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Treatment Options for High-Risk Follicular Lymphoma Cases

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Nathan H. Fowler, MD, The University of Texas MD Anderson Cancer Center; Ajay K. Gopal, MD, FACP, Seattle Cancer Care Alliance; Scott Huntington, MD, MPH, MSc, Yale University School of Medicine
Published: Monday, Jan 21, 2019



Transcript:

Ian W. Flinn, MD, PhD:
You both alluded to another group of patients that you’re a little worried about, right? I mean you haven’t proven that they’re a Richter transformation, but sometimes it’s hard. The PET [positron emission tomography] scans, the SUVs [standardized uptake values] are a bit high, maybe their LDH [lactate dehydrogenase] is up, but you’re worried. Is that a group that you’re using R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] in?

Nathan H. Fowler, MD: Yes, absolutely.

Ajay K. Gopal, MD, FACP: I would agree. There was some interesting data from the BC [British Columbia] Cancer Agency at this meeting showing that for the patients that got bendamustine/rituximab [BR] that relapsed within 24 months, three-quarters of those had transformation. I’m sure we’ve had these anecdotes of folks. They got BR and all of a sudden we find out they have transformed disease. It’s clearly not as effective for treating progressive lymphoma. So if there’s any suspicion, high LDH, whatever, significant B-cell symptoms, we’d usually use R-CHOP.

Scott Huntington, MD, MPH, MSc: And you can certainly have reassurance that BR versus R-CHOP, they’re similar overall. I’m sure PFS [progression-free survival] is benefitting. So if there’s any suspicion for large-cell transformation, and the patient can tolerate anthracycline, I think it really is a no-brainer to give the R-CHOP in those patients.

Nathan H. Fowler, MD: So we have consensus.

Ajay K. Gopal, MD, FACP: There you go.

Ian W. Flinn, MD, PhD.: Now we’ve had rituximab since, what, ’97 I think, and it’s been around, the first antibody to be approved for cancer therapy. And just when you think you knew all about it, now we have this subcutaneous formulation of it. We’re using a lot in our practice. I think it’s very popular with patients. I think it’s been popular with the infusion nurses. It gets people out of their chairs. Nathan, what’s your experience?

Nathan H. Fowler, MD: So at The University of Texas MD Anderson Cancer Center we’ve not quite adopted it as quickly I think as some of the other folks around the United States. I would say probably somewhere within 10% to 20% of our patients are now using this subcutaneous rituximab. But the drug is clearly, as you mentioned, easier to give with regards to how long patients have to be in an infusion center. About 6 to 7 minutes is the average time. Patients do have to be watched for 15 minutes afterwards. I find at least in our practice a lot of the barriers to subcutaneous rituximab are logistical. You know, getting the order sets, getting the nurses trained, getting the patients trained about the differences in administration. But my sense is, and I’d love to hear your opinions, is that patients really getting a shorter end fusion and spending less time in the clinic.

Ajay K. Gopal, MD, FACP: I would concur with that. In general, I can only think of 1 patient who wanted to switch back and he had a bit of a local reaction. But most patients prefer it.

Ian W. Flinn, MD, PhD: Especially when it’s a single agent, right? Someone is coming in and getting just that, they’re in and out. I think that not only is it a convenience, maybe it’s psychological too that you’re not getting such an intensive therapy that you’re tied up to the IV [intravenous therapy].

Nathan H. Fowler, MD: There are lots of randomized trials now in CLL [chronic lymphocytic leukemia], large-cell follicular, that suggest that it’s very similar when given with the chemotherapy backbone. I do have some questions about how it will be used if we’re integrating anti-CD20s with novel therapy. I’m not sure if equivalence with the chemotherapy backbone means equivalence with lenalidomide, for example, or with a checkpoint or some other therapy. So I would like to see more trials combining the subcutaneous version with some of these other novel treatments before we would switch in all settings.

Ian W. Flinn, MD, PhD: Let’s switch and talk about a different antibody. Scott, let’s talk about obinutuzumab. So we know the GALLIUM data where obinutuzumab was combined with chemotherapy versus rituximab. And now we have some new data looking at minimal residual disease [MRD] and progression-free survival. Walk us through some of that.

