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Potential of R2 Regimen in Treating Follicular Lymphoma

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: Wednesday, Feb 13, 2019



Transcript: 

Ian W. Flinn, MD, PhD: Nathan, let’s talk about a therapy that you’ve really been instrumental in moving forward, and that’s the R2 [rituximab and lenalidomide] regimen. So you had experience at The University of Texas MD Anderson Cancer Center, at your institution, that has gone on to that same therapy in several large randomized trials, including the RELEVANCE trial, which was recently published in the New England Journal of Medicine. Let’s start with the MD Anderson experience with R2: how you think about it and where you’re using this treatment.

Nathan H. Fowler, MD: As you know, we worked on this, gosh, it’s been, actually at this ASH [American Society of Hematology Annual Meeting & Exposition], I presented the median 7-year follow-up, so median means some of these patients we started on the very first initiated trial with that regimen in follicular over 10 years ago. And the long-term outcomes suggest that you can deliver this therapy and get 70% of our patients in remission going on 7 to 10 years now. We also completed the RELEVANCE trial, which showed that chemotherapy was not superior to lenalidomide-rituximab and vice versa. The study was designed as a superiority trial, and we didn’t meet that endpoint. But if you look at the progression-free survival curves, they’re literally overlapping with regard to disease control across different subsets of patients. The toxicity profile is slightly different. So at least in my practice, I think it’s a great option for frontline therapy.

At this ASH, we’ll see the AUGMENT study presented, which is looking at lenalidomide-rituximab versus rituximab in the relapsed setting. And the abstract suggests that there is a dramatic difference in progression-free survival in the relapsed setting compared with rituximab as a single agent. So with that, I think that it’s again a great option for both relapsed patients and in the frontline. Just actually this week, it was moved to a level 2A recommendation by the NCCN [National Comprehensive Cancer Network], which means it’s a preferred regimen for frontline patients in low-grade lymphoma. And again, because this conversation is really focused on, over the past several subjects, this individualization of therapy. And so again, I think it’s another bullet in my revolver to treat the disease.

Ian W. Flinn, MD, PhD: Scott, do you think your patients in frontline setting are an attractive approach? I mean, certainly, chemotherapy has all the baggage of just the name, right? Everyone associates something terrible with cytotoxic chemotherapy. Are you offering this as frontline therapy for patients? If you are, how many people are choosing that? What are your thoughts?

Scott Huntington, MD, MPH, MSc: Yeah, that’s a really good question. I have not yet offered it. I’ll discuss it as a potential, but I think my personal experience with bendamustine in managing those adverse effects, and the fact that it wasn’t a superior trial, there are perhaps concerns about duration of therapy and cost of therapy that could potentially be at play. So I think for the majority of my patients, with the discussion of pros and cons, we’ve been choosing bendamustine-based therapy with rituximab. I do think the AUGMENT data really [establish] it as a standard second-line treatment, and it’s certainly good to have multiple data points showing that this R2 regimen is very active, and there’s a good safety signal as well. So I think it’s certainly moving its way up, but for me, it hasn’t overwhelmed the bendamustine.

Ian W. Flinn, MD, PhD: How about in the relapsed setting?

Scott Huntington, MD, MPH, MSc: Yeah.

Ian W. Flinn, MD, PhD: The AUGMENT data.

Scott Huntington, MD, MPH, MSc: Yeah, that’s a really good question. For me, if someone has had, let’s say, R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] 12 years ago, and they had a really prolonged remission, I may go back to the chemo regimen at 12 years. If it’s been only a few years, even beyond the 2 years, I’m much more likely to say, all right, chemotherapy, this was it, you got a number of good years out of it, but let’s bring in the R2 up to the second line. So I think it’s still an individualized discussion. And I think as providers get more familiar with R2 in this setting, and there are different flavors and different durations, that also needs to be worked out a little bit. But it certainly has established itself as an important regimen in indolent lymphomas.

Nathan H. Fowler, MD: I’ll just comment. One thing we also presented at this ASH was duration of remission based on the number of cycles. I think Scott brings up a very good point. The RELEVANCE trial looked at 18 months of therapy, and we may not need 18 months of therapy with R2. At least in our hands, the 6-month and the 12-month dosing had actually fairly similar progression-free survival. Unfortunately, we don’t have randomized trials, but maybe we don’t need quite the length of R2 that we did in the randomized trial, and you get to very similar outcomes.

Scott Huntington, MD, MPH, MSc: Perhaps the dose, right? So does everyone need 20 mg? Can we dose-reduce patients?

