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Take-Home Messages From ASH 2018 in CLL

Panelists: William G Wierda, MD, University of Texas MD Anderson Cancer Center; Alexey V Danilov, MD, PhD, University School of Medicine in Portland, Oregon; Matthew S Davids, MD, MMSc, Dana-Farber Cancer Institute; Anthony R Mato, MD, Memorial Sloan Kettering Cancer Center; Susan M. OBrien, MD The University of California, Irvine Medical Center
Published: Thursday, Feb 07, 2019



Transcript: 

William G. Wierda, MD, PhD: I think maybe we’ll summarize the meeting and you can all think about what the most important features were for you for this meeting. We can start with Susan, what her take-home thoughts are for the meeting and what were you excited about.

Susan M. O’Brien, MD: Obviously the big trials that compared chemotherapy to small molecule therapy were very interesting. I’m, as I already expressed, a little skeptical that they’re actually going to change a lot of what goes on right now for the reasons that we had previously discussed. What seems to be the most exciting to me is the combinations. I would agree that they’re early, and I’m basically talking ibrutinib and venetoclax. They are early. The MRD [minimal residual disease] negativity rates are high. People have brought up, well … I put some of the patients on the CAPTIVATE study, and 2 patients said to me, “Well, wait a minute, if you’re going to use both drugs at once, what are you going to do when I relapse?” So I think that’s an issue. I think our hope is that we have high MRD negativity rates, ability to stop therapy and if not cure, at least very prolonged remission, such that potentially … patients would still be sensitive to those drugs when they relapse.

But early times in the combination, so hard to know. But I think that we know very well from chemoimmunotherapy that MRD is one of the most important determinants of long-term outcome. I don’t really have any reason to believe it would be different with small molecules, albeit we have less data and certainly no long-term data. So I think any kind of tolerable combination that gives rise to high MRD negativity rates is very exciting.

William G. Wierda, MD, PhD: Alexey, what were you excited about?

Alexey V. Danilov, MD, PhD: I agree with Susan that certainly the big randomized studies were one of the big deal presentations of this ASH [American Society of Hematology meeting]. I was also excited about the follow-up of the MURANO study data, how you can discontinue therapy and still see good progression-free survival and time to next therapy. There were some early data here as well with venetoclax, presented by Danielle Brander [MD] that you can actually re-treat some of those patients with venetoclax. I think that does alleviate some of our fears of what we will use in relapse. So that was certainly exciting to me. I do look forward to the CLL14 full data which weren’t presented at this ASH, but hopefully we’ll see it maybe at ECOG [the Eastern Cooperative Oncology Group meeting] or maybe even sooner.

William G. Wierda, MD, PhD: Do you want to elaborate a little bit more on CLL14?

Alexey V. Danilov, MD, PhD: Yes, CLL14 is a study that looked at upfront use of venetoclax in combination with the Gazyva versus chlorambucil/Gazyva. So the study, Susan mentioned it, the first 14 patients were published, and now there was a press release that there was an improved progression-free survival if I’m not mistaken, but there are no data so far. So I would really look forward to this data because this is a registration trial, which again will shift the landscape of upfront therapy in CLL as we now will have that potential option. Eventually we’ll have that potential option. So a very exciting ASH for CLL. I would call it CLL ASH this year.

William G. Wierda, MD, PhD: Matt?

Matthew S. Davids, MD, MMSc: I fully agree with what’s been said. I think that we got these very valuable data sets for ibrutinib to kind of fill in some of the gaps. We have a lot more information now about younger patients receiving ibrutinib in the frontline setting. We know a lot more about comparing ibrutinib to a more standard chemoimmunotherapy regimen, BR [bendamustine/rituximab], that we’re using, whereas before we had the RESONATE-2 data comparing to chlorambucil. So we’ve really filled in some of those data gaps, and I think this point was raised by our esteemed colleague from Long Island at the late-breaking abstract session. [Kanti] Rai [MD] made the point that these large cooperative group studies really do still validate the importance of the cooperative groups in the United States and their ability to get these types of studies done. The cooperative groups are launching a couple of new studies that are going to look at combinations with novel agents. And so hopefully they’ll also be able to do a nice job accruing these trials to answer some of the questions that have been raised about whether these novel combinations are needed as doublets or triplets and what the duration of therapy should be.

A couple of other points. One of the aha moments for me was actually in the CLARITY presentation. This is Peter Hillmen [MB ChB]’s trial from the United Kingdom, looking at ibrutinib and venetoclax for relapsed patients. And they put up the progression-free and overall survival curves, which really looked quite astounding, very few progression events with some follow-up now. I think it suggests there may be some durability to this type of approach. And I think that as we move forward into the future in CLL, I think it’s going to be different approaches for different therapies.

As Anthony mentioned earlier for older, frailer patients, perhaps a sequential single-agent approach may make sense. But for those younger patients, particularly those who have high-risk features, I think combination approaches, which Susan mentioned. You get to time limited therapy, you have a treatment-free interval, and then you can potentially even re-treat with the same drugs. And you’re not going to have the same kind of cumulative toxicities that we see with chemoimmunotherapy when we reuse it. So I think it’s a very exciting time for CLL.


