ASH 2016 Expert Roundtable: What Does Emerging CLL Research Mean for Patients?

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On location at the 2016 American Society of Hematology (ASH) meeting in San Diego, Patient Power founder Andrew Schorr hosts an expert roundtable, as experts review CLL news from the conference. The panel, including Drs. George Follows, Jeff Sharman and Philip Thompson, explores emerging research, including new data on inhibitors, combination approaches 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 this program. I’m Andrew Schorr from Patient Power, and we’re delighted you could join us. We’re on location in San Diego, California at the American Society of Hematology meeting for 2016, and there’s a lot of news, of course, about blood-related cancers. I’ve been living with CLL for 20 years, so my ears have been peeled for anything related to CLL. And now we’re going to talk about with some imminent experts not just from the U.S. but also from the UK.

To my right is Dr. Phil Thompson. Phil, you’re from MD Anderson. What's your title there now?

Dr. Thompson:  

I’m an assistant professor in the Leukemia Department there.

Andrew Schorr:

And one of the world’s largest leukemia departments. In the middle we have Dr. George Follows from Cambridge University Hospitals. What's your title there, George?

Dr. Follows:

Andrew, I’m the Consultant Hematologist. 

Andrew Schorr:

So simple with the NHS, the huge British health system and, of course, a CLL specialist. And then to his right, back again with Patient Power in our programs, of course, just like Dr. Thompson, Dr. Jeff Sharman from U.S. Oncology Network up in Oregon. What's the name of your clinic up there?

Dr. Sharman:       

I’m at the Willamette Valley Cancer Center. It’s a community practice, and it’s an affiliation with the U.S. Oncology Network. I serve as the Medical Director of Hematology Research for U.S. Oncology. 

Andrew Schorr:

Thank you so much. Let’s start right where we left off, with you, Jeff. Is this a big meeting, related to CLL or is this sort of a consolidation time where you have more data coming in, you’ve had some drugs approved a couple of years ago, so now you’re looking at how we’re doing.

Dr. Sharman:       

Yes. I think actually that consolidation phase is probably a good way to describe this. 

In 2014, we had the approval of Imbruvica, ibrutinib; idelalisib (Zydelig), and obinutuzumab (Gazyva). We also had label expansions or increasing labels for ofatumumab (Arzerra) in that year. And since that time we’ve had changes to the prescribing information for ibrutinib, additional labels for obinutuzumab, and so it’s been a busy time. We haven’t had any new drugs approved until just recently with venetoclax (Venclexta). 

So this year we’re seeing some updates of some of the studies that led the approval, and we’re starting to see some of the waves of the future in terms of what comes next both from a combination perspective and also understanding the biology an patient management issues that come with these drugs. And I think that probably in the next two years or so we will pick back up again with a bunch of new data from important clinical trials.

Andrew Schorr:

So you have some monoclonal antibodies, you have some pills, some monoclonal antibodies typically infused. And then you have therapies before some chemo-based therapies as well, in combination that you’ve had for a while. So you have a wide group of medicines, trying to figure out who to use, which one to use for which person, right?

Dr. Sharman:       

Right.

Andrew Schorr:

In the UK, a little different. Some of the drugs that we have in the U.S. are not always available in such quantity or so quickly or sometimes even at all. One of the drugs you mentioned that’s been approved here, venetoclax or they call it Venclexta, I think is the brand name; you’re considering that. That’s being considered in the UK, right? 

Dr. Follows:        

You’re right, Andrew. Venetoclax is a drug that interests all of us who manage patients with CLL 

It’s got a good toxicity profile, it’s got great activity, and I think we saw Jeff Jones update the 032 trial of monotherapy venetoclax in patients who’ve been on ibrutinib or idela[lisib]. And you know, pretty impressive data as monotherapy. I suspect combination therapy is going to be the future for that drug. But yes, we in the UK are lagging behind a bit. It’s just coming through European licensing now, and it’s going before the first round of our approvals meeting with our regulatory body called NICE in the UK. Your viewers might not know to much about UK health politics.

Andrew Schorr:

Some watch from the UK. Some people in the UK feel NICE is not always that nice, because they wonder that certain drugs that could help them may not be available or as readily available; that’s the concern.

Dr. Follows:        

So, of course, we work in a different healthcare model. NICE has its job to do, and I don’t want to bash NICE; it’s too easy to do it.

