ASCO 2017 Roundtable: CLL Research News and Updates From an Expert Panel - 2 | Transcript | Chronic Lymphocytic Leukemia | Patient Power


ASH 2017 Roundtable: CLL Research News and Updates From an Expert Panel

Andrew Schorr:

Dr. Mato, I haven't been calling you Anthony because I'm meeting you for the first time.  I've known Jennifer a Bill for a while. 

Dr. Mato:

That's fine.  You can call me Anthony. 

Andrew Schorr:

So let's just talk about that.  So CD20 antibody.  So I had Rituxan or rituximab.  There's also Gazyva or obinutuzumab.  Is there another one as well? 

Dr. Mato:

Ofatumumab.

Andrew Schorr:

All right.  So they target a protein on the surface of the cell.  So what do you feel about that?  Do you say to people, well, you can have an infused therapy and you're going to take this pill, but it again tries to attack the cell in two dinner ways, right? 

Dr. Mato:

Well, I think it's, you know, it's asking the question—first of all, the pills are incredibly active.  Regardless of which pill we're talking about, ibrutinib, venetoclax, idelalisib, these are all very active agents.  I think what we're trying to learn now is what the antibody is adding to those oral therapies.  And we've learned from years ago the work done comparing chemotherapy combinations versus chemotherapy combinations plus the antibody, the antibody improves the response rate, improves the duration of response, even makes patients live longer. 

Now we're circling back to that same question with the novel agents and trying to ask does the antibody improve the response rates?  Does it make the response last longer?  Can patients live longer because of it?  And I think right now at least with some of the novel agents we're learning there is some added activity.  The question is is it worth the benefit, and that's what these trials are hopefully going to decide over time. 

There's one presentation at the meeting that suggested the antibody probably has a little bit of activity added, but it doesn't seem to add all that much to ibrutinib when you compare it to ibrutinib by itself, but we'll see.  There are a lot of comparisons that are ongoing. 

Andrew Schorr:

Jennifer, there are many people who are watching who have had FCR.  I had it in 2000 and 2001, and many of us have gotten a long remission, but we come out of remission.  So, first of all, are we damaged in any way because we had FCR where these novel agents or these combinations you're talking about are less likely to work because we were previously treated with an FCR or a BR? 

Dr. Brown:

No, really not.  I mean, when we started testing these drugs it was inpatients who had many, many rounds of prior therapy, and they worked phenomenally well, and as we moved them earlier they continued to work phenomenally well.  In fact, in some of the randomized trial data with ibrutinib there is evidence that at least at two years getting ibrutinib second line was associated with about the same sustaining of response as getting it frontline.  And so I think that there's not a concern—the novel agents continue to work extremely well in most patients over time. 

Andrew Schorr:

Okay.  So, Bill, you were talking about these studies about ibrutinib and venetoclax, and the goal, say, can we stop it at some point, and there's another leukemia, CML, where people were taking a medicine and there have been trials, cessation trials to see if you could stop.  One wonders if you have a remission and you get to this MRD negative point but you fall out of it at some point, the cancer show its head again, can the medicines work for you again, or have you kind of exhausted that option? 

Dr. Wierda:

So that's a great question.  That's a question that we have limited data on so far.  So, for example, there was a trial that was done with venetoclax plus rituximab in which many patients went into a deep remission and were MRD negative.  A few patients went off treatment and had been followed, and subsequently their disease did come back, and they reinitiated treatment. 

Now, the numbers are low, but those patients responded again to treatment who they restarted on treatment.  So, so far it looks like the patients can be retreated without expecting them to be resistant, and we need to collect more information on just that question. 

Andrew Schorr:

Okay.

Dr. Wierda:

Or can you retreat with venetoclax after you have had a good, deep remission and patient's disease has come back.  I think yes.  With chemotherapy it was the same question or chemoimmunotherapy.  We would give patients six cycles of FCR.  They'd go in remission.  There was a variable length of remission between patients.  Generally speaking the longer the duration of remission the more likely patients would be to respond when you gave them the same treatment again later.  It may be the same pattern we see with the small molecule inhibitors.  We don't know yet though. 