Transcript Edited for Clarity
 

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Transcript: 

William G. Wierda, MD, PhD: I think maybe we’ll summarize the meeting and you can all think about what the most important features were for you for this meeting. We can start with Susan, what her take-home thoughts are for the meeting and what were you excited about.

Susan M. O’Brien, MD: Obviously the big trials that compared chemotherapy to small molecule therapy were very interesting. I’m, as I already expressed, a little skeptical that they’re actually going to change a lot of what goes on right now for the reasons that we had previously discussed. What seems to be the most exciting to me is the combinations. I would agree that they’re early, and I’m basically talking ibrutinib and venetoclax. They are early. The MRD [minimal residual disease] negativity rates are high. People have brought up, well … I put some of the patients on the CAPTIVATE study, and 2 patients said to me, “Well, wait a minute, if you’re going to use both drugs at once, what are you going to do when I relapse?” So I think that’s an issue. I think our hope is that we have high MRD negativity rates, ability to stop therapy and if not cure, at least very prolonged remission, such that potentially … patients would still be sensitive to those drugs when they relapse.

But early times in the combination, so hard to know. But I think that we know very well from chemoimmunotherapy that MRD is one of the most important determinants of long-term outcome. I don’t really have any reason to believe it would be different with small molecules, albeit we have less data and certainly no long-term data. So I think any kind of tolerable combination that gives rise to high MRD negativity rates is very exciting.

William G. Wierda, MD, PhD: Alexey, what were you excited about?

Alexey V. Danilov, MD, PhD: I agree with Susan that certainly the big randomized studies were one of the big deal presentations of this ASH [American Society of Hematology meeting]. I was also excited about the follow-up of the MURANO study data, how you can discontinue therapy and still see good progression-free survival and time to next therapy. There were some early data here as well with venetoclax, presented by Danielle Brander [MD] that you can actually re-treat some of those patients with venetoclax. I think that does alleviate some of our fears of what we will use in relapse. So that was certainly exciting to me. I do look forward to the CLL14 full data which weren’t presented at this ASH, but hopefully we’ll see it maybe at ECOG [the Eastern Cooperative Oncology Group meeting] or maybe even sooner.

William G. Wierda, MD, PhD: Do you want to elaborate a little bit more on CLL14?

Alexey V. Danilov, MD, PhD: Yes, CLL14 is a study that looked at upfront use of venetoclax in combination with the Gazyva versus chlorambucil/Gazyva. So the study, Susan mentioned it, the first 14 patients were published, and now there was a press release that there was an improved progression-free survival if I’m not mistaken, but there are no data so far. So I would really look forward to this data because this is a registration trial, which again will shift the landscape of upfront therapy in CLL as we now will have that potential option. Eventually we’ll have that potential option. So a very exciting ASH for CLL. I would call it CLL ASH this year.

William G. Wierda, MD, PhD: Matt?

Matthew S. Davids, MD, MMSc: I fully agree with what’s been said. I think that we got these very valuable data sets for ibrutinib to kind of fill in some of the gaps. We have a lot more information now about younger patients receiving ibrutinib in the frontline setting. We know a lot more about comparing ibrutinib to a more standard chemoimmunotherapy regimen, BR [bendamustine/rituximab], that we’re using, whereas before we had the RESONATE-2 data comparing to chlorambucil. So we’ve really filled in some of those data gaps, and I think this point was raised by our esteemed colleague from Long Island at the late-breaking abstract session. [Kanti] Rai [MD] made the point that these large cooperative group studies really do still validate the importance of the cooperative groups in the United States and their ability to get these types of studies done. The cooperative groups are launching a couple of new studies that are going to look at combinations with novel agents. And so hopefully they’ll also be able to do a nice job accruing these trials to answer some of the questions that have been raised about whether these novel combinations are needed as doublets or triplets and what the duration of therapy should be.

A couple of other points. One of the aha moments for me was actually in the CLARITY presentation. This is Peter Hillmen [MB ChB]’s trial from the United Kingdom, looking at ibrutinib and venetoclax for relapsed patients. And they put up the progression-free and overall survival curves, which really looked quite astounding, very few progression events with some follow-up now. I think it suggests there may be some durability to this type of approach. And I think that as we move forward into the future in CLL, I think it’s going to be different approaches for different therapies.

As Anthony mentioned earlier for older, frailer patients, perhaps a sequential single-agent approach may make sense. But for those younger patients, particularly those who have high-risk features, I think combination approaches, which Susan mentioned. You get to time limited therapy, you have a treatment-free interval, and then you can potentially even re-treat with the same drugs. And you’re not going to have the same kind of cumulative toxicities that we see with chemoimmunotherapy when we reuse it. So I think it’s a very exciting time for CLL.


Transcript Edited for Clarity
 
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