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Frontline Therapy in CLL: Combination Strategies and MRD

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew S. Davids, MD, MMSc, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute; Brad Kahl, MD, Washington University School of Medicine; John Pagel, MD, PhD, Swedish Cancer Institute
Published: Wednesday, Jul 31, 2019



Transcript: 

Ian W. Flinn, MD, PhD: We’re going to switch now and talk a little about ibrutinib combinations or BTK [Bruton tyrosine kinase] inhibitor combinations. We talked a little about CD20 combinations. You mentioned some data with obinutuzumab, the depth of the remission might be different. Can you elaborate on that at all? What’s your sense of that?

Matthew S. Davids, MD, MMSc: In terms of comparing rituximab and obinutuzumab, these are 2 very different antibodies. Obinutuzumab is a type II glycosylated CD20 antibody that can target CLL [chronic lymphocytic leukemia] cells directly and kill them. It doesn’t rely completely on antibody-dependent cytotoxicity, although it can certainly kill by that mechanism, too. One of the things that’s been seen with ibrutinib and rituximab is that there may actually be some antagonistic effects, because ibrutinib has a number of off-target effects, including inhibiting ITK [interleukin-2-inducible kinase], which can be important in natural killer cells and antibody-dependent cytotoxicity. I think we can’t assume that because ibrutinib and rituximab are not working better together than ibrutinib alone, that the same is going to be true for obinutuzumab combinations, including with ibrutinib. It’s going to be very interesting to see. Unfortunately, the iLLUMINATE study doesn’t help us there. There was no ibrutinib-only arm.

Ian W. Flinn, MD, PhD: It really wasn’t designed to answer that question.

Matthew S. Davids, MD, MMSc: Right.

Ian W. Flinn, MD, PhD: You saw the New England Journal of Medicine publication looking at the combination of ibrutinib and venetoclax recently. John, that data looked pretty exciting. We’re going to go through some of the different combinations. What do you think about that?

John Pagel, MD, PhD: I think the data are very exciting. Getting to a state of undetectable minimal residual disease [MRD], which you can get with these combinations—in particular, this combination of ibrutinib and venetoclax, BCL2 [B-cell lymphoma 2] inhibitor—is an important endpoint for not all patients, but a large number of patients, particularly because it leads us to the ability to stop therapy. One of the unappealing things for many patients who are taking oral targeted therapies is, as Brad’s alluded to, this long duration of treatment. Now of course, it’s doable. There are people who have been on ibrutinib for almost 10 years now and doing very well.

However, it leads us to this scenario that may be similar to what we’ve seen in CML [chronic myeloid leukemia]. Now, I’m not sure we’re ever going to be able to achieve those kinds of results with the targeted agents that we have in CML, but the idea of stopping treatment is very appealing. We do understand that if you’re MRD undetectable and can get there with a combination, whereas you can’t with a single agent for most settings, that likely leads to an ability to stop. We’ll have to see over some time if you can rechallenge patients and then get another subsequent remission or response, which I think you likely will in most patients, unless they have high-risk features.

I’m very excited about the combination therapies in the right patients. I say that specifically because I’m not sure you have to become MRD undetectable if you’re a patient who is, like you alluded to, an 80-year-old in a palliative situation. We’re not curing those people, and we’re trying to keep them happy, healthy, and out of the doctor’s office for as long as possible.

Ian W. Flinn, MD, PhD: Brad, what do you think about MRD-negativity and the different compartment effects we sometimes see with the CD20? Is that a valid endpoint today? Should we be doing something different if someone is MRD-positive or negative after the therapy?

Brad Kahl, MD: It’s a great question. There are a lot of unknowns there. Obviously, MRD is just another way to measure the depth of the response. An MRD-negative complete remission is presumably better than an MRD-positive complete remission. The big question is whether those sorts of measurements would allow us to give the therapy in a time-limited fashion. In other words, does it give us a rational stopping point for some of these indefinite therapies? There are a couple of very important ongoing trials, one of which can help answer this question.