Scott Huntington, MD, MPH, MSc: We had heard some preliminary data after a few years of follow-up that obinutuzumab chemotherapy backbone had an improvement of PFS over rituximab with chemotherapy; chemotherapy being CVP [cyclophosphamide/vincristine/prednisone], CHOP, or bendamustine.

On the updates at this year’s ASH [American Society of Hematology meeting], it seems like the PFS benefit is still there. Although it’s somewhat early, the overall survival is important to note that there was really no difference between the obinutuzumab containing arm and the rituximab containing arm.

In terms of other knowledge that’s being generated from GALLIUM, I think it’s been a very helpful study. They’ve looked at post-treatment PET/CT [computed tomography] and the fact that Lugano criteria of scoring those PET/CTs can be quite predictive and associated with prolonged remissions. I think there’s more data from that. There’s also data about MRD testing, which is coming out this year from GALLIUM where effectively the majority of patients, whether treated with R/chemo [rituximab/chemotherapy] or obinutuzumab/chemotherapy, are actually being MRD-negative at the end of induction.

What was really interesting is the majority of folks, that sliver of folks, that were still positive, maintenance typically got them over the edge and got them to MRD negativity. I think only 12 patients remained MRD-positive, and those patients did quite poorly after a short follow-up.

It’s also important to note that MRD seems to be equivalent in terms of what it means if you get R-CHOP or R/chemotherapy versus obinutuzumab/chemotherapy, in the sense that MRD-negative patients did just as well whether they had obinutuzumab versus the rituximab.

We’ll talk about MRD testing, but it’s certainly an interesting clinical trial question, probably not ready for prime time, but it’s nice to see that the GALLIUM data are really giving us a lot of encouraging data, and not only of PFS but also in some of the mechanistic and predictive populations.

Ian W. Flinn, MD, PhD: All right, I’m going to put you on the spot here and no one’s getting off this question easily. When are you using obinutuzumab versus rituximab?

Scott Huntington, MD, MPH, MSc: It’s a great question. If you actually look at the GALLIUM, who are these patients? These were younger, a little bit younger patients. Their median age was about 59. These patients also had high-volume disease and were quite sick at diagnosis. So the one thing that surprised me when I presented it last year was that the median time from diagnosis of follicular lymphoma to treatment was just 6 weeks. That’s not the typical patient that I’m seeing. I’m seeing patients and following them for years, and so I’ve selected obinutuzumab for those patients that are presenting with high volume, who might be younger, fit, and are symptomatic, and needing treatment right away. And in that situation I sometimes will choose obinutuzumab, often times CHOP backbone. I think the safety data might be a little bit more encouraging with obinutuzumab/CHOP versus say a bendamustine-based therapy.

Ian W. Flinn, MD, PhD: What about you guys?

Ajay K. Gopal, MD, FACP: I rarely use obinutuzumab. I’ll just admit that. I would say I’m a skeptic of that trial a bit. I’m a little concerned that the milligram dosing was quite a bit different and that might have driven things, and there was clearly more adverse events in the obinutuzumab arm. So when I sit down with my patient, with the rare exception of somebody that’s very sick, when we think about how do we relieve the symptoms that we’re treating for, why we’re treating, and think about the 20-year plan, I rarely pull obinutuzumab off the shelf.

Ian W. Flinn, MD, PhD: Nathan, thoughts?

Nathan H. Fowler, MD: It’s very interesting how Scott thinks about treating this. I have to admit, like Ajay, I generally don’t do this in the frontline. It’s my go-to in relapse disease, especially rituximab refractory. In the frontline I have not switched most of my patients. We have ongoing studies with lenalidomide and obinutuzumab, and there we’re seeing very interesting activity and again maybe due to the increased ADCC [antibody-dependent cellular cytotoxicity] when combined with lenalidomide. Despite even long-term follow-up of the early frontline trials, there is yet to be an overall survival advantage, which to me suggests that you could potentially use it in the second- or third-line setting and probably get to the same long-term endpoint, which is, hopefully that patients did well.

