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Maintenance and Frontline Therapy in CLL

Panelists: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center; Steven Coutre, MD, Stanford University Medical Center; Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute; Nicole Lamanna, MD, Columbia University Medical Center; Shuo Ma, MD, PhD, Robert H. Lurie Comprehensive Cancer Center
Published: Friday, Feb 02, 2018



Transcript: 

William G. Wierda, MD, PhD: We use maintenance therapy for other B-cell malignancies. Maybe, Nicole, you can comment on that just briefly because we’re going to move into the relapsed setting. Is there value to maintenance strategies? What has been tested for maintenance in CLL?

Nicole Lamanna, MD: Yes. We haven’t done this as much in CLL as we’ve done in the non-Hodgkin’s lymphomas, such as follicular lymphoma, settings. There have been some studies looking at maintenance both with lenalidomide and also rituximab. And certainly, there’s no doubt that when you continue additional agents as maintenance, depending upon the response after the therapy they might have gotten as their initial therapy, there can be an increase in response and efficacy. But the question always comes up with how long the duration should be. Are there increased side effects of long-term maintenance depending upon the drug? Lenalidomide, for example, can give some cytopenias and so on and so forth.

So, how do you grapple with some of the potential toxicities? Probably most frequently, if it’s done, it’s done with an antibody in practice, and I think we do see this a lot in the community where a lot of physicians are doing something similar to what they’re doing for their non-Hodgkin’s lymphoma patients. So, their follicular lymphoma patients. They are giving rituximab as a maintenance for some of the CLL patients, so we do see it. But do we have really great data or a lot of data? No we do not. So, I think it’s something we can consider doing. I guess it depends on how you look at these monotherapy approaches with the TKIs, if we’re going to continue them indefinitely or not as maintenance, if you want to consider it that way. But I think this is one area that we just need to delve into more in detail. And certainly, if you’re going to truncate therapy to begin with, or reinitiate therapy when patients are MRD-positive, do you need that? I think that it’s just an area that we have a lot more digging to do.

Steven Coutre, MD: If we’re talking about maintenance with ofatumumab or lenalidomide or rituximab, regardless of what the trial showed with ofatumumab, I strongly discourage it. We’re in a new era. That was post-chemoimmunotherapy. We have much better drugs. I would not do that.

Matthew S. Davids, MD, MMSc: And also, those studies were typically in patients who had been relapsing on a second-line chemotherapy. Those are patients we’d be targeting novel agents more now.

Nicole Lamanna, MD: Yes, so it’s just not done.

Shuo Ma, MD, PhD: Before we move on to the relapsed setting, I think maybe we can discuss the ultimate question for frontline: Ibrutinib versus chemoimmunotherapy, which is a better starting point? We always get this question from our colleagues and also from our patients. So I know there are a number of ongoing randomized studies. So, really the answer would come out from those randomized control trials to compare ibrutinib-based therapy, either alone or in combination with anti-CD20 antibody, against your standard immunochemotherapy. So I just want to point out a couple of them.

The ECOG 1912 study is for younger patients and compares ibrutinib/rituximab versus FCR. The ALLIANCE study is for older patients that’s comparing ibrutinib alone versus combination with rituximab versus BR. And then, there are a number of studies in Europe ongoing. I think the CLL13 study from the German study groups is comparing a number of novel combinations including ibrutinib with venetoclax-based combinations, novel therapies, versus your standard FCRBR. And there is a UK study. So, there are really a number of randomized studies ongoing.

But in this ASH, there is one abstract that’s very interesting. Dr. Roback did a retrospective analysis. He was pulling data from several really large randomized trials, including the CLL8 and CLL10, to get patients treated with FCR to patients treated with BR. He also pulled data from CLL11 for patients who were treated with obinutuzumab/chlorambucil versus R-chlorambucil or chlorambucil alone. And then, there are also data from the RESONATE-2 study to study the ibrutinib arm.

He was going to put all of the immunochemotherapy patients together and look at those patients versus patients who were treated with ibrutinib as a frontline therapy. So, based on his pulled analysis, it looks like patients who were treated with ibrutinib appeared to have a longer progression-free survival.

In addition to that, for elderly patients and frail patients, those patients also seemed to have improved overall survival compared to immunochemotherapy. And from a toxicity point of view, despite a much longer drug exposure time with ibrutinib compared to immunochemotherapy, the toxicity profile is also very favorable with the ibrutinib-treated patients. So, that’s definitely generating very interesting signals that I think the ultimate answer will come from the randomized clinical trials.

