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Ibrutinib in Relapsed Mantle Cell Lymphoma

Panelists: Alexey V. Danilov, MD, PhD, Oregon Health & Science University; Andre Goy, MD, Hackensack University Medical Center; John P. Leonard, MD, New York-Presbyterian/Weill Cornell Medical Center; John M. Pagel, MD, PhD, DSc, Swedish Medical Center Seattle and Issaquah; Stephen J. Schuster, MD, The University of Pennsylvania
Published: Friday, Jan 26, 2018



Transcript: 

John P. Leonard, MD: It sounds like a fair number of patients get ibrutinib in the relapsed setting, obviously. The question surrounding early data after ibrutinib and progression after ibrutinib was that people did quite poorly. Was it that the patients, at that point, had horrible disease and did poorly because they had few other options? Or did the post-ibrutinib patient somehow have a different disease that was less favorable? That made many people pause about rushing to use ibrutinib as second-line therapy. But we now have some data that Steve alluded to. Alexey, Simon Rule presented updated data with ibrutinib that really suggested that people who were getting it as second-line therapy did pretty well with it. This provided some reassurance in that regard. What are your thoughts?

Alexey V. Danilov, MD, PhD: In the original publication, there was a progression-free survival of 13 months. This was very good for a single agent, I would say, for the relapsed/refractory disease patient who has seen a median of 3 prior therapies. So, we are talking about fairly aggressive disease there. However, as you noted, John, following ibrutinib discontinuation for progression, the overall survival was 2.9 months. It didn’t make it to 3 months. And even in those patients who received therapy, their survival was under 6 months. Most patients who progressed on ibrutinib did so, actually, within the first 6 months.

So now, these data from the same study talk about whether the line of therapy matters. It does. Patients who had 1 line of therapy had a longer PFS. Whether you achieve a complete response or not also matters. So, actually, patients who went into complete response–and that was over 20% of the patients on that study–enjoyed a progression-free survival of several years, 40-months plus. I think there’s actually very interesting, very promising data for a single agent in this bad disease. I want to mention that in terms of ibrutinib, molecular abnormalities in relapsed mantle cell lymphoma are very important, such as acquisition of deletion 17p, or TP53 molecular aberrations. Do any of you use ibrutinib sooner, say, if you see underwhelming response to chemotherapy and find TP53 aberrations a month later? Would you switch to ibrutinib at that point?

Andre Goy, MD: I just want to make a point about the relapsed setting. I would tend to re-biopsy this patient. In terms of treatment, we have seen the progress from bortezomib/lenalidomide to ibrutinib. There is a much higher complete response rate, and very impressive response rates as well. But when you look at it, the median overall survival, as a single agent, is roughly in the same range of 24 months. So, we’re not saving anyone completely with the single agent. It’s great to have these trials, but I think what’s important is to try to build out the combination studies. We had a small presentation, similar to the trial that was presented last year at the ASH Annual Meeting from the Nordic group, that reviewed a combination with ibrutinib. Obviously, this is not an approved regimen yet, but the complete response rate was 60% to 75%. In those situations, I think we should not forget that we are trying to achieve a deep response in the frontline setting. It’s still valid in the relapsed setting where we would like to achieve a complete response. That’s what’s going to give us some clinical benefit.

Alexey V. Danilov, MD, PhD: At our center, we actually ran a multicenter study of combination ibrutinib with obinutuzumab, a second-generation CD20 antibody. So, that’s combining with an antibody in relapsed/refractory mantle cell lymphoma. That’s one approach as well.

John P. Leonard, MD: We’ll come back to some of the new drugs in a few minutes. But just very quickly, off protocol, when you’re starting a patient on therapy, say it’s a first or second relapse, when you use ibrutinib, do you use it alone or in combination?

Andre Goy, MD: With rituximab?

John M. Pagel, MD, PhD, DSc: I typically would use rituximab in mantle cell lymphoma as well.

Alexey V. Danilov, MD, PhD: More often, I use it alone.

John P. Leonard, MD: Yes, I do, too.