Transcript edited for clarity.
 

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Transcript:

Ian W. Flinn, MD, PhD:
You both alluded to another group of patients that you’re a little worried about, right? I mean you haven’t proven that they’re a Richter transformation, but sometimes it’s hard. The PET [positron emission tomography] scans, the SUVs [standardized uptake values] are a bit high, maybe their LDH [lactate dehydrogenase] is up, but you’re worried. Is that a group that you’re using R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] in?

Nathan H. Fowler, MD: Yes, absolutely.

Ajay K. Gopal, MD, FACP: I would agree. There was some interesting data from the BC [British Columbia] Cancer Agency at this meeting showing that for the patients that got bendamustine/rituximab [BR] that relapsed within 24 months, three-quarters of those had transformation. I’m sure we’ve had these anecdotes of folks. They got BR and all of a sudden we find out they have transformed disease. It’s clearly not as effective for treating progressive lymphoma. So if there’s any suspicion, high LDH, whatever, significant B-cell symptoms, we’d usually use R-CHOP.

Scott Huntington, MD, MPH, MSc: And you can certainly have reassurance that BR versus R-CHOP, they’re similar overall. I’m sure PFS [progression-free survival] is benefitting. So if there’s any suspicion for large-cell transformation, and the patient can tolerate anthracycline, I think it really is a no-brainer to give the R-CHOP in those patients.

Nathan H. Fowler, MD: So we have consensus.

Ajay K. Gopal, MD, FACP: There you go.

Ian W. Flinn, MD, PhD.: Now we’ve had rituximab since, what, ’97 I think, and it’s been around, the first antibody to be approved for cancer therapy. And just when you think you knew all about it, now we have this subcutaneous formulation of it. We’re using a lot in our practice. I think it’s very popular with patients. I think it’s been popular with the infusion nurses. It gets people out of their chairs. Nathan, what’s your experience?

Nathan H. Fowler, MD: So at The University of Texas MD Anderson Cancer Center we’ve not quite adopted it as quickly I think as some of the other folks around the United States. I would say probably somewhere within 10% to 20% of our patients are now using this subcutaneous rituximab. But the drug is clearly, as you mentioned, easier to give with regards to how long patients have to be in an infusion center. About 6 to 7 minutes is the average time. Patients do have to be watched for 15 minutes afterwards. I find at least in our practice a lot of the barriers to subcutaneous rituximab are logistical. You know, getting the order sets, getting the nurses trained, getting the patients trained about the differences in administration. But my sense is, and I’d love to hear your opinions, is that patients really getting a shorter end fusion and spending less time in the clinic.

Ajay K. Gopal, MD, FACP: I would concur with that. In general, I can only think of 1 patient who wanted to switch back and he had a bit of a local reaction. But most patients prefer it.

Ian W. Flinn, MD, PhD: Especially when it’s a single agent, right? Someone is coming in and getting just that, they’re in and out. I think that not only is it a convenience, maybe it’s psychological too that you’re not getting such an intensive therapy that you’re tied up to the IV [intravenous therapy].

Nathan H. Fowler, MD: There are lots of randomized trials now in CLL [chronic lymphocytic leukemia], large-cell follicular, that suggest that it’s very similar when given with the chemotherapy backbone. I do have some questions about how it will be used if we’re integrating anti-CD20s with novel therapy. I’m not sure if equivalence with the chemotherapy backbone means equivalence with lenalidomide, for example, or with a checkpoint or some other therapy. So I would like to see more trials combining the subcutaneous version with some of these other novel treatments before we would switch in all settings.

Ian W. Flinn, MD, PhD: Let’s switch and talk about a different antibody. Scott, let’s talk about obinutuzumab. So we know the GALLIUM data where obinutuzumab was combined with chemotherapy versus rituximab. And now we have some new data looking at minimal residual disease [MRD] and progression-free survival. Walk us through some of that.