Nathan H. Fowler, MD: In our studies we’ve led with 20 mg. A significant number of patients needed dose reduction because of intermittent cytopenias. I just need to push 1 of these buttons that says “individualization.” It turns out that the dose probably will be optimized in a lot of patients, and some patients need 15 or 10 and some 20.

Ian W. Flinn, MD, PhD: Ajay, what about you? I’m taking it that in different parts of the country, the way, even the patients have a very different request about the way their care is managed. What are you finding?

Ajay Gopal, MD, FACP: Yeah, I mean I would agree. I’m not an early adopter of R2 as frontline. I discuss it with patients. My takeaway is that it’s great. We have another; the progression-free survival is similar. My sense is the toxicity, net toxicity is similar. It may be different, and its area-under-the-curve toxicity is probably similar, and I counsel patients about duration of therapy. My patients tend to, if they’re going to do something that’s going to make them feel not great, and my experience with lenalidomide is patients have quite a bit of symptoms with it. It’s different in lymphoma from myeloma—that has been my experience. Then they would prefer to have an abbreviated course. But it’s good to have that option.

Ian W. Flinn, MD, PhD: We’ve done in a couple of studies, and I sort of agree with you in the sense that we’ve had an increased number of cutaneous reactions in some of the studies, not these 2 that we’re talking about but our own institutional studies. For a while there, I was wondering what we were doing wrong, but it is different from what I saw in MDS [myelodysplastic syndrome] and myeloma.

Nathan H. Fowler, MD: It does look as if the rate of cutaneous reactions is higher in lymphoma, especially in follicular lymphoma and in CLL [chronic lymphocytic leukemia], compared with myeloma. And that may be because many of the myeloma patients are immunosuppressed because of prior therapy, prior transplant. Now, in our own practice, we give patients Claritin, actually prophylactically, at day 1 of beginning lenalidomide, and we find that antihistamines actually mitigate a lot of the rash.

Ian W. Flinn, MD, PhD: That’s a great tip. I’m going to have to use it. Do you think it’s just the lenalidomide? Or you think it’s the patients? Or do you think the combination with rituximab?

Nathan H. Fowler, MD: So there were a lot of studies that were done at the Mayo Clinic looking at this drug as a single agent, and the rash does appear to be higher when you combine it with rituximab, at least compared with the reports that came out of Mayo Clinic and others using it as a single agent. So rituximab may also increase the rash rates slightly.


Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: Nathan, let’s talk about a therapy that you’ve really been instrumental in moving forward, and that’s the R2 [rituximab and lenalidomide] regimen. So you had experience at The University of Texas MD Anderson Cancer Center, at your institution, that has gone on to that same therapy in several large randomized trials, including the RELEVANCE trial, which was recently published in the New England Journal of Medicine. Let’s start with the MD Anderson experience with R2: how you think about it and where you’re using this treatment.

Nathan H. Fowler, MD: As you know, we worked on this, gosh, it’s been, actually at this ASH [American Society of Hematology Annual Meeting & Exposition], I presented the median 7-year follow-up, so median means some of these patients we started on the very first initiated trial with that regimen in follicular over 10 years ago. And the long-term outcomes suggest that you can deliver this therapy and get 70% of our patients in remission going on 7 to 10 years now. We also completed the RELEVANCE trial, which showed that chemotherapy was not superior to lenalidomide-rituximab and vice versa. The study was designed as a superiority trial, and we didn’t meet that endpoint. But if you look at the progression-free survival curves, they’re literally overlapping with regard to disease control across different subsets of patients. The toxicity profile is slightly different. So at least in my practice, I think it’s a great option for frontline therapy.

At this ASH, we’ll see the AUGMENT study presented, which is looking at lenalidomide-rituximab versus rituximab in the relapsed setting. And the abstract suggests that there is a dramatic difference in progression-free survival in the relapsed setting compared with rituximab as a single agent. So with that, I think that it’s again a great option for both relapsed patients and in the frontline. Just actually this week, it was moved to a level 2A recommendation by the NCCN [National Comprehensive Cancer Network], which means it’s a preferred regimen for frontline patients in low-grade lymphoma. And again, because this conversation is really focused on, over the past several subjects, this individualization of therapy. And so again, I think it’s another bullet in my revolver to treat the disease.

Ian W. Flinn, MD, PhD: Scott, do you think your patients in frontline setting are an attractive approach? I mean, certainly, chemotherapy has all the baggage of just the name, right? Everyone associates something terrible with cytotoxic chemotherapy. Are you offering this as frontline therapy for patients? If you are, how many people are choosing that? What are your thoughts?

