ASH 2015 Expert Roundtable: An In-Depth Review of Emerging CLL Research

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Topics include: Treatment

At the 2015 American Society of Hematology (ASH) meeting in Orlando, Patient Power founder Andrew Schorr led an expert panel as they reviewed CLL news from the conference. Drs. John Gribben, Constantine Tam and William Wierda explore the full gamut of developing treatment approaches. Watch as the panel shares an update on research, including new data on inhibitors, ABT-199 and immunotherapy.

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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.  We’re on location as we do every year at the American Society Hematology Meeting.  This is really sort of ground zero, where news breaks about illnesses we care about.  We’re talking about CLL.  I hang on every word.  I've had CLL since 1996 and was fortunate enough to be in a Phase II clinical trial, the FCR trial and it worked.  Since 2000, I've had no other treatment.  But that isn’t the case for everybody.  And now we have so many more approved medicines, and others coming; what does it all mean? 

Well, we’ve brought together part of the brain trust in CLL from really around the world, and I want you to meet them.  And in the next few minutes, we’re gonna extract from themsome wonderful perspective for you, the patient or the family member dealing with CLL. 

So first I want to introduce you to Dr. John Gribben.  Dr. Gribben, you're from the Barts Cancer Institute in London, right?

Dr. Gribben:        

That’s exactly correct.

Andrew Schorr:                  

Okay.  And how many years have you been devoted to CLL?

Dr. Gribben:        

Oh, gosh, I've been working in CLL since oh, the late ‘80s, early ‘90s. 

Andrew Schorr:                  

And both in the U.S. and… 

Dr. Gribben:        

…both in the U.S. and in London, yeah.

Andrew Schorr:                  

Okay.  Now, let’s go to Texas, Dr. William Wierda joins us from the MD Anderson Cancer Center in Houston.  Bill, what’s your title at MD Anderson now?

Dr. Wierda:          

I am the section head for CLL in the Department of Leukemia.  I'm also the Center Medical Director for Leukemia, so I oversee the inpatient and outpatient leukemia operations at Anderson. 

Andrew Schorr:                  

Okay.  And, of course, both these physicians see a lot of patients, do a lot of research.  Now let’s go over to Australia, Dr. Constantine TamThank you for joining us.  And you're in Melbourne, right?  What’s yourtitle there? 

Dr. Tam:                 

I'm the lead for the CLL and Low Grade Lymphoma Program at the Peter MacCallum Cancer Centre. 

Andrew Schorr:                  

Okay, and we know news that’s been coming out of Australia.  We’re gonna be talking about what had been called ABT-199 venetoclax, now.  How’s that going to mix in with everything else?  And you’ve been very involved in that, so we want to talk about that, too.  Okay.  Let’s start with you, John.  You and I have been talking a long time.  And you know me even when I went through treatment many years ago; we used to talk about that.  But in the last couple of years, we’ve had a bunch of new approved treatments, approved in the U.S. and proliferating in some places in Europe, as well.  We knew there was promise.  How’s it panning out? 

Dr. Gribben:        

I think much better than any of us had hoped or even thought a few years ago.  Bill and I were just talking before we started filming about who could have foreseen how far we’d have come in such a short period oftime. 

You have to remember, for 50 years we had one drug, chlorambucil (Leukeran).  Then I think the next big advance was the FC and then the FCR.  That combination is great for the small population of patients who are fit enough to have it.  We’ve always had big populations of patients for whom we had no options.  The problem’s always been that, as you’ve already said, most people's disease comes back.  Each time it comes back, it’s been more difficult to treat.  It acquires these genetic mutations that don’t respond well to chemotherapy.

What all of these novel agents have in common is that they work well in fit and unfit patients.  They work well in people who’ve got the higher risk abnormalities.  And what we’re seeing at this meeting is they’re working even better when we don’t wait until patients have truly refracted everything else to use them.  So we’ve been marching them forward, and we’re going to see, of course, data at this meeting. 

And we’ve seen the data at this meeting saying how good it is even up front.  So huge revolution.  What, of course, you’ve also got is the ability to start to tailor the right treatment to the right patient.  It’s not about trying to make one treatment fit everybody.

Andrew Schorr:                  

Okay.  And, Bill, clinical practice in MD Anderson, you’re seeing people who maybe in years past you wouldn’t have had much to offer them whether they were older and less fit, and now you have options. 

