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First-Generation BTK Inhibition in Mantle Cell Lymphoma

Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Published: Thursday, Mar 28, 2019



Transcript: 

Brad S. Kahl, MD: Ibrutinib has been a major advance in the management of mantle cell lymphoma. Mantle cell lymphoma that recurs has always been a major problem for clinicians and for patients affected. There just haven’t been great treatments to deal with relapsed mantle cell lymphoma. Historically, we had bortezomib. We could try other types of cytotoxic chemotherapy. We could try to get patients to stem cell transplant, but often we couldn’t even get them to stem cell transplant because you couldn’t get the disease under control. So when ibrutinib came along, it was a major breakthrough. The response rates are high, generally in the 60% to 70% range using ibrutinib for relapsed mantle cell lymphoma. The complete response rates are not terribly high. They are somewhere in the range of 20%. And what we’ve learned with long-term follow-up data is that you can really estimate how durable a patient’s response is going to be based on the quality of that response.

So there was a really important analysis that came out just in the last year, and it was pooled data from 3 different ibrutinib studies all in patients with relapsed mantle cell lymphoma. And what they showed is that the patients who were most likely to get a really high-quality durable remission are patients who are in their first relapse and/or patients who get a complete response to the ibrutinib therapy. Those patients had remission durations that exceeded 40 months, on average. On the other hand, if you have a patient with mantle cell lymphoma, who’s in their second or third or fourth relapse, who starts on BTK [Bruton tyrosine kinase] inhibition or who gets only a partial response to ibrutinib therapy, those responses were more like 8, 10, 12 months, on average.

And so that’s 1 of the real challenges with ibrutinib and other BTK inhibitors in mantle cell lymphoma, is trying to figure out how to make these remissions last longer. We’re delighted to have these high response rates and to have something that helps get patients back in remission, but surely we’d like those remissions to last longer than a year, because then you have to find something else. And so that’s kind of the next frontier in mantle cell lymphoma, trying to figure out how to make these remissions last longer.

Ibrutinib is generally well tolerated. Patients can get myalgias, arthralgias, rash, diarrhea. Those particular adverse effects tend to be a little more prominent when the patient first starts the treatment and tend to dissipate over time. Some of the later toxicities that can set in include hypertension and the development of atrial fibrillation. And then for some patients, these nagging symptoms just don’t go away—the rash or the diarrhea or the myalgias. About 1 in 5 patients have to stop their ibrutinib therapy just for toxicity. So that can be a problem for a significant minority of patients—the long-term adverse effects. What’s become clear with the long-term follow-up data is these adverse effects aren’t terribly cumulative. In other words, once you’ve been on your ibrutinib therapy for a year or so, you’re relatively unlikely to then start to develop new toxicities that force you to stop it. These things kind of sort themselves out in the first year on therapy, and you don’t see a whole lot of new added toxicities in year 2, and year 3, and beyond.

What to do with mantle cell lymphoma patients who develop resistance to ibrutinib therapy is a real medical challenge right now. Sometimes these patients will have very explosive disease once they develop resistance to ibrutinib, and the disease can be very hard to manage. If the patient has 1 of these very aggressive relapses while on BTK inhibition, we usually try to find some kind of fairly intensive cytotoxic chemotherapy because that’s the only thing that can help get the disease back under control. If the patient is young enough, we might consider stem cell transplant from a donor: an allogenic stem cell transplant. If the clinical presentation is a little more controlled or a little more indolent, a lot of times I’ll try to go to things like lenalidomide combined with rituximab, which can be a very active combination in relapsed mantle cell lymphoma.

Transcript Edited for Clarity
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Transcript: 

Brad S. Kahl, MD: Ibrutinib has been a major advance in the management of mantle cell lymphoma. Mantle cell lymphoma that recurs has always been a major problem for clinicians and for patients affected. There just haven’t been great treatments to deal with relapsed mantle cell lymphoma. Historically, we had bortezomib. We could try other types of cytotoxic chemotherapy. We could try to get patients to stem cell transplant, but often we couldn’t even get them to stem cell transplant because you couldn’t get the disease under control. So when ibrutinib came along, it was a major breakthrough. The response rates are high, generally in the 60% to 70% range using ibrutinib for relapsed mantle cell lymphoma. The complete response rates are not terribly high. They are somewhere in the range of 20%. And what we’ve learned with long-term follow-up data is that you can really estimate how durable a patient’s response is going to be based on the quality of that response.

So there was a really important analysis that came out just in the last year, and it was pooled data from 3 different ibrutinib studies all in patients with relapsed mantle cell lymphoma. And what they showed is that the patients who were most likely to get a really high-quality durable remission are patients who are in their first relapse and/or patients who get a complete response to the ibrutinib therapy. Those patients had remission durations that exceeded 40 months, on average. On the other hand, if you have a patient with mantle cell lymphoma, who’s in their second or third or fourth relapse, who starts on BTK [Bruton tyrosine kinase] inhibition or who gets only a partial response to ibrutinib therapy, those responses were more like 8, 10, 12 months, on average.

And so that’s 1 of the real challenges with ibrutinib and other BTK inhibitors in mantle cell lymphoma, is trying to figure out how to make these remissions last longer. We’re delighted to have these high response rates and to have something that helps get patients back in remission, but surely we’d like those remissions to last longer than a year, because then you have to find something else. And so that’s kind of the next frontier in mantle cell lymphoma, trying to figure out how to make these remissions last longer.

Ibrutinib is generally well tolerated. Patients can get myalgias, arthralgias, rash, diarrhea. Those particular adverse effects tend to be a little more prominent when the patient first starts the treatment and tend to dissipate over time. Some of the later toxicities that can set in include hypertension and the development of atrial fibrillation. And then for some patients, these nagging symptoms just don’t go away—the rash or the diarrhea or the myalgias. About 1 in 5 patients have to stop their ibrutinib therapy just for toxicity. So that can be a problem for a significant minority of patients—the long-term adverse effects. What’s become clear with the long-term follow-up data is these adverse effects aren’t terribly cumulative. In other words, once you’ve been on your ibrutinib therapy for a year or so, you’re relatively unlikely to then start to develop new toxicities that force you to stop it. These things kind of sort themselves out in the first year on therapy, and you don’t see a whole lot of new added toxicities in year 2, and year 3, and beyond.

What to do with mantle cell lymphoma patients who develop resistance to ibrutinib therapy is a real medical challenge right now. Sometimes these patients will have very explosive disease once they develop resistance to ibrutinib, and the disease can be very hard to manage. If the patient has 1 of these very aggressive relapses while on BTK inhibition, we usually try to find some kind of fairly intensive cytotoxic chemotherapy because that’s the only thing that can help get the disease back under control. If the patient is young enough, we might consider stem cell transplant from a donor: an allogenic stem cell transplant. If the clinical presentation is a little more controlled or a little more indolent, a lot of times I’ll try to go to things like lenalidomide combined with rituximab, which can be a very active combination in relapsed mantle cell lymphoma.

Transcript Edited for Clarity
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