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First-Line Therapy for Older Patients With 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: Friday, Jan 04, 2019



Transcript: 

William G. Wierda, MD, PhD:
There [have] been major shifts in treatment in the past 3 years for patients with chronic lymphocytic leukemia [CLL], including an abundance of development of new agents and combinations diminishing the role for chemoimmunotherapy. In this OncLive Peer ExchangeÒ discussion, I’m joined by a panel of experts in new treatments and treatment paradigms for patients with CLL. Together we will discuss the newest data from the ASH [American Society of Hematology] Annual Meeting [& Exposition], and we’ll provide a practical perspective on how novel therapeutic options and treatments are changing how we manage our patients with CLL.

I’m Dr William Wierda, [the] head of the CLL program and medical director at [The University of Texas] MD Anderson Cancer Center in the Department of Leukemia in Houston, Texas. Participating today in our discussion [are] a panel of esteemed colleagues. Dr Alexey [V.] Danilov, [an] associate professor of medicine [at] the Oregon Health & Science University School of Medicine in Portland, Oregon. Dr Matthew Davids, [the] associate director of the CLL program at the Dana-Farber Cancer Institute in Boston, Massachusetts. Dr Anthony Mato, [the] director of the CLL program at Memorial Sloan Kettering Cancer [Center] in New York City. And Dr Susan O’Brien, [the] associate director for clinical science for the Chao Family Comprehensive Cancer Center and [the] medical director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at the University of California, Irvine, in Orange County, California.

Thank you for joining us, and let’s begin.

So let’s start with some of the new trials that have been presented here. There have actually been 3 large phase III clinical trials presented in the frontline setting that I think are really practice changing. And they are small-molecule inhibitor-based therapies versus chemoimmunotherapy-based regimens. And so I think probably what we should do is sort of go through those and have a summary of them and what the key points are for each of them. So why don’t we start with the ILLUMINATE study, which is a study for older patients that was presented by Carol Marino. Susan, [maybe] you can start with a summary of that.

Susan M. O’Brien, MD: Sure. That was a randomized trial in patients over the age of 65 of chlorambucil and obinutuzumab versus ibrutinib and obinutuzumab. And I don’t think anybody is very surprised. We found out that the progression-free survival [PFS] was much better with ibrutinib, obinutuzumab than chlorambucil and obinutuzumab. Did we really need this study, given that we have the RESONATE-2 study comparing ibrutinib [with] chlorambucil? Well, we know chlorambucil with antibody is better than chlorambucil. We now that all chemos are, [with] CLL. But certainly I think you can tell from the RESONATE trial that adding antibody to chlorambucil was going to make that curve work like the ibrutinib curve. However, there was an interesting aspect of this trial, which I would say was the complete response rate. So we know the complete responses [CRs] are not very common with ibrutinib, but in this trial it was about 40%. So in this trial it does appear that the obinutuzumab is adding to the ibrutinib, at least in the response rate. That’s a very interesting point because, as we’re going to talk about, it doesn’t look like rituximab as much to the long-term outcomes with ibrutinib, and we’re going to get to that in the next trial. So is this because obinutuzumab is a more potent antibody? Will those CRs really translate into a major impact on the PFS, or will the long-term PFS look similar to ibrutinib alone? I think that remains to be seen.

William G. Wierda, MD, PhD: Practice changing?

Susan M. O’Brien, MD: No, I don’t think so.

William G. Wierda, MD, PhD: So your choice for an older patient who’s needing first-line therapy would be?

Susan M. O’Brien, MD: My choice would be ibrutinib.

William G. Wierda, MD, PhD: Ibrutinib.

Susan M. O’Brien, MD: Yes.

William G. Wierda, MD, PhD: All right. The next trial I think we should talk about, and then we’ll have a general discussion about these data, is the trial that was presented as a plenary session, the Alliance [A041202] trial, which was another randomized phase III trial with chemoimmunotherapy versus ibrutinib-based therapy. So I think, maybe Dr Danilov, will you sort of summarize the results of that?

Alexey V. Danilov, MD, PhD: So the Alliance [A041202] study presented by Jennifer Wick in the plenary session randomized patients to 3 arms. Ibrutinib alone, ibrutinib in combination with rituximab, or bendamustine [and] rituximab [BR], a standard chemotherapy regimen for older patients with CLL, all patients who were previously untreated over 65 years old. And again, unsurprisingly, this study demonstrated a benefit in progression-free survival to both experimental arms: ibrutinib or ibrutinib in combination with rituximab over bendamustine [and] rituximab.

Interestingly, there was no difference in PFS between ibrutinib and the ibrutinib and rituximab combination arms. And that sort of seconds what Jan Burger[, MD, PhD,] presented at [the] last ASH, where he also didn’t show any difference in PFS between those 2 arms, questioning whether adding a CD4 antibody like rituximab is helpful to patients who are already taking ibrutinib. However, the PFS benefit over BR was quite significant. Interestingly, there was no overall survival benefit to either of the arms and the curves completely overlapped over 32-month follow-up on the study.