There are many trials looking at this question, but I want to highlight the US Intergroup Alliance A041202 trial. Patients are randomized to the combination of ibrutinib and obinutuzumab versus ibrutinib/obinutuzumab plus venetoclax. It’s taking the 3 very best agents that we have in CLL, putting them up front, and adding the third agent for one of the arms. Then, patients will undergo an MRD assessment at some point in therapy, I believe at around a year. For patients who are MRD-negative, they then have a discontinuation strategy, whereas patients who are MRD-positive have a continuation strategy. For the MRD-negative patients, there’s actually a randomization to continuing or discontinuing. I think that trial, and trials like that, will be very helpful in sorting out how to use MRD to help determine duration of therapy.

Ian W. Flinn, MD, PhD: Yes, I think that is important. There are a number of trials looking at that discontinuation and whether you can stop therapy. It seems that most of those studies include venetoclax, right, Matt?

Matthew S. Davids, MD, MMSc: Right.

Ian W. Flinn, MD, PhD: It seems like it wasn’t really until we were adding venetoclax that we were getting to the level of undetectable minimal residual disease. You’ve done a lot of work with venetoclax. Your thoughts?

Matthew S. Davids, MD, MMSc: I think that the validity of the MRD endpoint really depends on the therapy. If you’re looking at ibrutinib as a monotherapy, it’s not really necessary or valid to look at MRD, because patients can be in a PR [partial remission] and do very well for many years on ibrutinib monotherapy. If you’re doing continuous therapy, you don’t need to worry about it, but if you’re doing time-limited therapy, that’s where I think it can be helpful, although this is still an unanswered question. We’re going to talk in more depth about some of the venetoclax combination data where they actually designed a time-limited regimen based on every patient getting the same duration of therapy—1 year in the frontline setting, 2 years in the relapsed/refractory setting.

We don’t know yet if that’s going to be feasible or whether we need to be measuring MRD, as Brad was saying, and then guiding therapy based on that. I think both strategies need to be explored in trials, and that will hopefully help settle the question. Clearly, when we’re using venetoclax-based therapies, we can get to these deep MRD undetectable responses, and I think that really provides an opportunity to discontinue therapy and hopefully have a good durability of remission after that. As John was saying, hopefully we’d be able to subsequently re-treat and get a response again.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: We’re going to switch now and talk a little about ibrutinib combinations or BTK [Bruton tyrosine kinase] inhibitor combinations. We talked a little about CD20 combinations. You mentioned some data with obinutuzumab, the depth of the remission might be different. Can you elaborate on that at all? What’s your sense of that?

Matthew S. Davids, MD, MMSc: In terms of comparing rituximab and obinutuzumab, these are 2 very different antibodies. Obinutuzumab is a type II glycosylated CD20 antibody that can target CLL [chronic lymphocytic leukemia] cells directly and kill them. It doesn’t rely completely on antibody-dependent cytotoxicity, although it can certainly kill by that mechanism, too. One of the things that’s been seen with ibrutinib and rituximab is that there may actually be some antagonistic effects, because ibrutinib has a number of off-target effects, including inhibiting ITK [interleukin-2-inducible kinase], which can be important in natural killer cells and antibody-dependent cytotoxicity. I think we can’t assume that because ibrutinib and rituximab are not working better together than ibrutinib alone, that the same is going to be true for obinutuzumab combinations, including with ibrutinib. It’s going to be very interesting to see. Unfortunately, the iLLUMINATE study doesn’t help us there. There was no ibrutinib-only arm.

Ian W. Flinn, MD, PhD: It really wasn’t designed to answer that question.

Matthew S. Davids, MD, MMSc: Right.

Ian W. Flinn, MD, PhD: You saw the New England Journal of Medicine publication looking at the combination of ibrutinib and venetoclax recently. John, that data looked pretty exciting. We’re going to go through some of the different combinations. What do you think about that?

John Pagel, MD, PhD: I think the data are very exciting. Getting to a state of undetectable minimal residual disease [MRD], which you can get with these combinations—in particular, this combination of ibrutinib and venetoclax, BCL2 [B-cell lymphoma 2] inhibitor—is an important endpoint for not all patients, but a large number of patients, particularly because it leads us to the ability to stop therapy. One of the unappealing things for many patients who are taking oral targeted therapies is, as Brad’s alluded to, this long duration of treatment. Now of course, it’s doable. There are people who have been on ibrutinib for almost 10 years now and doing very well.