As people always say, if you have a defined pot to spend in all of your healthcare spending, you’ve got to put in some areas of regulation. It just takes a while to work through. So to put this in perspective, ibrutinib has only just been approved by NICE literally one week ago, final approvals. We’ve had access to it through various things. We had the big compassionate access program, which some of your viewers might be interested in seeing our data set we’ve put together and just published in hematological. But in terms of access, we’ve got it through various ways, but only now is it actually approved on the NHS. And that’s where the journey starts with venetoclax—18th of January, I'll be at the review panel meeting in Manchester.

Andrew Schorr:

Good luck. Our view as a patient and the patient community is hopefully everybody gets the treatment they need and deserve, recognizing their costs. And now, Phil, we’re increasingly talking about combinations. Years ago, I had FCR, and now you’re talking about ibrutinibbeing combined with other drugs or venetoclax being combined. How do you figure out what's right for what patient? 

Dr. Thompson:  

We have increasing data now on looking at genetic factors in an individual’s CLL cells before they’re treated, which can give us a good idea as to who is going to—more than just what their prognosis is. Will they do better on one specific type of therapy, which is very useful early on. At MD Anderson now, when we have a patient who is about to have their first treatment for CLL, we get a number of tests done. We get FISH to look at the chromosomes in the cells. We get what's called IGHV mutation status testing, and we also do a panel of what we call next-generation sequencing which looks for small mutations in genes. And based on those three tests, we can get a good idea of how well is someone going to respond to chemotherapy.

And if they fall into a group of patients that’s likely to do well on chemotherapy and they’re young and fit, then we tend to go for that type of treatment. But for the remainder of the patients, we now have a combination study of ibrutinib and venetoclax. So we’re kind of dichotomizing treatment, in a sense based on those predictive markers.

Dr. Sharman:       

Andrew, I think this is an important area and one that is underappreciated by a lot of practicing clinicians. The paradigm until recently was primarily about looking at the patient, not necessarily the disease. The patient was a combination of age and functional status and the idea was treat as intensively as you can. And I think that the paradigmis changing.

And central to that paradigm change are some of these molecular characteristics. In particular, Philip’s group has looked at the long-term outcome for patients with FCR and there’s a clear delineation amongst those patients who have IGHV-mutated versus un-mutated disease. This is a situation where having the mutated version is actually good. So with FCR, I don’t know if there’s a completely representative population in that study; 57 years old was the typical age.

But there are patients out 14 years, 15 years without their disease coming back. You would not get that sort of result out of somebody who is IgVH unmutated. And so really I think central in that paradigm right now is the IgVH mutation status, and then following that are these additional tests: the FISH and the mutation tests.

Andrew Schorr:

So let me ask you a question about that.

You represent really community oncologists throughout the country. You are one of the leads. And so somebody goes to MD Anderson, and he runs all these tests. It’s a big university center; I don’t know to what extent you do that.

Dr. Follows:        

I think we run even more, Andrew.

Andrew Schorr:

Okay. But all these tests—if somebody says gee, doctor in whatever state I’m in or whatever community, I need all the—a broad range of tests. Maybe, but maybe not. So maybe you could help our viewers understand from your view, where do these come in?

Dr. Sharman:       

First of all, I think that the IGVH mutation analysis is poorly understood by most practicing providers. I think there is a significant misunderstanding and even amongst physicians I know firsthand who are interested in hematology, there’s oftentimes a lack of total awareness of what this means. To me, IGHV mutation analysis defines treatment intent.

So if my treatment intent is short duration therapy with sustained benefit, that’s a patient where I’m going to treat as intensively as age and functional status will allow me to. So those patients who have IGHV mutated disease, particularly if they have good FISH and none of the mutations, that’s a patient where I would still reach for FCR in a younger patient or in somebody who’s maybe, say, above age 65 but wants short duration therapy; I think that’s a patient who is still suitable for perhaps a bendamustine-based (Treanda) approach. 

Whereas if the treatment intent is just disease control as long as possible, continuous oral therapy may be the way to go and Imbruvica in IGHV un-mutated, or somebody who’s mutated with some of the adverse FISH findings such as 17p or next-generation TP53 mutation.

The tests, they’re expensive but relative to the therapies, they’re actually quite inexpensive. And so I think it’s money well spent to appropriately characterize the treatment intent for which you’re approaching a patient.

