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Predicting and Analyzing Response in 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, Jan 17, 2018



Transcript: 

Ian W. Flinn, MD, PhD: I want to change the discussion a little bit and talk about MRD testing. We know in chronic lymphocytic leukemia, this has become very important. The depth of remission as measured by MRD has become an important endpoint principally in studies, but I think soon it will make it into the clinic. Peter, do you have any thoughts about MRD testing in lymphoma once it’s ready for the clinic? Should I be doing this every day in my patients?

Peter Martin, MD, MS: I think it’s a great thing to include in prospective clinical trials. Beyond that, I don’t know. In CLL, there’s potentially a role. In mantle-cell lymphoma, we’re moving there, as in DLBCL (diffuse large B-cell lymphoma). You could argue that there may soon be a role for surveillance in follicular lymphoma. I’m still not sure where we would use that.

Ian W. Flinn, MD, PhD: It’s technically hard to do, right?

Peter Martin, MD, MS: Sure. There are a lot of different potential assays. Some of them have advantages over others. That’s another great point. We still have to figure out which is the right assay to do it with. Is it one that’s more expensive? Is it one that’s easier to do and more rapid?

Grzegorz S. Nowakowski, MD: It definitely should be studied though. Particularly, we were just discussing the role of maintenance therapy. If we could, for example, define the patients who would benefit from maintenance therapy based on MRD, this would be a great tool. But they’re all just technical challenges, and it will require prospective studies that will actually take a long time to produce results as well.

Ian W. Flinn, MD, PhD: We talked a little bit about PET scans earlier, but do you think PET scans are a close surrogate for any of this?

Grzegorz S. Nowakowski, MD: A positive PET scan at the end of therapy in follicular lymphoma is a very prognostic factor. But here, similar to MRD data, what do we do with these results? Will the intensification of therapy after actually improve the outcome of those patients? This remains to be established, and that’s why we need to start addressing those patients as well.

Ian W. Flinn, MD, PhD: We now have this new endpoint in predicting patients who perhaps have a worse survival, with the patients who are early progressors at 24 months. Peter, how are you using this? Are you changing how you approach those patients when they do relapse? Does it affect therapy choices?

Peter Martin, MD, MS: You’re referring to the data from the LymphoCare Study published by Carla Casulo and colleagues showing that people who progress within the first 2 years after rituximab plus chemotherapy have a survival that’s significantly worse than patients who don’t progress within the first 2 years. And so, I think the benefit of that study is that it gave us the words to discuss something that everybody already knew. Somebody who’s progressing quickly after a good treatment isn’t going to have a great outcome, but now they’ve given us something that we can study.

I think the other way we can use this is that it allows us to have an open and upfront discussion with our patient. If I see a patient who has been treated very well with rituximab/chemotherapy right now, maybe obinutuzumab/chemotherapy, who has progressed very quickly, it’s a discussion that says your outcomes may not be the same as other people’s outcomes with follicular lymphoma. I’m not necessarily sure how we’re going to change that, but we need to talk about potentially looking at options that might be different than otherwise, whether those are novel therapies, whether that’s more intensive therapy, or whether that’s transplant or in the future, CAR-T cells. I think these are all questions that remain to be answered. But this POD24 endpoint is something that’s being reproduced across multiple studies, and it’s clearly a valid endpoint.

Ian W. Flinn, MD, PhD: Greg, do you wait for your next therapy? When somebody progresses after their first-line therapy, do you use the same criteria that you begin with? Loretta discussed the GELF criteria. Are you using that same criteria? And what about if someone relapses really shortly after, does that change how you approach it?

