ASH 2015: Dr. Wiestner on B Cell Receptors and Toll-Like Receptors in CLL
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By Brian Koffman, MD and Richard Furman, MD
The data is maturing and the therapies just keep getting better. Dr. Rick Furman of Weill Cornell has been one of the pioneers in treating CLL patients with novel agents and a strong advocate for avoiding chemotherapy. He discusses the latest research presented at the CLL session at ASH 2015 in Orlando, December 2015. He also makes several predictions, one of which has already proven true only a few months later – the approval of ibrutinib for frontline use.
Please enjoy reading or viewing the video interview below.
Dr. Brian Koffman: Hi I’m Brian Koffman, a family doctor turned CLL patient, at ASH 2015. Dr. Furman, do you want to introduce yourself?
Dr. Richard Furman: Hi, I’m Richard Furman from Weill-Cornell Medical College in New York.
BK: Dr. Furman, you were really there at the very beginning of these new oral targeted agents, these kinase inhibitors. You’ve watched them evolve over the years. What’s got you really excited this year at ASH 2015? What do you see moving things forward for patients, in terms of where we started not that many years ago, and how rapidly we’ve progressed, what’s got you excited about in the papers that you were involved in or that you’ve heard about?
RF: I think what’s so important is not that there are new oral agents, but that they are highly effective and so extremely well tolerated. So, of course, we talk about the B-cell receptor antagonists, currently ibrutinib and idelalisib, but we now have additional BCR antagonists in the pipeline. The one that is furthest along is ACP-196 which is also known as Acalabrutinib. These are oral therapies and they’re highly effective and extremely well tolerated. Not only do we have the new BCR antagonists, we also have other therapies like ABT-199, or venetoclax. For those patients that might progress on a BCR antagonist, it’s not a problem. We can rescue them with venetoclax.
BK: We heard a paper on that too.
RF: We heard about both of those papers in the CLL session and both really show amazing results. ACP-196 has an extremely high response rate and extremely long disease control. What’s really so important about the disease control is that it’s really not associated with any of those adverse effects that we see associated with ibrutinib. We do see a little bit of bruising, but we’ve seen no major bleeding. We haven’t seen any atrial fibrillation, and we don’t see any diarrhea. This is really because ACP-196 is more targeted than ibrutinib is. It’s not a BTK effect that’s causing these side effects, but the off-target effects of ibrutinib. Out of the 40,000 enzymes that are in our bodies, ibrutinib inhibits 9 of them, so it’s very specific. ACP-196 targets 3, so we’ve been able to modify and to refine the molecule. It’s really helped us to knock out those few toxicities, which really aren’t that big of a deal, but it’s always nice to do a little bit better.
BK: So I have to ask you this. All drugs look good when they first come out. Could it be just that they’re there, but we haven’t done a big enough study or we haven’t waited long enough. I mean, atrial fibrillation wasn’t recognized as a big issue at the beginning with ibrutinib. Could we have the same issue with ACP-196, that we’ll discover it has the same issues down the line?
RF: I have to say that we’ve been hypervigilant with ACP-196 and we haven’t seen any, so I think we might be ok. One of the other things about ibrutinib and Afib is that most of the people that develop it do it early.
BK: OK.
RF: It’s certainly a problem whenever you do a phase 2 study, which is a single arm study where everyone gets treated the same, that you could miss adverse events just because you don’t have a comparator arm. So that’s always a possibility, but we haven’t seen any atrial fibrillation in the phase 2 study. The other reason is that because ibrutinib was first, it’s a little bit more important for us to go forward with mature data in order to be a little more of an interesting paper. Our data from ACP-196 is quite mature. Patients have been on the drug for over a year by now, so we really do have a lot of good long follow-up to support that ACP-196 does look very promising.
BK: All right. Let me ask you about the other paper that you talked about which is that when patients do relapse on ibrutinib or idelalisib, we have rescue therapies for them now.
RF: Venetoclax, also known as ABT-199, which inhibits BCL2 and there’s no cross tolerance between the BCR antagonists and venetoclax. If you’re resistant to one, you’ll respond to the other. It actually works in both directions, so the hope is that between the 2 of them, we’ll be able to get everyone taken care of and get people into really long-term disease remissions. I really think this is such an amazing time because if you basically do away with the toxicities of chemotherapy, there’s no reason why a CLL patient can’t enjoy a normal life span in 2015. I really do believe that. We know all those survival curves that people are always worried about when you look up CLL on Wikipedia and see that curve with the median survival of 9-10 years. It is just so irrelevant in 2015. I can’t emphasize enough how the survival curves that we currently want to look at are still at 96% progression free survival and 100% overall survival. So you’re gonna say ‘Call me in 10 years and tell me if there are any differences’, but I suspect there very well may not be.
BK: I always tell patients, when you’re looking at survival data, you’re always looking backwards, and the treatments are looking forward.
RF: That’s so very true.
BK: It’s always state of the art treatment from ten years ago, but we’re just radically so different now. Any final thoughts from ASH 2015 to share with patients?
RF: I really think that we now have mature data. We have mature data on ibrutinib. We have mature data on ACP-196 and venetoclax. You know, venetoclax will be approved shortly. ACP-196 will be a year and a half to 2 years away. Ibrutinib will shortly get an upfront approval, so there really should be no obstacles to patients getting treated with these agents first, and hopefully the only time they’ll need treatment.
BK: Thanks so much.
RF: My pleasure.
Here is the link to the ACP-196 abstract mentioned by Dr. Furman and also the abstract on venetoclax we discussed.
Richard Furman, MD is Director of the CLL Research Center at Weill Cornell Medical College and a member of the Lymphoma/Myeloma Service in the Division of Hematology/Oncology. He is a member of the Medical Advisory Board for the CLL Society.
Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the unpaid medical director of the CLL Society Inc.
Originally published in The CLL Tribune Q1 2016.
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