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Promising CLL Research and Updates Offer Hope to Patients

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Published on December 18, 2019

Key Takeaways

  • What trials are available to CLL patients now and what is in the pipeline
  • Insight into combination therapies that were discussed at ASH, especially ongoing treatments and fixed duration treatments
  • CLL Patients should feel hopeful and inspired by work of researchers

On location in Orlando, Florida at the world's largest hematology event of the year, the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, a panel of three renowned experts share important takeaways for chronic lymphocytic leukemia (CLL) patients from the conference. Watch as Dr. Brian Hill, Dr. Matthew Davids and Dr. Nicole Lamanna discuss promising clinical trial data and the latest treatment and research news.

This program is sponsored by AbbVie, Inc., Genentech, Inc. and Adaptive Biotechnologies. These organizations have no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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As a CLL patient, I appreciate all you do for this community. I was diagnosed in January 2014. I am in watch and wait. I am an RN, wife and grandma - and 66 years old. I always recommend you to anyone that is diagnosed or needs help for a family member.

— Rosemarie, CLL Patient

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Transcript | Promising CLL Research and Updates Offer Hope to Patients

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 on location in Orlando, Florida, where we have had maybe more than 25,000 people who treat or research blood related conditions and certainly blood-related cancers, like chronic lymphocytic leukemia, come from all around the world. They’ve been here. We have three noted experts in CLL with us. And I have an expert, my friend—and I’m Andrew, by the way, Andrew Schorr. This is Michele Nadeem-Baker living with CLL, how long now? 

Michele Nadeem-Baker:       

Since mid-2012, I was diagnosed. So that’s seven years. 

Andrew Schorr:         

Okay. And you live in Boston and go to Dana-Farber. And you’ve been in a clinical trial and in a minute, we’re going to lead somebody who’s very involved in that trial. How you doing?

Michele Nadeem-Baker:       

I’m feeling great. I’m feeling great. 

Andrew Schorr:         

You look marvelous.

Michele Nadeem-Baker:       

Oh, thank you, Andrew. So, do you. So, I am in remission. I did not reach MRD negativity fully. I’m almost there. It’s like always a bridesmaid, never a bride. I’m at .06 percent, and it should be 0.001 percent or less.

Andrew Schorr:         

Well, we’re going to talk about that. 

Michele Nadeem-Baker:       

Yeah, so, but very close and feeling great. Back to all my activities, and it feels good.

Andrew Schorr:         

And I was treated with FCR, some of our viewers know, fludarabine, cyclophosphamide, rituximab (Rituxan), in a clinical trial, Phase II, at MD Anderson. It was only at MD Anderson, then it spread out and that was in 2000, and then I had a 17-year remission. And then I was treated with another monoclonal antibody, obinutuzumab or Gazyva, and my doctor believed in adding steroid to that, so I lost a little sleep. But that worked out well and I remain in remission for CLL. So that’s us as patients. Let’s meet our guests.

Okay, I feel like a gameshow. So, way over there is Dr. Brian Hill. What is your position at the Cleveland Clinic? 

Dr. Hill:                     

Thanks for having me. So, I’m Dr. Brian Hill. I’m the director of lymphoid malignancies at the Cleveland Clinic, Tosi Cancer Institute. And I’m happy to be here and happy to also be the only one with a microphone.

Andrew Schorr:         

Okay, the others are mic’d too. Okay, in the middle is someone that the Patient Power audience knows so well, Nicole Lamanna from Columbia University. What’s your title there?

Dr. Lamanna:             

What, do titles matter? So, I’m the associate professor, I’m also the director of CLL, but it’s me and my leukemia crew.

Andrew Schorr:         

She’s such a New Yorker. And then who’s this guy? 

Michele Nadeem-Baker:       

Dr. Matt Davids.

Andrew Schorr:         

Matt Davids. What’s your position at the Dana-Farber Cancer Institute? 

Dr. Davids:                

So, I’m the associate director for the CLL center there, I’m also an assistant professor of medicine at Harvard Medical School, and this is my first time appearing on Patient Power, so I’m very excited. 

Andrew Schorr:         

Thank you. We’ve had your colleague Jennifer Brown many times, and she’s such a scientist. Well, thank you.