Scott Huntington, MD, MPH, MSc: We had heard some preliminary data after a few years of follow-up that obinutuzumab chemotherapy backbone had an improvement of PFS over rituximab with chemotherapy; chemotherapy being CVP [cyclophosphamide/vincristine/prednisone], CHOP, or bendamustine.

On the updates at this year’s ASH [American Society of Hematology meeting], it seems like the PFS benefit is still there. Although it’s somewhat early, the overall survival is important to note that there was really no difference between the obinutuzumab containing arm and the rituximab containing arm.

In terms of other knowledge that’s being generated from GALLIUM, I think it’s been a very helpful study. They’ve looked at post-treatment PET/CT [computed tomography] and the fact that Lugano criteria of scoring those PET/CTs can be quite predictive and associated with prolonged remissions. I think there’s more data from that. There’s also data about MRD testing, which is coming out this year from GALLIUM where effectively the majority of patients, whether treated with R/chemo [rituximab/chemotherapy] or obinutuzumab/chemotherapy, are actually being MRD-negative at the end of induction.

What was really interesting is the majority of folks, that sliver of folks, that were still positive, maintenance typically got them over the edge and got them to MRD negativity. I think only 12 patients remained MRD-positive, and those patients did quite poorly after a short follow-up.

It’s also important to note that MRD seems to be equivalent in terms of what it means if you get R-CHOP or R/chemotherapy versus obinutuzumab/chemotherapy, in the sense that MRD-negative patients did just as well whether they had obinutuzumab versus the rituximab.

We’ll talk about MRD testing, but it’s certainly an interesting clinical trial question, probably not ready for prime time, but it’s nice to see that the GALLIUM data are really giving us a lot of encouraging data, and not only of PFS but also in some of the mechanistic and predictive populations.

Ian W. Flinn, MD, PhD: All right, I’m going to put you on the spot here and no one’s getting off this question easily. When are you using obinutuzumab versus rituximab?

Scott Huntington, MD, MPH, MSc: It’s a great question. If you actually look at the GALLIUM, who are these patients? These were younger, a little bit younger patients. Their median age was about 59. These patients also had high-volume disease and were quite sick at diagnosis. So the one thing that surprised me when I presented it last year was that the median time from diagnosis of follicular lymphoma to treatment was just 6 weeks. That’s not the typical patient that I’m seeing. I’m seeing patients and following them for years, and so I’ve selected obinutuzumab for those patients that are presenting with high volume, who might be younger, fit, and are symptomatic, and needing treatment right away. And in that situation I sometimes will choose obinutuzumab, often times CHOP backbone. I think the safety data might be a little bit more encouraging with obinutuzumab/CHOP versus say a bendamustine-based therapy.

Ian W. Flinn, MD, PhD: What about you guys?

Ajay K. Gopal, MD, FACP: I rarely use obinutuzumab. I’ll just admit that. I would say I’m a skeptic of that trial a bit. I’m a little concerned that the milligram dosing was quite a bit different and that might have driven things, and there was clearly more adverse events in the obinutuzumab arm. So when I sit down with my patient, with the rare exception of somebody that’s very sick, when we think about how do we relieve the symptoms that we’re treating for, why we’re treating, and think about the 20-year plan, I rarely pull obinutuzumab off the shelf.

Ian W. Flinn, MD, PhD: Nathan, thoughts?

Nathan H. Fowler, MD: It’s very interesting how Scott thinks about treating this. I have to admit, like Ajay, I generally don’t do this in the frontline. It’s my go-to in relapse disease, especially rituximab refractory. In the frontline I have not switched most of my patients. We have ongoing studies with lenalidomide and obinutuzumab, and there we’re seeing very interesting activity and again maybe due to the increased ADCC [antibody-dependent cellular cytotoxicity] when combined with lenalidomide. Despite even long-term follow-up of the early frontline trials, there is yet to be an overall survival advantage, which to me suggests that you could potentially use it in the second- or third-line setting and probably get to the same long-term endpoint, which is, hopefully that patients did well.

Transcript edited for clarity.
 
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