Grzegorz S. Nowakowski, MD: I think the point that you brought up is very important. So, if you see somebody relapsing right away, early after chemoimmunotherapy, and relapsing rapidly with rapid progression of the disease, I’d be more inclined to treat those patients even if they do not meet the GELF criteria. On the other hand, some patients could be relapsing years after the initial therapy with a relatively low pace of relapse, changing slowly from scan to scan. I believe that those patients can be observed initially until they get more bulky disease or symptomatic disease, which would require treatment. I just go back to what Peter said about counseling the patients about early relapse. The opposite view to this is that you can actually counsel the patients who are past 2 years that their outcome is excellent. It is actually very rewarding when I see those patients to say, “Well, you’re now more than 2 years out of your chemoimmunotherapy, and our data indicate that in all likelihood, your expected outcome is excellent.”

Anas Younes, MD: Can I add one more thing to the POD24/PFS24? I think all these were based on CT-based staging. When we looked at our own database, more than 1000 patients treated in one center where many patients got PET staging up front, we did not confirm this. We confirmed the CT-based POD24 or PFS24 is still prognostically significant, predicts a worse outcome. But if you use a PET scan, this prognostic value is actually diminished significantly. And the reason for this is because you are now identifying the early transformers when you use a PET scan. You take them out of the bucket and you treat them differently. So, I think we need to be cautious about jumping the gun for patients who progress within 24 months and offering them more intensive and toxic therapy outside of the clinical trials. If there’s a clinical trial where you want to test this hypothesis that if I intensify therapy, it may change the outcome, I think perfectly fine. But I don’t think it is standard of care now to offer patients autologous transplant outside a clinical trial for early progressors unless this is confirmed.

Grzegorz S. Nowakowski, MD: I agree. That brings up another issue also of importance, the biopsy at relapse.

Loretta J. Nastoupil, MD: Correct.

Grzegorz S. Nowakowski, MD: It’s really critical to actually repeat the biopsy in those patients to see if there is occurrence of transformation or if they’re relapsing with low-grade disease.

Ian W. Flinn, MD, PhD: How are you picking what lymph node to biopsy?

Grzegorz S. Nowakowski, MD: That’s a very difficult issue, but a PET scan is somewhat helpful in guiding it. Typically, we would try to pick up the area that is pretty hot on the PET scan, and I always prefer to use excisional biopsies to needle biopsies as much as we can. Obviously, it’s not always feasible clinically.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: I want to change the discussion a little bit and talk about MRD testing. We know in chronic lymphocytic leukemia, this has become very important. The depth of remission as measured by MRD has become an important endpoint principally in studies, but I think soon it will make it into the clinic. Peter, do you have any thoughts about MRD testing in lymphoma once it’s ready for the clinic? Should I be doing this every day in my patients?

Peter Martin, MD, MS: I think it’s a great thing to include in prospective clinical trials. Beyond that, I don’t know. In CLL, there’s potentially a role. In mantle-cell lymphoma, we’re moving there, as in DLBCL (diffuse large B-cell lymphoma). You could argue that there may soon be a role for surveillance in follicular lymphoma. I’m still not sure where we would use that.

Ian W. Flinn, MD, PhD: It’s technically hard to do, right?

Peter Martin, MD, MS: Sure. There are a lot of different potential assays. Some of them have advantages over others. That’s another great point. We still have to figure out which is the right assay to do it with. Is it one that’s more expensive? Is it one that’s easier to do and more rapid?

Grzegorz S. Nowakowski, MD: It definitely should be studied though. Particularly, we were just discussing the role of maintenance therapy. If we could, for example, define the patients who would benefit from maintenance therapy based on MRD, this would be a great tool. But they’re all just technical challenges, and it will require prospective studies that will actually take a long time to produce results as well.

Ian W. Flinn, MD, PhD: We talked a little bit about PET scans earlier, but do you think PET scans are a close surrogate for any of this?

Grzegorz S. Nowakowski, MD: A positive PET scan at the end of therapy in follicular lymphoma is a very prognostic factor. But here, similar to MRD data, what do we do with these results? Will the intensification of therapy after actually improve the outcome of those patients? This remains to be established, and that’s why we need to start addressing those patients as well.

Ian W. Flinn, MD, PhD: We now have this new endpoint in predicting patients who perhaps have a worse survival, with the patients who are early progressors at 24 months. Peter, how are you using this? Are you changing how you approach those patients when they do relapse? Does it affect therapy choices?