Andrew Schorr:

All right.  I have one question for you, staying on you, Bill for a second.  So I had FCR at MD Anderson years ago, and then the trials went on around the world, and many of us have had it.  So the F and the C, chemo drugs, right?  And I know the worry has been does it lead to a second cancer or the toxicities etc.  So as you're talking about novel agents and monoclonal antibodies, kind of nonchemo kind of drugs, is the F and the C, or the B, bendamustine, are those passé now, do you think? 

Dr. Wierda:

Well, right now we're not willing to dispose of those drugs for certain groups of patients.  With the FCR experience, and we have years of FCR experience and hundreds of patients literally treated at MD Anderson with the FCR regimen, we have an idea about who does best with that regimen.  That is, what is the group of patients that is most likely to go in remission and to have the longest remission and perhaps cured with that regimen, and those are patients who have a mutated immunoglobulin, heavy chain variable gene.  So we think that that regimen particularly is important for that subgroup of patients, and that data has also been confirmed by other groups like the German CLL Study Group. 

So our new regimens right now are modifications of FCR, intended to give less chemotherapy because we are worried about that risk for second malignancies and selection of—for 17p and things that happen when patients get chemotherapy that might not happen with the small molecule inhibitors.  We don't know as—we don't have as much data on that, but—so we're trying to give and develop regimens that have less chemotherapy that will achieve the same end point.  And we haven't yet given up on chemotherapy, but particularly for a group who benefits most and potentially are cured with it. 

Andrew Schorr:

Jennifer, this relates to testing.  He used the term "17p," so help our audience understand a little bit of it.  He talked about mutation.  What are the testing for?  Somebody comes into Dana-Farber, what are you trying to see which—how they—what their version of CLL is?  What are you looking at to make a decision on what treatment you're going to recommend? 

Dr. Brown:

Well, we do a whole panoply of tests as you might imagine, but there are really two central, most important categories of tests.  And so one is the test that Bill mentioned for mutation or deletion of a cancer gene called p53.  That's the target of what's on 17p involved in many other cancers as well, and we know that if that's deleted in the CLL cells it makes them resistant to many of our older therapies or chemoimmunotherapies, for example. 

Andrew Schorr:

And FCR would be a bad idea. 

Dr. Brown:

FCR would be a bad idea, and that's something for sure.  And we've also learned more recently that sometimes there are other ways of affecting that gene through—that we can identify through mutation testing which is a different type of test which is not quite as widespread yet but probably should become more widespread as a way of understanding who has this risk profile, which remains higher risk with the novel agents even though the novel agents are quite effective in the setting of that genetic abnormality. 

Andrew Schorr:

So novel agents, so it used to be sometimes somebody with this 17p, more aggressive CLL, could you even sometimes could talk about transplant as well, right?  So now it seems like you have these medicines that have utility for what used to be the most aggressive CLL that's been fairly effective, right? 

Dr. Brown:

That's right, especially frontline ibrutinib/venetoclax is approved in relapse as well and idelalisib, also the PI3 kinase, all of them have quite a lot of activity in the sending of 17p. 

Andrew Schorr:

Okay.

Dr. Brown:

That being said, after a person has been—had multiple of those therapies with 17p who is fit for a transplant we would still consider it in certain specific cases at our institution

Andrew Schorr:

Okay.

Dr. Brown:

And there is one other genetic test…

Andrew Schorr:

Yes, please. 

Dr. Brown:

…for therapy selection, which is called the mutation status.  And that's a test that actually looks specifically at the CLL cells themselves and sort of divides them in two categories based on where it looks like the CLL came from in the development of the cell arc. 

Andrew Schorr:

Is one mutated or un—is one better than the other? 

