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Managing Ibrutinib Toxicity in CLL

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Published Online: Wednesday, Feb 15, 2017



Transcript:

Leo I. Gordon, MD:
I have a question for Michael and John, actually, about ibrutinib. It has to do with the toxicity. Adrian Wiestner just published some data suggesting that PCP (pneumocystis pneumonia) is occurring a little bit more than you might have expected, not related to T cell count. That’s one question about toxicity. The other is the audience is really dealing with the atrial fibrillation, which is not common, but not uncommon either. So, maybe either one of you might address that.

John Byrd, MD: I’ll address the pneumocystis. Ray Weiss, in mentoring me, told me that it’s really hard to report toxicity with a drug that everybody is excited about, and that’s true. We were happy to publish that paper in Blood, but if you read the paper carefully, we probably missed pneumocystis in some patients. It occurred relatively early, and it wasn’t the blowing ill pneumocystis that people die from. But it’s something. Again, most of the studies, we use prophylaxis in our study, and in most of the studies, we may have missed it. I think it’s a worthy safety thing, but it’s probably not a big safety concern for ibrutinib, say, much less than atrial fibrillation or the bleeding diatheses that can sometimes occur.

Michael J. Keating, MB, BS: We don’t use PCP prophylaxis in our ibrutinib studies at all. I think that we’re only seeing 1 or 2 cases of PCP, and it’s usually in patients who had multiple treatments. Many of them actually had corticosteroids as treatment for autoimmune hemolysis, etc. And if you go back to the old days, we saw almost no pneumocystis with fludarabine alone, despite the fact that it was a dramatic T cell-depleting therapy. As soon as Susan O’Brien added the prednisone to the fludarabine, the pneumocystis began to appear. So, there are specificities about the immunosuppression that we don’t really understand fully.

We talk about the atrial fibrillation being not common, but it’s the common complication that causes me the most angst. And the patients are very nervous about it. They talk to their doctor and they’re going to have a stroke. You have to be anticoagulated, but we can’t use that nasty warfarin, so we’ll do one of these new, less nasty—allegedly—treatments along the way. It really does disturb the patients a lot.

John Byrd, MD: There are 2 patterns of atrial fibrillation, too, with that. There’s the early kind that occurs usually within the first 3 months, where almost always, if you continue the drug, it’s going to continue happening. But your point is well, and whether it’s warfarin or any of the new anticoagulants, people will bleed with this drug. It puts us in a good position, though, that there are several more selective BTK (Bruton's tyrosine kinase) inhibitors that are coming along that whack some of these alternative target effects. With acalabrutinib, there is an abstract that was going to be presented at this meeting, showing that in most patients who are intolerant for one reason or another, they can go on to that. So, it’s following the path of CML, the second-generation molecules. They have their own side effects, but we’re going to have a second-generation molecule hopefully that will be available to patients that don’t tolerate ibrutinib.

Transcript Edited for Clarity

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Transcript:

Leo I. Gordon, MD:
I have a question for Michael and John, actually, about ibrutinib. It has to do with the toxicity. Adrian Wiestner just published some data suggesting that PCP (pneumocystis pneumonia) is occurring a little bit more than you might have expected, not related to T cell count. That’s one question about toxicity. The other is the audience is really dealing with the atrial fibrillation, which is not common, but not uncommon either. So, maybe either one of you might address that.

John Byrd, MD: I’ll address the pneumocystis. Ray Weiss, in mentoring me, told me that it’s really hard to report toxicity with a drug that everybody is excited about, and that’s true. We were happy to publish that paper in Blood, but if you read the paper carefully, we probably missed pneumocystis in some patients. It occurred relatively early, and it wasn’t the blowing ill pneumocystis that people die from. But it’s something. Again, most of the studies, we use prophylaxis in our study, and in most of the studies, we may have missed it. I think it’s a worthy safety thing, but it’s probably not a big safety concern for ibrutinib, say, much less than atrial fibrillation or the bleeding diatheses that can sometimes occur.

Michael J. Keating, MB, BS: We don’t use PCP prophylaxis in our ibrutinib studies at all. I think that we’re only seeing 1 or 2 cases of PCP, and it’s usually in patients who had multiple treatments. Many of them actually had corticosteroids as treatment for autoimmune hemolysis, etc. And if you go back to the old days, we saw almost no pneumocystis with fludarabine alone, despite the fact that it was a dramatic T cell-depleting therapy. As soon as Susan O’Brien added the prednisone to the fludarabine, the pneumocystis began to appear. So, there are specificities about the immunosuppression that we don’t really understand fully.

We talk about the atrial fibrillation being not common, but it’s the common complication that causes me the most angst. And the patients are very nervous about it. They talk to their doctor and they’re going to have a stroke. You have to be anticoagulated, but we can’t use that nasty warfarin, so we’ll do one of these new, less nasty—allegedly—treatments along the way. It really does disturb the patients a lot.

John Byrd, MD: There are 2 patterns of atrial fibrillation, too, with that. There’s the early kind that occurs usually within the first 3 months, where almost always, if you continue the drug, it’s going to continue happening. But your point is well, and whether it’s warfarin or any of the new anticoagulants, people will bleed with this drug. It puts us in a good position, though, that there are several more selective BTK (Bruton's tyrosine kinase) inhibitors that are coming along that whack some of these alternative target effects. With acalabrutinib, there is an abstract that was going to be presented at this meeting, showing that in most patients who are intolerant for one reason or another, they can go on to that. So, it’s following the path of CML, the second-generation molecules. They have their own side effects, but we’re going to have a second-generation molecule hopefully that will be available to patients that don’t tolerate ibrutinib.

Transcript Edited for Clarity
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