A CLL Expert Roundtable: Treatment News From ASH 2018

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Topics include: Treatments and Understanding

On-site in San Diego, from the 2018 American Society of Hematology (ASH) annual meeting, a panel of experts in chronic lymphocytic leukemia (CLL), including Dr. Susan M. O'Brien, from the University of California Irvine Medical Center, Dr. Nitin Jain, from The University of Texas MD Anderson Cancer Center, and Dr. Javier Pinilla-Ibarz, from the H. Lee Moffitt Cancer Center & Research Institute, joined Patient Power to discuss recent developments in CLL care. The panel shares breakthroughs in treatment research announced at the conference and explores emerging approaches to therapy. Watch now to stay up-to-date with the latest CLL news.

Sponsored by Pharmacyclics.

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Transcript

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 in San Diego, my home county. And we’re just outside of the American Society of Hematology meeting. Thousands of doctors, researchers from around the world coming to discuss the latest in blood-related conditions. And also, of course, blood-related cancers, including CLL, chronic lymphocytic leukemia, which I’ve been living with for 22 years. And I’m sure you or someone you love is affected by it. We have an eminent panel to discuss the latest with us. I’m going to let them introduce themselves.

They have long titles and a lot of credibility in this field. Let’s start with you, Dr. Jain.

Dr. Jain:          

Hi. I’m Nitin Jain. I’m a leukemia doctor at MD Anderson Cancer Center. I treat patients with CLL and also run clinical trials for patients with CLL.

Andrew Schorr:           

Okay. An old friend, not so old though.

Dr. O’Brien:     

Be careful. So, I’m Susan O’Brien, and I am the Associate Director for Clinical Sciences at the Chao Family Comprehensive Cancer Center, which is part of the University of California Irvine. And I also am a leukemia doctor and predominantly interested in CLL.

Andrew Schorr:           

Okay.

Dr. Pinilla:       

I am Javier Pinilla. I’m the head of lymphoma at the Moffitt Cancer Center in Florida in Tampa. And I pretty much see patients with CLL. As well, I do basic research in the laboratory on this issue.

Andrew Schorr:           

Right. And over the years, I’ve met patients that you treat, all of you. And they’re very grateful for your leadership in the field. So, we’re here to really talk about the news in CLL. And there is quite a lot. Lots of studies coming out. The people here have been involved in these clinical trials also making presentations. Dr. Jain, let’s start with you. So, people are very curious about these novel agents, ibrutinib (Imbruvica) and venetoclax (Venclexta).

Can they work together? And can you get sort of a bigger bang? And could it be better than some of the traditional approaches you’ve studied that?

Dr. Jain:          

Right. So, we have a clinical trial, which was designed a few years ago, combining these two drugs. So, ibrutinib is not currently approved for patients with CLL. And venetoclax is also approved for patients with relapsed CLL, whose diseases come back, after initial therapy. And there were some pre-clinical work in the lab, which suggested that, if you combine the two drugs, maybe you will be able to synergize together. Maybe you’ll get better activity.

So, based on that hypothesis and rationale, we designed the study where patients who have not received prior therapy for their CLL, or they’re needing therapy now for their first therapy, we gave patients ibrutinib at the standard dose, for 20 milligrams daily for 3 months. And then, we added venetoclax. And then, the entire treatment duration for the combination of two was for two years. And that’s the data we reported for at this ASH meeting for the first 80 patients we have treated on that study.

So, that study included patients who are high risk for CLL. So, patients who have deletion 17P, P53 mutation, deletion 11Q, and also patients with IgVH unmutated, which do not—with chemo immunotherapy, there is less of a response in this subgroup of patients. So, that’s the group of patients we enroll in the study. We treated 80 patients on the study so far. And at one year of the combination therapy, close to 61 percent of the patients were MRD negative, which is that by a test, which can detect one cancer cell in ten thousand normal cells, we were not able to detect any cancer cell in the bone marrow of those patients.

So, that’s very high rate of MRD negativity, which you would not have expected to achieve, if you were to use ibrutinib by itself and/or likely venetoclax by itself. So, and, at the same time, our complete remission rate was close to 85 percent to 90 percent, which, again, is much higher than what you would have achieved with single agent alone.

Andrew Schorr:           

So, that’s after a year. But you designed this for two years. So, where are we with that?