Also, what we noticed is that…there were grade 5 toxicities on both experimental arms at 7.8%, 7.9%, compared [with] less than 3% on [the] bendamustine-rituximab arm. And [because] this study has already been published, there [were] some cardiac deaths and hemorrhage episodes on the ibrutinib arm. So this is certainly interesting. It does seem [as if] some patients may still be at high risk for toxicities with ibrutinib. But nevertheless, a very important study [that] again establishes the superior efficacy of ibrutinib in older patients with CLL over chemoimmunotherapy.

Susan M. O’Brien, MD: And I think some of the difference, in terms of…not seeing a difference in survival, could also be related to the fact that the patients who were randomized to not get ibrutinib up front could cross over to ibrutinib later. So that, I think, might [affect] the ability to see a survival difference.

William G. Wierda, MD, PhD: So my impression in speaking to physicians who are practicing in the community, the predominant chemo, or a predominant chemoimmunotherapy regimen, that we’re using is BR. And so, for you, [are] the results of this trial practice changing? Are you going to recommend ibrutinib over chemoimmunotherapies?

Alexey V. Danilov, MD, PhD: I think, for me, it will remain a discussion with the patient. There are certain, as Anthony’s latest data [have] shown, there is still a 20%, 30% rate of discontinuation of ibrutinib [caused by] adverse events. It was about 20% of this study. There are certain patients who, [because of] their comorbidities, may not be the best candidates for ibrutinib. We actually have published a paper. We have shown that high...comorbidities resulted in reduced progression-free survival and overall survival among patients with ibrutinib in the retrospective analysis. So I think it will, for me, remain a discussion [among] bendamustine, rituximab, and ibrutinib in those patients over 65 years old. Reviewing the risks and benefits of both regimens and understanding that now we have this data, that PFS is better with ibrutinib. And then it’s difficult to ignore the financial toxicity of the drug.

William G. Wierda, MD, PhD: So no difference in overall survival in this randomized study. Susan, do you want to just touch on overall survival?

Susan M. O’Brien, MD: Well, in the ILLUMINATE, the crossover was allowed also. So, and again, I’m actually surprised if we’re going to talk about another trial [in which] there was a difference. I’m actually surprised to see a difference in survival in frontline trials now, mainly because we have so many effective salvage regimens. So obviously ibrutinib is very effective in people who relapse after BR, and now have venetoclax, which is very effective even in patients failing chemo and failing ibrutinib. So I kind of think that, with time, it’s going to be much harder to see any real difference in survival in any frontline studies.


Transcript Edited for Clarity 
 

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Transcript: 

William G. Wierda, MD, PhD:
There [have] been major shifts in treatment in the past 3 years for patients with chronic lymphocytic leukemia [CLL], including an abundance of development of new agents and combinations diminishing the role for chemoimmunotherapy. In this OncLive Peer ExchangeÒ discussion, I’m joined by a panel of experts in new treatments and treatment paradigms for patients with CLL. Together we will discuss the newest data from the ASH [American Society of Hematology] Annual Meeting [& Exposition], and we’ll provide a practical perspective on how novel therapeutic options and treatments are changing how we manage our patients with CLL.

I’m Dr William Wierda, [the] head of the CLL program and medical director at [The University of Texas] MD Anderson Cancer Center in the Department of Leukemia in Houston, Texas. Participating today in our discussion [are] a panel of esteemed colleagues. Dr Alexey [V.] Danilov, [an] associate professor of medicine [at] the Oregon Health & Science University School of Medicine in Portland, Oregon. Dr Matthew Davids, [the] associate director of the CLL program at the Dana-Farber Cancer Institute in Boston, Massachusetts. Dr Anthony Mato, [the] director of the CLL program at Memorial Sloan Kettering Cancer [Center] in New York City. And Dr Susan O’Brien, [the] associate director for clinical science for the Chao Family Comprehensive Cancer Center and [the] medical director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at the University of California, Irvine, in Orange County, California.

Thank you for joining us, and let’s begin.

So let’s start with some of the new trials that have been presented here. There have actually been 3 large phase III clinical trials presented in the frontline setting that I think are really practice changing. And they are small-molecule inhibitor-based therapies versus chemoimmunotherapy-based regimens. And so I think probably what we should do is sort of go through those and have a summary of them and what the key points are for each of them. So why don’t we start with the ILLUMINATE study, which is a study for older patients that was presented by Carol Marino. Susan, [maybe] you can start with a summary of that.