Dr. Wierda:          

We’ve always tried to have clinical trial available for patients who come to MD Anderson; this is the primary reason why we see patients at Anderson is to do clinical research.  And we always have intended to have a trial available for them.  Now there [are] even more options, so we have a lot of different options for patients.  In the relapse study, for example, now we have almost too many trials available for the number of patients that we’re seeing. 

We really need to redouble our efforts in terms of educating patients and working on informing them about what their clinical trialoptions are and to perhaps have discussions that would encourage patients to potentially participate in clinical trials. 

Andrew Schorr:                  

We’re gonna talk about that in a minute, particularly in combining drugs in trials, as well. 

Dr. Wierda:          

Can I just add one thing to what John was saying…

Andrew Schorr:                  

Sure, please.

Dr. Wierda:          

…that I think that for me illustrates how significant the advances have been.  For a long time, we talked about clinical trials and looking at progression-free survival as the endpoint.  And we never saw improvements in overall survival for a particular trial.  And now there’s multiple trials within the last three to five years where there’s a clear, overall survival advantage just within one clinical trial observation period.  So for me, that really illustrates how much we’ve come in terms of advance of treatment for patients with CLL.

Andrew Schorr:                  

So basically changing the natural history of the disease. 

Dr. Wierda:          

Changing the natural history, exactly. 

Andrew Schorr:                  

Okay.  Because I remember years ago, we did a program, and a woman was so frustrated.  She looked up in a book and it said an always fatal condition; life expectancymay be five, seven years. 

She was terrified.  And we’re changing that for so many people. 

Dr. Wierda:          

For sure.

Andrew Schorr:                  

Well, Con, so let’s talk about this.  We are seeing research going on where maybe there are new classes of medicine that will be added, and you’ve been involved in that.  And so that’s very exciting, too, this idea that we’ll have other agents operating in different ways—new ways—that can make a big difference.  And maybe—maybe, maybe—if we combine them, learn more, maybe will people even get to what we hope could be a cure?  I'd love to use that word; that’s what we want. 

Dr. Tam:                 

Sure.  Certainly we’re very lucky to have multiple classes of very active agent, now.  So to me, the exciting things are twofold.  So first the existing classes are getting redefined.  So at this ASH, what we hear about the next generation of BTK inhibitors and the early results.

And how they may be different from already the amazing results achieved by ibrutinib (Imbruvica) in the first-generation BTK inhibitors.  And the second thing that I think is exciting, which is not specifically mentioned at this ASH but certainly talked about on the sidelines is the potential to combine multiple classes.  You’ve got new antibodies, you’ve got your BTK inhibitors, you have your Bcl-2 inhibitors like venetoclax 199.  Certainly, we’ve had some preliminary experience combining ibrutinib and 199 in a different disease, in manta cell lymphoma.

And so far, the results that we’ve seen are very encouraging.  They’re not public, but they're very encouraging.  And we think in the next year or so we will see a proliferation of similar combinations of highly active therapies across the world in clinical trials.  So I think it is a very exciting time to be researching in CLL.

Dr. Wierda:          

If I could just pick up?

Andrew Schorr:                  

Go ahead, please.

Dr. Gribben:        

I think what is exciting for all of us is how thescience and the clinical work have come together.  Now, of course, all of the MD Anderson trials were based on good, solid science that Bill Plunkett and Bill Varshagandi did about looking.  But that was about looking about using the drugs we had available.  What these drugs have done are targeting pathways that we knew were fundamentally important in the CLL. 

So we’re really targeting the therapy down to the science of what’s happening, and then using that information to go back and using it to come back with real, rational combinations based upon what we know is likely to happen and work well in individual CLL cases.  So I think this is a really exciting time for us all to be working on this disease. 

Andrew Schorr:                  

All right, so let’s see if we can understand that as patients.  So you’re finding characteristics of the CLL.  Like we used to know—I knew I received rituximab (Rituxan), which was an FCR, and it targeted a protein on the cell and hit it. And it was like a bomb, and it blew it up and it did good for me—not everybody but for a lot of people.

But now you're understanding other things that are fueling the cell, right?  And you're trying to cut off these sort of power—things that power it, an escape route story?