Dr. Jain:          

Right. So, the patients we—what we reported the data was up to 18 months. Now, there are only a few patients who have reached the two-year mark, because we started the study just over two years ago. So, I think we will need more patients. So, all of these patients were at one year mark. They are continuing with the therapy. And they will continue up until two years. and then, we will stop the therapy, on these patients.

Andrew Schorr:           

Okay. So, the idea is can you retain that MRD negativity, when you’ve stopped therapy. So, we have kind of a panel here. These are two peer CLL experts. Your commentary on that, Dr. O’Brien, is this a big deal?

Dr. O’Brien:     

I think it’s hugely exciting. It gets us away from chemo, which is where we want to go. As Nitin said, it’s clearly dramatically better than you would get with ibrutinib alone, in the front line setting. It might be important for you to comment on toxicities though.

Is there anything that’s negative about adding the two drugs together?

Dr. Jain:          

Yeah. So, that’s a very valid point. So, when we combine the two drugs, one toxicity, which we saw almost in 50 percent of the patients, was neutropenia, so low blood counts, the infection fighting cells. And with ibrutinib by itself, we expect maybe 15 percent to 20 percent of the patients may have it or maybe less than that. But when you combine the two together, we almost saw half of the patients getting neutropenia, what is called grade 3 or 4 neutropenia, which is neutrophil count less than 1,000. And because of that, we had several patients, almost 40 percent of the patients with ibrutinib and 20 percent of the patients with venetoclax.

We had to decrease the dose of the drugs. And then, almost one-quarter of the patients required growth factors such as filgrastim (Neupogen) and pegfilgrastim (Neulasta). So, that’s only, I think, when you combine these two drugs together, I think, the neutropenia risks are only something we have to kind of…

Andrew Schorr:           

…comment from you, do you think it’s a big deal?        

Dr. Pinilla:       

Absolutely. I completely agree with Susan. I think, today, any kind of intervention of combination of therapy that really is heading to limited therapy is extremely appealing for patients and also for doctors because we know that, when a patient can be off therapy very likely for a long period of time, although we still need to really see these data, in the near future. But I was just discussing, usually, toxicity for the drugs is something that we see, mainly with ibrutinib alone. Very, very excellent drug, but we know that this drug is associated with long-term toxicity sometimes.

So, I think that the possibility that giving this drug for a fixed amount of time will really, really achieve such a remarkable deep levels of response, really open new opportunities for our treatment in our patients with CLL.

Andrew Schorr:           

I hope so. So, Dr. O’Brien, let’s talk about another study, ibrutinib instead of bendamustine-rituximab (Bendeka-Rituxan).

It was used in a couple of different ways. So, tell us about that and what’s significant about that.

Dr. O’Brien:     

So, there was a very big trial that was presented at the plenary session. And the plenary sessions are generally regarded as some of the most important talks. So, you can see how this trial was assessed. And it was a randomized trial in patients with CLL, all over the age of 65 who were needing treatment but were randomly assigned to either bendamustine-rituximab, very commonly used chemotherapy regimen in the U.S., probably the most commonly used one in CLL, or Ibrutinib, or there was a third arm combining Ibrutinib with rituximab. We know that rituximab always makes chemotherapy better.

And so, this was asking the same question, when we move out of chemo but into small molecules, will that continue to hold true. And the randomized trial showed that ibrutinib or ibrutinib-rituximab were both better than BR, in terms of progression free survival.

And, basically, what that means is the durability of the remissions that these people achieved. So, the remissions were lasting longer with ibrutinib based therapy than they were with BR. The other important point, however, is that the Ibrutinib and rituximab and ibrutinib looked exactly the same so far. So, no difference. So, a little bit different than the picture and chemo where adding the antibody always improves the outcome. That doesn’t appear to be the case with Ibrutinib. But here, the most important question really was the comparison of BR to ibrutinib, since BR is such a commonly used frontline regimen.

Andrew Schorr:           

Okay. So, with BR though, people are able to stop, after so many cycles.

Dr. O’Brien:     

That’s right.

Andrew Schorr:           

And with ibrutinib, it would assume, versus the ibrutinib-venetoclax, you continue, right?

Dr. O’Brien:     

Right.

Andrew Schorr:           

And so, in this age of financial toxicity where we worry about the cost of therapy, too. So, it’s great if you don’t have to use the rituximab.

So, that saves the money from that drug. But you’d still stay on therapy.

