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Dr. Michael Keating: My Reflections on CLL Research

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Published on November 6, 2015

With a career that spans decades, Dr. Michael Keating, a world-renowned specialist from MD Anderson Cancer Center, is on the front lines of CLL research and has witnessed its evolution. Patient Power founder Andrew Schorr sat down with Dr. Keating to discuss promising developments in CLL research and Dr. Keating’s ongoing commitment: “to stay alive until CLL is cured.” 

Sponsored by CLL Global Research Foundation.

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Transcript | Dr. Michael Keating: My Reflections on CLL Research

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That's how you’ll get care that's most appropriate for you.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello and welcome to Patient Power.  I'm Andrew Schorr.  I'm delighted to be sitting once again with my doctor in CLL, Dr. Michael Keating from MD Anderson.  Michael, I'm still here, and you're still here.  Thank you for being with us.  

Dr. Keating:

Well, you've got a lot to do in your life, and I have one challenge in my life and that's to stay alive until CLL is cured. 

Andrew Schorr:

Right.  Okay. 

Dr. Keating:

We're getting there. 

Andrew Schorr:

And the rumor had been that you were cutting back, but I don't see that at all.  

Dr. Keating:

There are four things that I do.  One is patient care, and one is research, and one is mentorship, and the other could be called B.S., or it could be called bureaucracy.  So if I go partially retired when they want me to be on committees and task forces, I say, sorry, I'm retired. 

Andrew Schorr:

Okay.  

Dr. Keating:

But I've actually decided I'll only see patients four days a week, Monday through Thursday, and Friday is thinking day.  

Andrew Schorr:

Okay.  Well, let's talk about what you've been thinking about.  You've been at this a long time.  Not too long ago we had your international gathering, the IWCLL, International Workshop on CLL, back in your original home country…

Dr. Keating:

Yep. 

Andrew Schorr:

…Australia, so putting what you were discussing with your colleagues there in perspective with where we've been, where are we now?  What are some of the issues, and what does it mean for patients?  

Dr. Keating:

I think there's a lot of maturation in the chemoimmunotherapy area with the FCR data and also the bendamustine-Rituxan, or BR, data. And in the next few weeks the Germans will be publishing their semi long-term follow-up with their study of FCR versus FC and showing that there's a plateau that's appearing on the curve of some patients on FCR but not FC. 

And we have a paper that's going to be published with Dr. Thompson as the first author with a minimum of 10 to 11 years follow-up getting out to 16 years, and a third of the patients that we've had on our original study have never relapsed. And the question is now appearing as the potential cure of that subset of patients that we have to identify, and we're a fair way along with that. 

So it's crystalizing in that there are some patients that have the prospect of very, very long control with an FCR program.  The concerns are does it actually increase the risk of getting other cancers, and there is some increase in risk which is balanced by the control of the CLL.  But the unmutated group of patients we're getting long-term control in very few of them, so that's the group that we need to work on. 

So I think the platform now is to say, okay, well, now let's have a look at what we can do particularly for the unmutated group and the very high-risk group of patients with chromosomes 17 and 11.  So we know the target group, and we now have to develop rational and mechanism-based treatments that are going to change their lot in life. 

Andrew Schorr:

So over the last year, we've had some pretty exciting new therapies, oral therapies, and they're being used widely. 

Dr. Keating:

Mm?hmm.  

Andrew Schorr:

And we're getting some longer-term experience with that.  How is that turning out?  I mean, these are pills you have to take every day, where FCR you sort of did it and then you move on if it worked for you.  It did for me for so many years.  How is that working out as far as the oral medicines and also the prospect of combining them with even FCR?  

Dr. Keating:

Well, there are a number of different approaches that are being explored. And I think one of the challenges that we have at the present time is deciding on the best strategy, so that my conclusion with the agents that are commercially available now and approved by the FDA for previously treated patients or all patients with a 17p abnormality is that ibrutinib (Imbruvica) appears to the best tolerated and probably the best long-term or semi long-term control of relapsed patients and certainly appears to be the best treatment we've ever had for the 17p group of patients. 

So I think there are conclusions that can be made.  I think that one of the concerns that we have is, as with all of the medications that inhibit the tyrosine kinase enzymes, there are so-called off-target effects so that there are other enzymes that these drugs affect.  So even though the BTK, or the Bruton's tyrosine kinase, is the target for ibrutinib—and it's got a very high affinity—but it also affects other enzymes so that a number of patients over time are developing an increase in the blood pressure.  They're increasing the number of cases that have atrial fibrillation, or an irregular heartbeat, and a number of patients as time goes on gets this musculoskeletal arthritic or peri-arthritic… 

Andrew Schorr:

Myalgia. 

Dr. Keating:

…myalgias, and after three or four years they just don't want to wake up every day with that to greet them in the morning.  And there's—we have to figure out what the causes are. 