William G. Wierda, MD, PhD: I agree.

Transcript Edited for Clarity 

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Transcript: 

William G. Wierda, MD, PhD: We use maintenance therapy for other B-cell malignancies. Maybe, Nicole, you can comment on that just briefly because we’re going to move into the relapsed setting. Is there value to maintenance strategies? What has been tested for maintenance in CLL?

Nicole Lamanna, MD: Yes. We haven’t done this as much in CLL as we’ve done in the non-Hodgkin’s lymphomas, such as follicular lymphoma, settings. There have been some studies looking at maintenance both with lenalidomide and also rituximab. And certainly, there’s no doubt that when you continue additional agents as maintenance, depending upon the response after the therapy they might have gotten as their initial therapy, there can be an increase in response and efficacy. But the question always comes up with how long the duration should be. Are there increased side effects of long-term maintenance depending upon the drug? Lenalidomide, for example, can give some cytopenias and so on and so forth.

So, how do you grapple with some of the potential toxicities? Probably most frequently, if it’s done, it’s done with an antibody in practice, and I think we do see this a lot in the community where a lot of physicians are doing something similar to what they’re doing for their non-Hodgkin’s lymphoma patients. So, their follicular lymphoma patients. They are giving rituximab as a maintenance for some of the CLL patients, so we do see it. But do we have really great data or a lot of data? No we do not. So, I think it’s something we can consider doing. I guess it depends on how you look at these monotherapy approaches with the TKIs, if we’re going to continue them indefinitely or not as maintenance, if you want to consider it that way. But I think this is one area that we just need to delve into more in detail. And certainly, if you’re going to truncate therapy to begin with, or reinitiate therapy when patients are MRD-positive, do you need that? I think that it’s just an area that we have a lot more digging to do.

Steven Coutre, MD: If we’re talking about maintenance with ofatumumab or lenalidomide or rituximab, regardless of what the trial showed with ofatumumab, I strongly discourage it. We’re in a new era. That was post-chemoimmunotherapy. We have much better drugs. I would not do that.

Matthew S. Davids, MD, MMSc: And also, those studies were typically in patients who had been relapsing on a second-line chemotherapy. Those are patients we’d be targeting novel agents more now.

Nicole Lamanna, MD: Yes, so it’s just not done.

Shuo Ma, MD, PhD: Before we move on to the relapsed setting, I think maybe we can discuss the ultimate question for frontline: Ibrutinib versus chemoimmunotherapy, which is a better starting point? We always get this question from our colleagues and also from our patients. So I know there are a number of ongoing randomized studies. So, really the answer would come out from those randomized control trials to compare ibrutinib-based therapy, either alone or in combination with anti-CD20 antibody, against your standard immunochemotherapy. So I just want to point out a couple of them.

The ECOG 1912 study is for younger patients and compares ibrutinib/rituximab versus FCR. The ALLIANCE study is for older patients that’s comparing ibrutinib alone versus combination with rituximab versus BR. And then, there are a number of studies in Europe ongoing. I think the CLL13 study from the German study groups is comparing a number of novel combinations including ibrutinib with venetoclax-based combinations, novel therapies, versus your standard FCRBR. And there is a UK study. So, there are really a number of randomized studies ongoing.

But in this ASH, there is one abstract that’s very interesting. Dr. Roback did a retrospective analysis. He was pulling data from several really large randomized trials, including the CLL8 and CLL10, to get patients treated with FCR to patients treated with BR. He also pulled data from CLL11 for patients who were treated with obinutuzumab/chlorambucil versus R-chlorambucil or chlorambucil alone. And then, there are also data from the RESONATE-2 study to study the ibrutinib arm.

He was going to put all of the immunochemotherapy patients together and look at those patients versus patients who were treated with ibrutinib as a frontline therapy. So, based on his pulled analysis, it looks like patients who were treated with ibrutinib appeared to have a longer progression-free survival.

In addition to that, for elderly patients and frail patients, those patients also seemed to have improved overall survival compared to immunochemotherapy. And from a toxicity point of view, despite a much longer drug exposure time with ibrutinib compared to immunochemotherapy, the toxicity profile is also very favorable with the ibrutinib-treated patients. So, that’s definitely generating very interesting signals that I think the ultimate answer will come from the randomized clinical trials.

William G. Wierda, MD, PhD: I agree.

Transcript Edited for Clarity 
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