Dr. Follows:

Then I would follow that on and say our job as physicians really is to translate this complexity for our patients to give them a feel for balance of risk. Because I think that’s what all of these mutational tests, whether it’s a targeted mutation of a particular oncogene or sequencing of urine globulin protein, immunoglobulin sequence, it’s giving us this big feel of how we think that patient will do. Now, of course, the toxicity, the short-term toxicity of FCR is going to be the same whether you’re mutated or unmutated. But if you’re saying to a patient look, I’m aware you’ve got some comorbidities and your 60, 62 but you’re 13q deleted, you’re mutated; we think you can do really well.

So actually, taking that upfront risk is worth doing. But if you’re saying you’re a mutated compared with BR, this is going to push out your remission, well, an extra maybe 12, 14 months or so. But we’ve got so many other things down the line. Is it worth taking that risk? So I think for me, that’s what the molecular allows us to do with our patients.

Andrew Schorr:

And people need to have that discussion with their doctor. But based on the test results, so you get that picture. Now, some people say, Phil, I want one of these new drugs. I really want what's new, and what's new isn’t necessarily better. When they’re talking about some things, I mean I had FCR 16 years ago; I still haven’t had any more CLL treatment so hallelujah, and I am mutated. But people say well, you’ve got these new pills, and I can just take that every day. First of all, there’s no free lunch, right? These are powerful drugs, and they do have side effects, correct?

Dr. Thompson:  

Absolutely. And I guess the other thing to say is that we now have data looking at FCR and the favorable prognostic patients that goes out to 15 years. With ibrutinib or with idelalisib, we’ve got a much shorter period of follow-up, and we can’t really say what's going to happen to those patients in the future, both in terms of disease control and in terms of side effects, particularly as they’re on continuous therapy. But in terms of side effects, it’s a completely different paradigm to chemotherapy. Chemotherapy is given for short duration up front. 

Patients often have lower blood counts during treatment, and they have infection risk. And then there is a risk down the track, two to five years down the track after FCR of developing other types of cancers, and we worry most about a second leukemia called acute myeloid leukemia,which can happen in up to 5 percent of patients.

But with ibrutinib and with idelalisib, the side effects are different. In ibrutinib, we worry about two things in particular. One is a heart rhythm disturbance called atrial fibrillation. It can occur in up to 10 percent of patients, and it seems to increase in frequency the longer you’re on the medication. It can often be controlled, but it can have some worrisome risks. And the other thing we worry about with ibrutinib is the risk of bleeding. Those two things can interact, so patients with atrial fibrillation are at risk of stroke, and as a result of that, we generally give them blood-thinning medications to prevent that. Now, ibrutinib already thins the blood, and so those things interact, and it can be a difficult management problem when it occurs.

So they’re not without risk. Some people have I guess a perception that chemotherapy is bad; lots of side effects and these new medications are targeted, so they have few or no side effects, and that’s not quite true.

Andrew Schorr:

So, George, how do you explain to people how you figure this out? One is take the therapy, like some of these chemo-based therapies, and you may do it for six months or however long, and then hopefully you’ll have a long remission. Otherwise, you have to remember to take this medicine, and it may have some side effects over an extended time.

Dr. Follows:        

Yes, so, Andrew, this is difficult. But, of course, in the UK, our off-trial experience is dominated with relapsed-refractory patients.

And I must say when you have patients who have been through two or three lines of chemotherapy, they’ve looked at some pretty dark places, haven’t they? These patients, many of them love ibrutinib. Because compared with some of the cumulative toxicity of multiple lines of chemotherapy, ibrutinib is easier to take. People often feel better quite quickly. My experience is those patients tend to stay on their tablets. If I say to them now, how many left in the bottle this month? They look at me as if I'm mad. 

But our frontline experience in the UK, which has been completely trial because we’ve had no access really for the 17p deleters which is a separate story but on trial, it’s a bit different now. You get patients seven months out, nine months out we’ve had a couple of atrial fibrillations and arthralgiathat are affecting quality of life. I suspect some of those patients aren’t always taking their tablets.

Actually, I should be careful what I say on camera, but one asked if our research nurse could leave, and then he quietly told me he’d worked out his cure for his arthralgia. He just didn’t take the ibrutinib on a day he wanted to go out and do something. So I suspect there’s first-line patients and compliance and side effect profiles and everything; perhaps it’s a bit different from the relapsed ones.