Alexey V. Danilov, MD, PhD: In fact, if you look at chronic lymphocytic leukemia data presented by Jan Burger, which was a randomized trial at University of Texas MD Anderson Cancer Center of ibrutinib versus ibrutinib/rituximab, at 2 years, there was no PFS benefit. But again, different disease, still early.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: It sounds like a fair number of patients get ibrutinib in the relapsed setting, obviously. The question surrounding early data after ibrutinib and progression after ibrutinib was that people did quite poorly. Was it that the patients, at that point, had horrible disease and did poorly because they had few other options? Or did the post-ibrutinib patient somehow have a different disease that was less favorable? That made many people pause about rushing to use ibrutinib as second-line therapy. But we now have some data that Steve alluded to. Alexey, Simon Rule presented updated data with ibrutinib that really suggested that people who were getting it as second-line therapy did pretty well with it. This provided some reassurance in that regard. What are your thoughts?

Alexey V. Danilov, MD, PhD: In the original publication, there was a progression-free survival of 13 months. This was very good for a single agent, I would say, for the relapsed/refractory disease patient who has seen a median of 3 prior therapies. So, we are talking about fairly aggressive disease there. However, as you noted, John, following ibrutinib discontinuation for progression, the overall survival was 2.9 months. It didn’t make it to 3 months. And even in those patients who received therapy, their survival was under 6 months. Most patients who progressed on ibrutinib did so, actually, within the first 6 months.

So now, these data from the same study talk about whether the line of therapy matters. It does. Patients who had 1 line of therapy had a longer PFS. Whether you achieve a complete response or not also matters. So, actually, patients who went into complete response–and that was over 20% of the patients on that study–enjoyed a progression-free survival of several years, 40-months plus. I think there’s actually very interesting, very promising data for a single agent in this bad disease. I want to mention that in terms of ibrutinib, molecular abnormalities in relapsed mantle cell lymphoma are very important, such as acquisition of deletion 17p, or TP53 molecular aberrations. Do any of you use ibrutinib sooner, say, if you see underwhelming response to chemotherapy and find TP53 aberrations a month later? Would you switch to ibrutinib at that point?

Andre Goy, MD: I just want to make a point about the relapsed setting. I would tend to re-biopsy this patient. In terms of treatment, we have seen the progress from bortezomib/lenalidomide to ibrutinib. There is a much higher complete response rate, and very impressive response rates as well. But when you look at it, the median overall survival, as a single agent, is roughly in the same range of 24 months. So, we’re not saving anyone completely with the single agent. It’s great to have these trials, but I think what’s important is to try to build out the combination studies. We had a small presentation, similar to the trial that was presented last year at the ASH Annual Meeting from the Nordic group, that reviewed a combination with ibrutinib. Obviously, this is not an approved regimen yet, but the complete response rate was 60% to 75%. In those situations, I think we should not forget that we are trying to achieve a deep response in the frontline setting. It’s still valid in the relapsed setting where we would like to achieve a complete response. That’s what’s going to give us some clinical benefit.

Alexey V. Danilov, MD, PhD: At our center, we actually ran a multicenter study of combination ibrutinib with obinutuzumab, a second-generation CD20 antibody. So, that’s combining with an antibody in relapsed/refractory mantle cell lymphoma. That’s one approach as well.

John P. Leonard, MD: We’ll come back to some of the new drugs in a few minutes. But just very quickly, off protocol, when you’re starting a patient on therapy, say it’s a first or second relapse, when you use ibrutinib, do you use it alone or in combination?

Andre Goy, MD: With rituximab?

John M. Pagel, MD, PhD, DSc: I typically would use rituximab in mantle cell lymphoma as well.

Alexey V. Danilov, MD, PhD: More often, I use it alone.

John P. Leonard, MD: Yes, I do, too.

Alexey V. Danilov, MD, PhD: In fact, if you look at chronic lymphocytic leukemia data presented by Jan Burger, which was a randomized trial at University of Texas MD Anderson Cancer Center of ibrutinib versus ibrutinib/rituximab, at 2 years, there was no PFS benefit. But again, different disease, still early.

Transcript Edited for Clarity 
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