However, it leads us to this scenario that may be similar to what we’ve seen in CML [chronic myeloid leukemia]. Now, I’m not sure we’re ever going to be able to achieve those kinds of results with the targeted agents that we have in CML, but the idea of stopping treatment is very appealing. We do understand that if you’re MRD undetectable and can get there with a combination, whereas you can’t with a single agent for most settings, that likely leads to an ability to stop. We’ll have to see over some time if you can rechallenge patients and then get another subsequent remission or response, which I think you likely will in most patients, unless they have high-risk features.

I’m very excited about the combination therapies in the right patients. I say that specifically because I’m not sure you have to become MRD undetectable if you’re a patient who is, like you alluded to, an 80-year-old in a palliative situation. We’re not curing those people, and we’re trying to keep them happy, healthy, and out of the doctor’s office for as long as possible.

Ian W. Flinn, MD, PhD: Brad, what do you think about MRD-negativity and the different compartment effects we sometimes see with the CD20? Is that a valid endpoint today? Should we be doing something different if someone is MRD-positive or negative after the therapy?

Brad Kahl, MD: It’s a great question. There are a lot of unknowns there. Obviously, MRD is just another way to measure the depth of the response. An MRD-negative complete remission is presumably better than an MRD-positive complete remission. The big question is whether those sorts of measurements would allow us to give the therapy in a time-limited fashion. In other words, does it give us a rational stopping point for some of these indefinite therapies? There are a couple of very important ongoing trials, one of which can help answer this question.

There are many trials looking at this question, but I want to highlight the US Intergroup Alliance A041202 trial. Patients are randomized to the combination of ibrutinib and obinutuzumab versus ibrutinib/obinutuzumab plus venetoclax. It’s taking the 3 very best agents that we have in CLL, putting them up front, and adding the third agent for one of the arms. Then, patients will undergo an MRD assessment at some point in therapy, I believe at around a year. For patients who are MRD-negative, they then have a discontinuation strategy, whereas patients who are MRD-positive have a continuation strategy. For the MRD-negative patients, there’s actually a randomization to continuing or discontinuing. I think that trial, and trials like that, will be very helpful in sorting out how to use MRD to help determine duration of therapy.

Ian W. Flinn, MD, PhD: Yes, I think that is important. There are a number of trials looking at that discontinuation and whether you can stop therapy. It seems that most of those studies include venetoclax, right, Matt?

Matthew S. Davids, MD, MMSc: Right.

Ian W. Flinn, MD, PhD: It seems like it wasn’t really until we were adding venetoclax that we were getting to the level of undetectable minimal residual disease. You’ve done a lot of work with venetoclax. Your thoughts?

Matthew S. Davids, MD, MMSc: I think that the validity of the MRD endpoint really depends on the therapy. If you’re looking at ibrutinib as a monotherapy, it’s not really necessary or valid to look at MRD, because patients can be in a PR [partial remission] and do very well for many years on ibrutinib monotherapy. If you’re doing continuous therapy, you don’t need to worry about it, but if you’re doing time-limited therapy, that’s where I think it can be helpful, although this is still an unanswered question. We’re going to talk in more depth about some of the venetoclax combination data where they actually designed a time-limited regimen based on every patient getting the same duration of therapy—1 year in the frontline setting, 2 years in the relapsed/refractory setting.

We don’t know yet if that’s going to be feasible or whether we need to be measuring MRD, as Brad was saying, and then guiding therapy based on that. I think both strategies need to be explored in trials, and that will hopefully help settle the question. Clearly, when we’re using venetoclax-based therapies, we can get to these deep MRD undetectable responses, and I think that really provides an opportunity to discontinue therapy and hopefully have a good durability of remission after that. As John was saying, hopefully we’d be able to subsequently re-treat and get a response again.

Transcript Edited for Clarity
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