Susan M. O’Brien, MD: Sure. That was a randomized trial in patients over the age of 65 of chlorambucil and obinutuzumab versus ibrutinib and obinutuzumab. And I don’t think anybody is very surprised. We found out that the progression-free survival [PFS] was much better with ibrutinib, obinutuzumab than chlorambucil and obinutuzumab. Did we really need this study, given that we have the RESONATE-2 study comparing ibrutinib [with] chlorambucil? Well, we know chlorambucil with antibody is better than chlorambucil. We now that all chemos are, [with] CLL. But certainly I think you can tell from the RESONATE trial that adding antibody to chlorambucil was going to make that curve work like the ibrutinib curve. However, there was an interesting aspect of this trial, which I would say was the complete response rate. So we know the complete responses [CRs] are not very common with ibrutinib, but in this trial it was about 40%. So in this trial it does appear that the obinutuzumab is adding to the ibrutinib, at least in the response rate. That’s a very interesting point because, as we’re going to talk about, it doesn’t look like rituximab as much to the long-term outcomes with ibrutinib, and we’re going to get to that in the next trial. So is this because obinutuzumab is a more potent antibody? Will those CRs really translate into a major impact on the PFS, or will the long-term PFS look similar to ibrutinib alone? I think that remains to be seen.

William G. Wierda, MD, PhD: Practice changing?

Susan M. O’Brien, MD: No, I don’t think so.

William G. Wierda, MD, PhD: So your choice for an older patient who’s needing first-line therapy would be?

Susan M. O’Brien, MD: My choice would be ibrutinib.

William G. Wierda, MD, PhD: Ibrutinib.

Susan M. O’Brien, MD: Yes.

William G. Wierda, MD, PhD: All right. The next trial I think we should talk about, and then we’ll have a general discussion about these data, is the trial that was presented as a plenary session, the Alliance [A041202] trial, which was another randomized phase III trial with chemoimmunotherapy versus ibrutinib-based therapy. So I think, maybe Dr Danilov, will you sort of summarize the results of that?

Alexey V. Danilov, MD, PhD: So the Alliance [A041202] study presented by Jennifer Wick in the plenary session randomized patients to 3 arms. Ibrutinib alone, ibrutinib in combination with rituximab, or bendamustine [and] rituximab [BR], a standard chemotherapy regimen for older patients with CLL, all patients who were previously untreated over 65 years old. And again, unsurprisingly, this study demonstrated a benefit in progression-free survival to both experimental arms: ibrutinib or ibrutinib in combination with rituximab over bendamustine [and] rituximab.

Interestingly, there was no difference in PFS between ibrutinib and the ibrutinib and rituximab combination arms. And that sort of seconds what Jan Burger[, MD, PhD,] presented at [the] last ASH, where he also didn’t show any difference in PFS between those 2 arms, questioning whether adding a CD4 antibody like rituximab is helpful to patients who are already taking ibrutinib. However, the PFS benefit over BR was quite significant. Interestingly, there was no overall survival benefit to either of the arms and the curves completely overlapped over 32-month follow-up on the study.

Also, what we noticed is that…there were grade 5 toxicities on both experimental arms at 7.8%, 7.9%, compared [with] less than 3% on [the] bendamustine-rituximab arm. And [because] this study has already been published, there [were] some cardiac deaths and hemorrhage episodes on the ibrutinib arm. So this is certainly interesting. It does seem [as if] some patients may still be at high risk for toxicities with ibrutinib. But nevertheless, a very important study [that] again establishes the superior efficacy of ibrutinib in older patients with CLL over chemoimmunotherapy.

Susan M. O’Brien, MD: And I think some of the difference, in terms of…not seeing a difference in survival, could also be related to the fact that the patients who were randomized to not get ibrutinib up front could cross over to ibrutinib later. So that, I think, might [affect] the ability to see a survival difference.

William G. Wierda, MD, PhD: So my impression in speaking to physicians who are practicing in the community, the predominant chemo, or a predominant chemoimmunotherapy regimen, that we’re using is BR. And so, for you, [are] the results of this trial practice changing? Are you going to recommend ibrutinib over chemoimmunotherapies?

Alexey V. Danilov, MD, PhD: I think, for me, it will remain a discussion with the patient. There are certain, as Anthony’s latest data [have] shown, there is still a 20%, 30% rate of discontinuation of ibrutinib [caused by] adverse events. It was about 20% of this study. There are certain patients who, [because of] their comorbidities, may not be the best candidates for ibrutinib. We actually have published a paper. We have shown that high...comorbidities resulted in reduced progression-free survival and overall survival among patients with ibrutinib in the retrospective analysis. So I think it will, for me, remain a discussion [among] bendamustine, rituximab, and ibrutinib in those patients over 65 years old. Reviewing the risks and benefits of both regimens and understanding that now we have this data, that PFS is better with ibrutinib. And then it’s difficult to ignore the financial toxicity of the drug.

William G. Wierda, MD, PhD: So no difference in overall survival in this randomized study. Susan, do you want to just touch on overall survival?

Susan M. O’Brien, MD: Well, in the ILLUMINATE, the crossover was allowed also. So, and again, I’m actually surprised if we’re going to talk about another trial [in which] there was a difference. I’m actually surprised to see a difference in survival in frontline trials now, mainly because we have so many effective salvage regimens. So obviously ibrutinib is very effective in people who relapse after BR, and now have venetoclax, which is very effective even in patients failing chemo and failing ibrutinib. So I kind of think that, with time, it’s going to be much harder to see any real difference in survival in any frontline studies.


Transcript Edited for Clarity 
 
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