So the nay-sayers can say, oh, well, they have side effects as time goes on.  Well, they do.  Our job is to find out what's causing the side effects and how we can ameliorate them, so that's a very important research question in all of these new enzymes.  The idelalisib is a very, very good drug.  Perhaps the remissions are not as long as they are with ibrutinib, but it's very good for patients that come in with atrial fibrillation, and you have to make it choice, and they do very well on idelalisib (Zydelig) during that time. 

So everyone thinks, okay, I'm going to be on this for the rest of my life.  I don't believe that that's true.  And what's happening now is that we're—been given permission by a number of drug companies to say, okay, in patients that haven't gotten a really good response to these new agents why don't we just add our drug to them at a certain point.  So they don't have to come off of the Imbruvica or the Zydelig and say, okay, well, I don't want to give that up, so we can actually add something. 

And the approach we're taking at the moment is to use checkpoint inhibitors, and the one that we're using predominantly in that arena is nivolumab (Opdivo), which is attacking the PD1-PD1 ligand pathway, and very successful in solid tumors.  And it works through an immune mechanism, so a totally different mechanism, so that I think that the things that we'll be testing in people that have been previously treated, we'll be able to move up to the frontline therapy, particularly in patients that are unmutated. 

Andrew Schorr:

Hmm.  All right.  One other question.  There are sort of second generation drugs in development.  I know you discussed that at your IWCLL.  Some of them are coming from smaller biotech companies developing these, and just looking at the radar what's the promise of these drugs doing better?  

Dr. Keating:

The—one of the drugs, ACP-196, is a BTK inhibitor that has a lower affinity for the BTK than ibrutinib, but it has a more selective spectrum of enzymes that it inhibits.  So the question for that drug is two questions.  Is it as good from an antitumor effect, and does it have a different profile of side effects, a lower incidence of side effects?  The Beijing compound, we don't have enough information, but both of them are very active in the early stages. 

I think the big agent that's coming along has already been given fast-track status or breakthrough status from the FDA…

Andrew Schorr:

Venetoclax. 

Andrew Schorr:

…venetoclax, and at least when you Google it will probably come up as ABT-199.  And this was a drug that was developed largely in my home country of Australia, and Andy Roberts and a couple of my students, John Seymour and Con Tam, have been involved in its development.  And there are combinations that have already started in mantle cell lymphoma of ibrutinib plus the ABT-199, and I'm not sure whether it will be presented at ASH. 

I'm hoping that it will be because it's a very logical sequence, because the ibrutinib stops you developing new CLL cells and allows a lot of the others to die off.  But the CLL cells that are left behind have a long survival of a hundred days or more, and the normal B cell only lives for about seven days. And long-lived cells are kept alive by this survival protein Bcl-2, and venetoclax blocks Bcl-2's function so that the cells just fall apart. 

So we have a combination that inhibits new cells and kills off the long-lasting cells, so it makes a lot of sense, and they have different toxicity profiles.  So ABT-199 doesn't have the atrial fibrillation.  It has some suppression of normal white cells, neutrophils, etc., whereas ibrutinib doesn't. So the combination makes a lot of sense, and that's probably why AbbVie bought Pharmacyclics for such a… 

Andrew Schorr:

Put them together. 

Dr. Keating:

…large amount of money so that they could explore it.  

Andrew Schorr:

So when you look at this whole landscape now, which is changing, I always ask you this, Michael, are you encouraged for a broader range of CLL patients?  

Dr. Keating:

Very much so in that I think we know what to look for now in terms of response.  The best early response is—that we have got from the chemoimmunotherapy strategies is the early achievement of complete remission with no residual disease, so MRD negative.  So that's a good thing for us to aim at, and if we don't get to that point we then have to think of adding other agents to it. 

But right now we're inhibited from using ibrutinib and Zydelig, etc., in frontline, but there's a study that will be presented at ASH comparing ibrutinib to the FDA gold standard for older patients, namely chlorambucil (Leukeran), and the early rumors are that the responses are very dramatically in favor of ibrutinib.  So I think that the drug will be fairly soon approved for older patients for frontline.  And once they do, that it's going to be hard to resist the push to make it available for younger patients as well. 

Andrew Schorr:

Hmm. 

Dr. Keating:

So a lot of patients now go on to nonchemotherapy programs, younger patients with some of the monoclonal antibodies like rituximab (Rituxan) or Gazyva, or obinutuzumab, together with chlorambucil so that if they don't get a good response, they can then go on to ibrutinib.  So the results that we all know seduce patients, at least, and some doctors into playing games with what we do. And once we get over that hurdle I think we'll be able to accelerate the development.  

Andrew Schorr:

Dr. Keating, thanks for all you do.  You've been at it, I've known you 19 years and appreciate your ongoing dedication to us. 

On location at MD Anderson in Houston, I'm Andrew Schorr.  Remember, knowledge can be the best medicine of all.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.