Dr. Gribben:        

Cut off the fuel supply.

Andrew Schorr:                  

Yeah, cut off the fuel supply.  All right, so is the idea, just like we had with FCR, that if you combine medicines, the cancer in a sense can’t escape.  Bill, do you want to talk about that? 

Dr. Wierda:          

Sure.  That’s the rationale behind combining these agents and targeting different mechanisms at the same time that our survival signals, for example, for the cell so if you block BTK and you're blocking Bcl-2, for example, then you're hitting the cells.  These drugs don’t have overlapping toxicities, necessarily so you can—patients will relatively well tolerate them together.  The CLL cells have less of an opportunity to develop resistance and to survive that doublehit of toxicity to them.

Andrew Schorr:                  

Let me just follow up on one thing about that resistance.  So we’ve seen in some other conditions a concern where you take a single medicine, and it works great, but it doesn’t keep working after a while.  So that’s resistance, where the cancer kind of figures a way out.  So is the idea if you combine medicines all at once, that cancer can't develop that resistance? 

Dr. Wierda:          

Right.  Or there [are] fewer cells that are potentially able to develop that resistance.

Andrew Schorr:                  

Okay.  So you’ve been involved in research.  They have, too, but what we had called ABT-199, venetoclax, you and Dr. Seymour in particular.  So there’s been a lot of buzz about that.  So how would that work in combination with ibrutinib or some of these other medicines that we have? 

So your question was about how the two drugs may work.  I think from Varsha’s lab and also from Varshagani’s lab and also from Metho David’s lab, we’ve seen some results where they’ve combined different drugs and looked at the effects on cells in the test tube.  And certainly one of the most promising signals to come up is the combination of a BCL receptor antagonist like ibrutinib and a Bcl-2 antagonist like venetoclax.

That in itself is very promising because the laboratories have told us that when you mix different drugs, that this is probably one of the most active combinations.  Now, from my practical sense, these are two drugs which are both taken by mouth as tablets, so they’re convenient to give. 

And as Dr. Wierda mentioned, they don’t really have overlap in toxicity so we can put them in a patient, and we won’t get horrible overlapping side effects, because one drug causes nausea. The other drug caused nausea, so you get very bad nausea.  It’s not like that.  The toxicities are different.  Lastly, when it comes back to your point about resistance, we don’t understand why resistance happens.  But we think that either the cells evolve under the pressure of treatment, or maybe amongst the many, many cells in our body, it’s based on the one or two cells that carry the resistant gene already.  And if—suppress everything and allow those cells to grow up.

Andrew Schorr:                  

Stronger cells. 

Dr. Tam:                 

Stronger cells.  But if you think about it mathematically, it is highly unlikely for a cell in a given patient to be resistant to a potent drug like ibrutinib maybe one in 10 billion or something like that.

And if you find—put a second drug in, that one in however many billion cell also has to be resistant to the second drug.  So the probability goes even lower and gets to a point where they’re probably lower than the number of cells in a patient’s body which are cancerous.  And so it is possible that with combinations of two or three highly potent drugs, they will get to a stage where there will be more resistance.  But only time will tell.

Andrew Schorr:                  

Okay, well that’s what we’ll learn about in trials.  So let’s talk about where we’re headed.  You’re gonna do different combinations, and we’ll talk about people being in trials and the benefit to that.  But when you develop cancer, your immune systems let you down.  There’s been a lot of buzz about the immuno-oncology in solid tumors, etc.  Can your immune system be helped, just like a transplant helps it, and kind of a—if you can tolerate that—with these checkpoint inhibitors that we’ve talked about in other illnesses to help fight the cancer.  Bill, do you want to comment on that? 

Dr. Wierda:          

Sure, and probably John is in a better position to comment on that, because he’s generated a lot of the laboratory studies that have been the basis for what we’re doing now in the clinic.  I, several years ago, was looking at one of these checkpoint inhibitors referred to as CTLA-4, and we found that there were increased levels of CTLA-4 expressed in T cells of patients with CLL.  CTLA-4 is a way that the immune system will down-modulate the activation in T cells.  And so the T cells in patients with CLL have higher levels.  And in the lab we showed that if you block CTLA-4, you could reactivate T cells against patients’ own leukemia cells.             