Dr. O’Brien:     

That’s exactly right. And so, one of the advantages for patients is that, for financial reasons, they may actually prefer the chemotherapy. There’s no difference in survival in that trial so far, although there’s very few events, meaning most people are still alive. So, there’s no difference in survival. So, even if the remissions last longer with ibrutinib, you could argue that if you gave the BR first and got a few years out of it, and then, you gave ibrutinib, you’d still have very long remissions. We know it works great in patients after chemo. So, I think it still leaves the door open for the role of chemotherapy there.

Andrew Schorr:           

Okay. And would that include FCR that still has been a gold standard around the world? What do we know about that place in treatment?

Dr. O’Brien:     

So, we have not heard the presentation yet, but that will also be a presentation here as a late breaking abstract.

The data was just submitted, and that’s a two arm randomized trial. And that is sort of the opposite group of patients. All of these patients are under the age of 65. And they could receive FCR or ibrutinib-rituximab. So, this trial didn’t have an ibrutinib only arm. And partly, that’s because, when they designed this trial, they were betting that the paradigm of antibody making treatment better would hold, which now, it appears it didn’t. On the other hand, there’s, other than the cost, which you just mentioned, there was no negative to adding Ibrutinib. So, I think the results from that trial we can probably extrapolate to single agent ibrutinib versus FCR.

And interestingly, that trial also showed a better progression free survival for ibrutinib and rituximab. Now, the one caveat to that is I think where many of us still consider using FCR is in the patients who have a mutated immunoglobulin gene. And the reason for that is there’s now been three studies published showing that, in patients who have a mutated immunoglobulin gene that they’re sometimes remaining in remission 10 to 15 years, after getting the chemo.

And I think…

Andrew Schorr:           

…seventeen years for me.

Dr. O’Brien:     

There you go. And so, I think people—that’s six months’ worth of therapy for seventeen years. And so, there’s going to be a lot of attention going forward. As we get more follow-up from the trial, what about that mutated population? So, although that looks interesting, I’m not sure, for the group and whom we predominantly use FCR now, that data is going to be enough so far to change anything, without longer follow-up.

Andrew Schorr:           

So, Dr. Pinilla, where we are is we’ve been hearing about two novel agents used together. But maybe to a two year stopping point.

Dr. Pinilla:       

Sure. Less amount of time, a year of 15 months in the frontline studies.

Andrew Schorr:           

Right.

Could we do that? Or is there still a place for chemo that can have some side effects as well? Sometimes, the risk of a second cancer, right?

Dr. O’Brien:     

Yes.

Andrew Schorr:           

It remains a concern. So, is that where you think we’re going to end up with do we have some fixed time of novel agents versus some advantage of still using some chemo for some people? How do you think it’s going to shake out?

Dr. Pinilla:       

So, I think it’s all about stratification of our patients. Age is very important. Obviously, the IgG, HbS status is extremely important as the mutation status of heavy chain of immunoglobulin is extremely important because, as Susan was mentioning, these patients are doing extremely well. With Nitin, his study knows the institution, and he can really discuss even further, is how to increase even further these good data that we have had with FCR trying to decrease the toxicity of FCRs doing less chemotherapy, adding another agent, as ibrutinib or even a second-generation antibody with a goal to do limited therapy.

But substantially increase the number of complete responses, even MRD, who are the ones who have been associated with these long-term remissions, with these chemo immunotherapy regimens. And I think it’s something that I really, really feel like we’re going to continue to study to really increase. So, at the end of the day, we cannot say that chemo immunotherapy is completely gone. Obviously, in my practice, my patients because you mentioned finance and toxicity may ask for limited duration, even at the frontline. So, we need to really discuss this with our patients. And different patients may have different points of view about getting long-term therapy versus fixed therapy.

Andrew Schorr:           

Okay. Let’s talk about side effects for a minute. So, with ibrutinib for sure, and even a drug that we haven’t talked about a lot, idelalisib (Zydelig), of those classes there are coming second generation, maybe somewhere down in your list there are third generations.

What about the promise of those? Could the side effects be less? Could they be right for other patients? In other words, other generations in these same classes.

Dr. Pinilla:       

Right. So, certainly, the acalabrutinib (Calquence), which is a second-generation BDK and is currently approved for mantles and lymphoma. So, it is not yet approved for CLL.

Andrew Schorr:           

Yeah, it is approved for…

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Page last updated on February 1, 2019