So, what we want to do is talk about the news. Let me go to Michele for a minute. Michele, you’ve been doing interviews at the convention center, where those 25,000 people have been going. They’ve been among them. But related to some headlines that you’ve been hearing from other CLL experts, and you’ve been going to the sessions to try to understand what they’re talking about. 

Michele Nadeem-Baker:       

I so more appreciate everything that you do with all the sessions I’ve been to. So, the news that I’ve been hearing a lot about, and I’d love to hear your opinions, are on the CAPTIVATE trial. That seems to be one of the hot news topics. MURANO, I’ve heard a bit about, but more it seems CAPTIVATE. Some new findings about newer generation technology for being able to single out cells to better predict what will happen for patients like us. There’s just so much.

Different combination therapies, more combination than mono, trying to figure out which combinations are the best for front-line, for relapse, so.

Andrew Schorr:         

Well, let’s dive in. So, Matthew, you want to tell us, CAPTIVATE, they come up with these words, what does it mean? So, tell us about some of these trials, and we’ll talk with the others too.

Dr. Davids:                

Sure. I think the theme right now in CLL is we have so many good treatment options for patients, which is a great thing. And what we’re learning is how to put these together in various ways and whether we even need to put them together in combinations. We don’t know right now whether it’s better to use these drugs together at the same time or to use one at a time in sequence. So, there’s a lot of studies going on right now trying to answer those questions.

Specifically, with the CAPTIVATE study, this is a combination of two of better-known novel drugs, ibrutinib (Imbruvica), which we’ve kind of had the most experience with over the last several years. And venetoclax (Venclexta), which was just recently approved as a first therapy for CLL. So, this is a combination of ibrutinib and venetoclax together.

We’ve seen some data for this in earlier versions. We’ve seen the study from MD Anderson which looked promising. But one of the criticisms was it was just from a single center. So, what would happen if this drug combination was used in a multi-center setting? Meaning lost of different centers from around the study, and that’s what the CAPTIVATE study looked at.

Andrew Schorr:         

What do we know?

Dr. Davids:                

It looks very good. So, it actually looks similar to what they had seen at MD Anderson. The majority of patients are getting into very deep remissions. And it raises the prospect of time-limited therapy, so using a combination of the two drugs may allow patients to not have to continue on long-term ibrutinib treatment.

Andrew Schorr:         

Okay. So, Nicole, I had FCR, went through six months, it wasn’t easy. Okay, but then I was done. I mean, I had some sinus infections and stuff that continued. And I needed antibiotics, it was a long tail related to that. My immune system kind of getting back. But so, time limited.

So, before now, with the oral pills, they’ve been saying, well, you’re going to have to take it. Just keep taking it. And they’re expensive. And then there’s been information with venetoclax, where with Gazyva, Rituxan, could you have it for a fixed duration. But taking these two kinds of star drugs, putting them together, fixed duration where you could stop at some point. Maybe not forever, that’s a big deal.

Dr. Lamanna:             

Yeah, no, absolutely. I want to highlight and say again, this is a really exciting time for patients with CLL because there’s so many new drugs available and the combinations that everybody’s trying to tweak. I think all the combinations, whether it’s ibrutinib, venetoclax, some of the other doublets, we’ll call them, doublets, or triplets, they’re all yielding very good responses, very high responses in front-line. I think the question that we all don’t know is—I’m going to echo what Matt said, is do all people need dual therapy? Triplet therapy? Are there subgroups that might benefit from that? Is sequential therapy better? We have long-term data on how well patients have done on ibrutinib in front-line.

 So, there are I think appropriate for clinical trial. I think that we’re still trying to translate into what will be in clinical practice, but we need the data to mature. I think there’s a very big appeal to do combination therapy, because of the time-limited duration, everybody wants to get off a drug.

Andrew Schorr:         

And cost.

Dr. Lamanna:             

And cost. And so that is an important thing. But with that, there’s extra toxicity that goes with any of these combinations. So, you may have to have a little bit of that. There’s always a little bit of a price to pay, because oral agents are not without side effects either. But if it’s in a time-limited fashion, that may push to move in that direction, absolutely. And then you have venetoclax, obinutuzumab and other combinations. So, I think they’re all gearing towards sort of limited therapy if possible.