Peter Martin, MD, MS: You’re referring to the data from the LymphoCare Study published by Carla Casulo and colleagues showing that people who progress within the first 2 years after rituximab plus chemotherapy have a survival that’s significantly worse than patients who don’t progress within the first 2 years. And so, I think the benefit of that study is that it gave us the words to discuss something that everybody already knew. Somebody who’s progressing quickly after a good treatment isn’t going to have a great outcome, but now they’ve given us something that we can study.

I think the other way we can use this is that it allows us to have an open and upfront discussion with our patient. If I see a patient who has been treated very well with rituximab/chemotherapy right now, maybe obinutuzumab/chemotherapy, who has progressed very quickly, it’s a discussion that says your outcomes may not be the same as other people’s outcomes with follicular lymphoma. I’m not necessarily sure how we’re going to change that, but we need to talk about potentially looking at options that might be different than otherwise, whether those are novel therapies, whether that’s more intensive therapy, or whether that’s transplant or in the future, CAR-T cells. I think these are all questions that remain to be answered. But this POD24 endpoint is something that’s being reproduced across multiple studies, and it’s clearly a valid endpoint.

Ian W. Flinn, MD, PhD: Greg, do you wait for your next therapy? When somebody progresses after their first-line therapy, do you use the same criteria that you begin with? Loretta discussed the GELF criteria. Are you using that same criteria? And what about if someone relapses really shortly after, does that change how you approach it?

Grzegorz S. Nowakowski, MD: I think the point that you brought up is very important. So, if you see somebody relapsing right away, early after chemoimmunotherapy, and relapsing rapidly with rapid progression of the disease, I’d be more inclined to treat those patients even if they do not meet the GELF criteria. On the other hand, some patients could be relapsing years after the initial therapy with a relatively low pace of relapse, changing slowly from scan to scan. I believe that those patients can be observed initially until they get more bulky disease or symptomatic disease, which would require treatment. I just go back to what Peter said about counseling the patients about early relapse. The opposite view to this is that you can actually counsel the patients who are past 2 years that their outcome is excellent. It is actually very rewarding when I see those patients to say, “Well, you’re now more than 2 years out of your chemoimmunotherapy, and our data indicate that in all likelihood, your expected outcome is excellent.”

Anas Younes, MD: Can I add one more thing to the POD24/PFS24? I think all these were based on CT-based staging. When we looked at our own database, more than 1000 patients treated in one center where many patients got PET staging up front, we did not confirm this. We confirmed the CT-based POD24 or PFS24 is still prognostically significant, predicts a worse outcome. But if you use a PET scan, this prognostic value is actually diminished significantly. And the reason for this is because you are now identifying the early transformers when you use a PET scan. You take them out of the bucket and you treat them differently. So, I think we need to be cautious about jumping the gun for patients who progress within 24 months and offering them more intensive and toxic therapy outside of the clinical trials. If there’s a clinical trial where you want to test this hypothesis that if I intensify therapy, it may change the outcome, I think perfectly fine. But I don’t think it is standard of care now to offer patients autologous transplant outside a clinical trial for early progressors unless this is confirmed.

Grzegorz S. Nowakowski, MD: I agree. That brings up another issue also of importance, the biopsy at relapse.

Loretta J. Nastoupil, MD: Correct.

Grzegorz S. Nowakowski, MD: It’s really critical to actually repeat the biopsy in those patients to see if there is occurrence of transformation or if they’re relapsing with low-grade disease.

Ian W. Flinn, MD, PhD: How are you picking what lymph node to biopsy?

Grzegorz S. Nowakowski, MD: That’s a very difficult issue, but a PET scan is somewhat helpful in guiding it. Typically, we would try to pick up the area that is pretty hot on the PET scan, and I always prefer to use excisional biopsies to needle biopsies as much as we can. Obviously, it’s not always feasible clinically.

Transcript Edited for Clarity 
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