Dr. Brown:

Well, they're a little bit different.  The mutated is slower moving, and so it might be a much longer time until a person needs treatment. 

Andrew Schorr:

So you may have that watch-and-wait period. 

Dr. Brown:

Right, and it might be long.  And then that's the subgroup of patients that can have the very prolonged benefit and possibly cure from the chemoimmunotherapy with FCR. 

Andrew Schorr:

You were at Penn Medicine, famous guy there, Carl Jung early on with David Porter, I think in your department, did a lot of work in CAR-T cell therapy.  Tell us what it is because there's big buzz about it, other institutions are working on it as well.  What is it, and where does it stand now for CLL? 

Dr. Mato:

That's a great question, and it's—having worked at the University of Pennsylvania that's a question that many patients ask because of the experience with CAR-Ts for patients with ALL, for patients with lymphomas.  CAR-Ts are essentially utilizing your immune system.  You take out your T-cells, you modify them in different ways, but at our center they're exposed to a virus that inserts a new gene that allows for expression on the cell surface that retrains that T cell to be focused on cancer. 

And in this particular case they're called CAR-T cells or CART-19 where those cells are focused on a protein on the cell surface called CD19.  And so you are able to take a T-cell which is relatively nonspecific and make it focus on cancer cells.  And in cancers that have expressed CD-19 they've been active.  And they've studied this in patients with ALL, particularly in children, very active, in patients with non-Hodgkin lymphoma particularly DLBCL, very active, and actually there are different products that have approvals. 

They've also been studied in patients with CLL, and there's activity, but I think one of the areas where we're trying—what we're trying to learn right now is how do those cells fit in to sort of the large armamentarium of agents that are available.  And those other diseases, once you've failed your first therapy there isn't a lot of choice.  In cell we're talking about agents like ibrutinib, idelalisib, venetoclax combinations and what-not, and CAR-T where now we're sort of learning how to fit them into the CLL space. 

There have been some reports—there have been some series of patients that have been reported, 40 or 50 patients, where it looks active in a subset of patients, and there are even some long-term responders where we're getting to the point where we think those patients may be cured of their CLL.  But at this point in time they aren't yet approved for CLL, and we're trying to learn either how to use them following these newer agents, or there is some exciting data about how to combine them in patients receiving agents like ibrutinib for example which actually may make the T cells work even better. 

Andrew Schorr:

And I know one of your patients who you had early on, and he did well for a number of years with CLL.  He was near death, and so he had a remarkable recovery which I understand you can have like the worst flu of your life but if you can get through it then you may well be cancer-free. 

Dr. Mato:

And I know the same patient, and he was one of the first three patients treated at Penn with CAR-T, and it's true.  It's been several years, more than five years now, and he's disease-free and doing quite well, and someone who had absolutely no treatment options available to him. 

These cells are not without potential toxicity.  In some patients they can cause some confusion or neurological issues.  You can actually have a sort of a flare of the immune system called cytokine release syndrome which can make patients quite sick, but it seems to be reversible at this point in time if you pick it up early and use certain agents to reverse that phenomenon.  So they do require expertise in terms of how to administer them and how to make sure that it's a safe process for patients. 

Andrew Schorr:

So, Bill, couple of questions about this.  This is expensive, to sort of make a drug out of your T cells and then have it target back.  It's expensive and it's almost like a custom pharmaceutical in a way.  You and I have talked previously about for this to be used broadly we have to find kind of—I don't want to say an off-the-shelf way of doing it, but for where it can be done more easily and you can maybe add a—don't want to trivialize it, but it's kind of like, well, if we all drank lattes at Starbucks could your favorite flavor just be added and then it's easy to give quickly and efficiently and not dangerously.  I mean, do we have the hope of that? 

Dr. Wierda:

So there's a hope of that.  Right now there--things have been somewhat delayed in CLL in terms of CAR T-cell development

Andrew Schorr:

Because of what Anthony was talking about, you have other options. 

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Page last updated on July 30, 2018