And so for a long time, I have intended to do clinical trials in these antibodies.  The original antibody that was studied clinically was a drug that targeted CTLA-4 called ipilimumab (Yervoy).  It was very difficult for us to get access to that for patients with CLL. 

Nevertheless, it went forward, and there’s clinical activity in solid tumors.  We still haven’t been able to test it in patients with CLL.  The toxicity is a little bit high.  It has a high side effect profile.  And there’s another checkpoint molecule that John can discuss I think better than I can in terms of the laboratory investigations but it’s referred to as PD-1.  It’s overexpressed—or there’s high levels of expression of PD-1 also in T cells of patients with CLL.  And there’s an antibody that targets PD-1 that appears to be a little bit better tolerated than the CTLA-4 antibody.  So we’ve recently opened—and it’s called nivolumab (Opdivo). 

And it’s a Bristol Myers Squibb drug that they’ve gained approval in solid tumors.  So we have a trial that just recently opened with nivolumab plus ibrutinib for patients with CLL.  I'm optimistic that we’ll not only see activity in terms of treating the CLL but also some evidenceof immune reconstitution; fixing the defects that patients have in their immune system that predisposes them to develop infections and, perhaps, second cancers; skin cancers, etc. 

Andrew Schorr:                  

John, let me see if I understand this, and you can add your perspective.  So our immune system let us down, if you will, and we started—the CLL cells proliferated.  So this is the idea that we can help the immune system do the job that it didn’t do that time. 

Dr. Gribben:        

Sure, and it’s a little more complicated than that.  There are some cases where your immune system fails, and you develop cancer.  It looks very much in CLL as if something else happens; you develop CLL.  And CLL is very effective at switching off the immune system to be recognized.  So it’s not like some lymphomas that come from viruses in people whose immune system is suppressed.  We’ve got very clear data that it’s the CLL itself, which is very immuno-suppressive.

Andrew Schorr:                  

It’s like stealth.  It has like a shield. 

Dr. Gribben:        

Confoundedby the fact that treatments that we have like fludarabine (Fludara) really, as well as killing off the CLL cell, killed off a lot of the immune system.  So we’ve spent a lot of time trying to understand what was wrong with the immune system in CLL.  We could see clearly by any measurement that you did that T cells and K cells, B cells in individuals with CLL didn’t work very well, as everyone with CLL knows in terms of the risk of increased infections.

We did a lot of work trying to understand at the molecularlevel why that happened and found out that one of the most important molecules that did this is the PDL-1 molecule that is the one on the CLL cell that sticks onto the PD-1 on the T cell that Bill’s got the clinical trials running on, now.  And so we had very clear evidence in CLL this was an important molecule.  Actually, long before it was being developed in the solid tumors, the issue was, of course, that the companies were much more interested in developing it for the bigger markets.

But I think we had very, very strong evidence to suggest that this was gonna be a really effective target here in this disease.  And, of course, another huge advantage is the toxicity profile looks pretty low.  So again, another whole arm you could add into the other types of treatments we’ve been talking about. 

Dr. Wierda:          

Just to add to what John’s saying, he mentioned PDL-1.  We also have a clinical trial with another monoclonal antibody that’s directed against PDL-1, which is again the molecule… 

Andrew Schorr:                  

...so PD-1, PDL-1…

Dr. Wierda:          

Right. 

Andrew Schorr:                  

Okay. 

Dr. Wierda:          

But the PDL-1 is on the CLL cells and that’s how they suppress the T cells.

Andrew Schorr:                  

But all the ideas to help the immune system do its job and help the CLL cell be recognized.

Dr. Gribben:        

What you’d really hope is that, as Con was mentioning earlier, if you’ve got a cell that’s in there becoming resistant to BTK inhibition, what you're really hoping at the same time is we can use someone's own immune system as it recovers to go in and attack those cells.  So you’re looking to attack those cells from every direction.

And really whatwe want to get to—don’t get me wrong; it’s a great advance.  We’ve got agents like ibrutinib and ABT-199 that you could go onto and take for the rest of your life.  But I think what all of us are looking for is you get rid of the last cell, and you stop the last treatment and you’re off it, and we’ve really cured the disease.  And at the speed with which things have been changing in this disease, I'm really optimistic that we will get there. 

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.

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Page last updated on January 19, 2017