Andrew Schorr:

Jeff, let’s talk about that for a second. Hallelujah if you can go to oral medicine, powerful medicines if you can remember to take it. but is that an issue of what you call adherence or compliance for some, these oral medicines now you have in CLL?

Dr. Sharman:       

It’s a major issue, and it’s not the first time we’ve seen this. I think it’s relevant to look back on our history. Chronic myelogenous leukemia, CML, I was going through medical school, and CML was a fatal disease. Patients had it for a number of years. There were a handful of things we could do for them. None of them worked very well. They all made the patients feel badly, and then the patients died.

That was CML up until about 2000. What it means to have CML changed with the invention of imatinib, or Gleevec. Suddenly these patients who didn’t know what those dark places were, were honestly spoiled by the success which is CML is no different from hypertension; you just take your pills. But in a lot of these cancer drugs, because we’re addressing a potentially fatal diagnosis, we allow side effects through in cancer drugs that we might not allow in other drugs. So some chronic, low-grade joint aches, muscle pains, diarrhea that would make a blood pressure medication fail completely is acceptable to a cancer drug.

So for our patients who don’t know what chemotherapy—I really appreciate the way you described that. The patients who have been through treatment before, you bet; they do not miss their pills. But it’s not uncommon seven, eight months after you’ve had somebody on this frontline for them to sort of: geez, I have a couple pills left this month, and they forget about it. There are a couple important things about that. Number one, data has been presented that dose interruptions in excess of eight days doubles the risk of treatment failure.

Doses less than the prescribed dose, less than three capsules daily, is associated with inferior outcome. And we see in data at this meeting that there is a somewhat alarming rate of treatment discontinuation if you follow patients for about a year. I would be super curious to know more about what you published in Hematologic, because I actually hadn’t seen that manuscript yet.

Dr. Follows:        

Yes, Jeff. We crawled all over this, actually. We had data from 315 patients from 62 centers across the UK and Ireland. I know people are slightly nervous about this term “real world,” but you know, it is real world; this is out there—community hospitals, university centers, a real mix. We got some pretty hard data points in terms of the number of patients still on therapy at one year, which is about three-quarters. It’s a bit down on resonate but still pretty good for a drug going out there in wide usage. 

And survival was 83, 84 percent at one year. But interestingly, we did have quite a lot of dose interruption, quite a lot of breaks in therapy. We spent a lot of time with a statistician crawling all over this data. And you can chop it in many ways, and I’ve got to be careful what I say because remember, this is retrospective. It’s not prospective.

But for us, treatment breaks, and being off therapy for beyond 14 days did clearly associate with worse outcome, not just in the year on therapy but actually our statisticians did a really good thing. They in effect did a landmark analysis, which is where you take all of your patients at one year who are alive and say look, you’re alive; you’ve never come off. You’re alive; you’ve had dose reductions. And you’re alive, but you had breaks in therapy in your first year.

And then track them, their data over the coming year and found again that even those patients who are taking their drug at one year but had long breaks, seemed to have an inferior outcome the following period of time. So all of this, take it carefully, because it’s retrospective analysis, and it needs longer follow-up. But it just reminds us that these drugs, they work and you’ve probably got to keep taking them.

Dr. Sharman:       

They work if you take them.

Andrew Schorr:

I have another condition that I developed, a second malignancy called myelofibrosis. I take a drug called ruxolitinib (Jakafi), and I have my pill box nextto the sink when I brush my teeth in the morning and at night, and the days and I never miss it.

I really worry about it. I’ve been told that if I did miss it, there’d be sort of a rebound effect that wouldn't be good. And I’ve been through chemotherapy, and I know what that’s like so I want to take the pill. Let’s talk about another drug. You mentioned it a little bit along the way, and Jeff had said early on about its approval not that long ago, venetoclax (Venclexta). So where does that fit in? It’s another oral therapy, but it was approved for people with a certain, specific type of CLL. Does it have promise for a broader group, and how’s it doing for the people that fit that 17p category? 

Dr. Thompson:  

The 17p category has always been the hardest group of patients to treat, and in particular patients with 17p deletion don’t respond well to chemotherapy at all.