Scott Huntington, MD, MPH, MSc: Yeah, that’s a really good question. I have not yet offered it. I’ll discuss it as a potential, but I think my personal experience with bendamustine in managing those adverse effects, and the fact that it wasn’t a superior trial, there are perhaps concerns about duration of therapy and cost of therapy that could potentially be at play. So I think for the majority of my patients, with the discussion of pros and cons, we’ve been choosing bendamustine-based therapy with rituximab. I do think the AUGMENT data really [establish] it as a standard second-line treatment, and it’s certainly good to have multiple data points showing that this R2 regimen is very active, and there’s a good safety signal as well. So I think it’s certainly moving its way up, but for me, it hasn’t overwhelmed the bendamustine.

Ian W. Flinn, MD, PhD: How about in the relapsed setting?

Scott Huntington, MD, MPH, MSc: Yeah.

Ian W. Flinn, MD, PhD: The AUGMENT data.

Scott Huntington, MD, MPH, MSc: Yeah, that’s a really good question. For me, if someone has had, let’s say, R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] 12 years ago, and they had a really prolonged remission, I may go back to the chemo regimen at 12 years. If it’s been only a few years, even beyond the 2 years, I’m much more likely to say, all right, chemotherapy, this was it, you got a number of good years out of it, but let’s bring in the R2 up to the second line. So I think it’s still an individualized discussion. And I think as providers get more familiar with R2 in this setting, and there are different flavors and different durations, that also needs to be worked out a little bit. But it certainly has established itself as an important regimen in indolent lymphomas.

Nathan H. Fowler, MD: I’ll just comment. One thing we also presented at this ASH was duration of remission based on the number of cycles. I think Scott brings up a very good point. The RELEVANCE trial looked at 18 months of therapy, and we may not need 18 months of therapy with R2. At least in our hands, the 6-month and the 12-month dosing had actually fairly similar progression-free survival. Unfortunately, we don’t have randomized trials, but maybe we don’t need quite the length of R2 that we did in the randomized trial, and you get to very similar outcomes.

Scott Huntington, MD, MPH, MSc: Perhaps the dose, right? So does everyone need 20 mg? Can we dose-reduce patients?

Nathan H. Fowler, MD: In our studies we’ve led with 20 mg. A significant number of patients needed dose reduction because of intermittent cytopenias. I just need to push 1 of these buttons that says “individualization.” It turns out that the dose probably will be optimized in a lot of patients, and some patients need 15 or 10 and some 20.

Ian W. Flinn, MD, PhD: Ajay, what about you? I’m taking it that in different parts of the country, the way, even the patients have a very different request about the way their care is managed. What are you finding?

Ajay Gopal, MD, FACP: Yeah, I mean I would agree. I’m not an early adopter of R2 as frontline. I discuss it with patients. My takeaway is that it’s great. We have another; the progression-free survival is similar. My sense is the toxicity, net toxicity is similar. It may be different, and its area-under-the-curve toxicity is probably similar, and I counsel patients about duration of therapy. My patients tend to, if they’re going to do something that’s going to make them feel not great, and my experience with lenalidomide is patients have quite a bit of symptoms with it. It’s different in lymphoma from myeloma—that has been my experience. Then they would prefer to have an abbreviated course. But it’s good to have that option.

Ian W. Flinn, MD, PhD: We’ve done in a couple of studies, and I sort of agree with you in the sense that we’ve had an increased number of cutaneous reactions in some of the studies, not these 2 that we’re talking about but our own institutional studies. For a while there, I was wondering what we were doing wrong, but it is different from what I saw in MDS [myelodysplastic syndrome] and myeloma.

Nathan H. Fowler, MD: It does look as if the rate of cutaneous reactions is higher in lymphoma, especially in follicular lymphoma and in CLL [chronic lymphocytic leukemia], compared with myeloma. And that may be because many of the myeloma patients are immunosuppressed because of prior therapy, prior transplant. Now, in our own practice, we give patients Claritin, actually prophylactically, at day 1 of beginning lenalidomide, and we find that antihistamines actually mitigate a lot of the rash.

Ian W. Flinn, MD, PhD: That’s a great tip. I’m going to have to use it. Do you think it’s just the lenalidomide? Or you think it’s the patients? Or do you think the combination with rituximab?

Nathan H. Fowler, MD: So there were a lot of studies that were done at the Mayo Clinic looking at this drug as a single agent, and the rash does appear to be higher when you combine it with rituximab, at least compared with the reports that came out of Mayo Clinic and others using it as a single agent. So rituximab may also increase the rash rates slightly.


Transcript Edited for Clarity
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