I think it’s not as reasonable to do.

Matthew Lunning, DO: I think cost can factor into that when there’s not a survival advantage, you know. It’s very similar, and I believe it was 18 months of lenalidomide. It’s not 6 months of lenalidomide.

Pier Luigi Zinzani, MD, PhD: Yes, and it’s more than 1 year, so it’s a long time.

John M. Pagel, MD, PhD: Let’s not ever forget co-pays on patients. It’s something that we don’t really absorb and think about, but it’s something we should be paying attention to.

Ian W. Flinn, MD, PhD: So maybe for the select patient, but not for every patient frontline. But Pier Luigi, you brought up something about it in the second line. You’re quite taken with the AUGMENT data, the randomized trial?

Pier Luigi Zinzani, MD, PhD: Yeah. The data really—as I said before, R2 [lenalidomide-rituximab], for relapsed-refractory patients, is a very good chemotherapy-free regimen; it’s very important. The first time there is an advent of chemotherapy-free regimen with an immunomodulator, lenalidomide, and an anti-CD20 monoclonal, rituximab. These are really good in terms of clinical response with a very low toxicity and could be, and I think it will be the best of second-line treatment for our patients with follicular lymphoma.

As I said before, in Europe we are waiting only for the EMA [European Medicines Agency] official indication, because we are 6, 8 months later than FDA, as usual. But I think it is a really good combination, and probably in the future we can try to combine it with another drug, like a triplet, to increase the clinical response; the efficacy without any kind of cumulative toxicity. Why not with other new biological agents? There are several other phase I, phase II studies concerning whether to include another agent too.

Ian W. Flinn, MD, PhD: Matt, you brought up a really important point about the design of the AUGMENT trial, which was basically, you had to be appropriate for single-agent rituximab to be entered on for that trial. There’s a population of patients that you’re probably not going to want to use that in, right?

Matthew Lunning, DO: Yeah. You know the people who can’t get access to it because they can’t afford the up-front cost to get on to lenalidomide I think would be the first population. Having used it in the maintenance setting in multiple myeloma, I’m not too afraid of the DVT [deep vein thrombosis] risks. I think there’s something to say about having a steroid plus lenalidomide from that standpoint. But I think it is an investment in potential; you know rash does come out. The cytopenias are definitely there, and I think you have to be on guard for dose reductions and dose holds. You know the cytopenias are very responsive to growth factor and dosing holds. But respect those and don’t press the envelope in a disease where you know the goal is quality of life for as long as possible, rather than push through at doses that they’re not necessarily...

John M. Pagel, MD, PhD: Again, I think it comes back to what we said earlier. A lot of these people will do very well with great efficacy at lower doses. So I have a very low threshold to dose reduce. Frankly, I start patients at a lower dose because of those reasons.

Ian W. Flinn, MD, PhD: What about the group of people that are the early progressors, people that you’re particularly worried about, right? That you know maybe relapse within 6 or 9 months or a year after frontline therapy. John, are you going to use R2 [lenalidomide-rituximab] in those people? You probably wouldn’t give single-agent Rituxan.

John M. Pagel, MD, PhD: No, I’m not going to give them single-agent rituximab, but I am going to give them R2 [lenalidomide-rituximab]. I think the regimen is impressive in those patients, and I would say it’s not a home run. They’re still going to end up doing worse than somebody who has longer remissions from up-front therapy. But I like the idea of doing something that’s not nominally the same type of chemoimmunotherapy or close to it that they got before. I think R2 [lenalidomide-rituximab] is really going to become the major standard of care in second-line treatment even for more aggressive patients.

Matthew Lunning, DO: I’ll say that I would hope that they would potentially be at a center that had the SWOG study open, which has an arm which is obinutuzumab, lenalidomide in that patient in population, but I know that that’s not going to happen for everybody.

John M. Pagel, MD, PhD: But that’s a good point. I think we should really stress that. That’s something we haven’t talked about. And those kinds of patients, those are the patients we should be thinking about a clinical trial for especially, right? I mean, we all want to say everybody should be on a trial, but very few patients go on a trial. The ones who really need a trial are those, and we should never forget about that.

Pier Luigi Zinzani, MD, PhD: Yeah, and you have to remember that the historical data by Michael Wang concerning the role of R2 [lenalidomide-rituximab] also in diffuse large B-cell lymphoma. I mean, for aggressive follicular lymphoma, you can use R2 [lenalidomide-rituximab] because it’s quite active also in this setting of patients.

Matthew Lunning, DO: Actually there’s an abstract at ASH [the American Society of Hematology Annual Meeting & Exposition]. I mean, transformed follicular lymphoma has a pretty decent response rate. I know the PFS [progression-free survival] is quite short, but in that disease, it’s going to be a bridge to something.

Transcript Edited for Clarity
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