So it’s actually really exciting that venetoclax as well as ibrutinib (Imbruvica) and idelalisib (Zydelig) seem to work really well in patients who have the 17p deletion. But it’s not specific to the 17p deletion; it works for all CLL patients. It’s just that often there’s a lot of focus on that group, because they’ve always been the ones that we’ve had the most difficulty in treating. So we now have a number of effective treatments for that group, which is exciting. 

In that group who receive venetoclax, we see about 80 percent of them will respond to the treatment, which is similar to the response rate in all patients that receive venetoclax. Although maybe their responses don’t last quite as long as other patients. Because that’s been the area of need, that was the area that the drug was approved in first. But actually, we’ve been using it in all patients with relapsed CLL, and in trials we’ve been using it in patients who haven’t been treated before, as well. 

It’s a fantastically effective medication.

Andrew Schorr:

Let’s talk about this for a second. We talked about testing, and we talked about these drugs that deal with this more aggressive CLL, this so-called 17p deletion. But yet, I understand that labs vary in how they assess whether you have 17p or how much. And in the communities sometimes, the doctors are not so attuned to it; it varies. They have a lot of different cancers to treat. So, Jeff, do you have any guidance for patients on how their CLL can be analyzed correctly? And maybe if they didn’t do well on a treatment earlier and now they need to be retreated, should they be tested again and their 17p be looked at so that they get the benefit of a drug that may be focused on that?

Dr. Sharman:

We talked about IGHV mutation analysis. 

Once that’s been tested, that should be stable for the entire duration of somebody’s disease. That’s not a variable that changes. In contrast, and in sharp contrast, FISH evolves. So what you are when you’re first treated is not necessarily what you are at relapse or subsequent relapse.

Andrew Schorr:

The genetic aberrations. 

Dr. Sharman:       

The genetics change. So CLL, I like to think of a patient’s course—over the course of CLL as survival of the fittest. When you treat somebody with chemotherapy, you might eradicate 99.99 percent of the disease, but that .01 percent may be what survives. And it wouldn't, therefore, surprise us that things such as 17p which are actually quite infrequent in the frontline setting, constituting about 5 to 7 percent of patients, enriches with subsequent lines of therapy. So that when patients are on their third-, fourth-line therapy, that frequency is much higher; say around 30, 35, 40 percent.

Furthermore, there is a gene on the short arm of chromosome 17, so the chromosome, the long arm is the Q, the short arm is the P: and there’s a gene that lives on 17p called Tp53. That can be mutated, and that’s not tested by FISH either. This is where these next-generation things—and having a Tp53 mutation is every bit as bad as having FISH. All that’s to say you cannot know your FISH unless it’s retested. I think that we have data from community settings to say that about half of patients are getting FISH before their first-line therapy, and with each successive line that decreases such that when patients are on third-line therapy, FISH is done in about a third of patients.

So it’s not being done frequently enough, and here’s why it’s dangerous. Treating somebody with 17p with chemotherapy is harmful.

Dr. Thompson:  

Agreed.

Dr. Sharman:       

I will go so far as to say that amongst the alternative therapies, you are making a wrong choice, and we don’t say that that often in cancer. We like to say that’s okay. No, this is a wrong choice to treat 17p with chemotherapy, because you’re taking a disease that is genetically unstable and potentially destabilizing it further with therapy that rarely yields benefit for much time at all. You’re getting all the side effects with little of the benefit. Treating 17p with chemotherapy is wrong. 

Andrew Schorr:

Let me see if I’ve got this right. Let’s say I had been treated with FCR or Brett:like that. And now my disease comes back. So I’ve been through the chemo approach one time. 

You’re saying that before, they’d just say well, you didn’t have long remission, but let’s just do it again. That would be wrong. I should have an analysis to see has this survival of the fittest, the 17p and p53 and all of that grown up where maybe there’s some other direction we should go. Is that correct?

Dr. Sharman:       

I think to treat 17p with chemotherapy is wrong. And those patients should go on either ibrutinib or idelalisib, rituximab (Rituxan) or venetoclax. Those are all agents available in that setting, and you may pick one regimen over another, depending upon side effects or treatment availability or so forth. 

Andrew Schorr:

So, George, are we saying then that the patient and the doctor should work together to make sure they have a clear picture of their situation at the outset?

And then if after that initial treatment or depending upon if they’re 17p at the beginning, but if they’re not, as most people are not, they have their initial treatment, and the cancer shows up again; they need to work together to have a close analysis before they do the next treatment.

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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