Andrew Schorr:         

She mentioned—you mentioned MURANO, isn’t that near Venice or something? But what is that? What’s the MURANO trial?

Dr. Hill:                     

Right. So, the MURANO trial was the first study to really compare chemotherapy versus a novel treatment in a head to head fashion for patients with relapsed CLL. It compared bendamustine-rituximab, which bendamustine (Bendeka), many patients are probably familiar with, because it’s commonly used. It’s generally well-tolerated, and I think very popular in the community.

So, this trial compared patients in a flip of a coin fashion, head to head, with venetoclax and rituximab. And really the results were not even close in terms of how much better venetoclax was then bendamustine with these combinations. And by that, I mean that not only were the responses higher and patients were able to be off treatment longer after two years of venetoclax, but there was actual an overall survival advantage to venetoclax plus rituximab versus bendamustine plus rituximab.

Andrew Schorr:         

Okay, so is the headline here—one of the headlines, new combinations whether approved or in trials. I mean, look, I had FCR in a trial, F and C and R. In oncology, your field had done that forever. Let’s take one over here, one over there, and see if we get a bigger bang, right? So, is that the headline now, is combinations? 

Dr. Davids:                

That’s certainly one of the key things from this meeting and other recent meeting, that we’re getting more and more data about that approach. But to echo what Nicole said, I think we still don’t know whether that’s better than a sequential novel agent approach. We have patients who have been on ibrutinib for seven, eight years now doing well on a monotherapy. And so, I think it really is going to be on us to figure out which is the optimal strategy and it may be a different strategy for different patients.

For younger patients who want to really have time-limited therapy, it might be good to do combination approaches. For more typical CLL patients, patients who are older and frailer, patients in their late 70s and 80s, maybe a single novel agent makes more sense. So, we really need to be careful how we apply the data.

Michele Nadeem-Baker:       

As we’re talking about this, and we were talking about how you were on FCR, my trial, what is iFCR, ibrutinib plus FCR?

Andrew Schorr:         

You’re like the principal investigator, right? It’s your show.

Michele Nadeem-Baker:       

And I’m curious to learn—I started on that trial about four years ago. We know so much more, things are moving at such a fast speed, probably within a year of my starting that, it became known that—and I’m unmutated IGHV, 11q. So now it’s known that FCR wasn’t the best necessarily for me to have, is that correct? Or just going for short term? 

Dr. Davids:                

I don’t know about that.

Michele Nadeem-Baker:       

I saw this in some sessions they were saying that. So, I’m curious about that and if FCR… 

Andrew Schorr:         

You should get FCR.

Michele Nadeem-Baker:       

And is it FCR like—or it stays numbered? 

Dr. Davids:                

So, I’ll start maybe. I think this remains a controversial subject amongst CLL experts, kind of get that out of the way to start. But I would say my perspective, we designed the iFCR trial around 2012, 2013, so before we had some of this data. But I would argue that the approach is still valid, and I would put patients on a trial of iFCR today if it were still open, and I’ll explain why.

The results that we showed from the trial showed the deepest rates of this MRD undetectability in the bone marrow that have ever been described.

Andrew Schorr:         

Minimal residual disease.

Dr. Davids:                

I was getting there. And we also saw many patients who didn’t quite make it to that undetectable MRD, but were very low, like you were. And we think patients like that can do extremely well.

We’ve seen with ibrutinib on its own that patients can do equally well, whether they have that mutated IGHV or unmuted IGHV. So actually, the whole point of the study was for patients like you with unmutated IGHV to see if we could get FCR to work even better by using the ibrutinib.

And it’s just too early to know right now what the long-term outcome is going to be. And that’s true of the other combination strategies that don’t involve the chemo. So, I think time will tell whether this iFCR strategy does provide more durable benefit than the novel agent only combinations. At this point, we really don’t know.

Andrew Schorr:         

Brian, go ahead. 

Dr. Hill:                     

I just want to echo what Matt says. I think we have such a long track record of chemotherapy. In other cancers, I think chemotherapy has sort of a bad connotation, because people view chemotherapy as this very difficult to tolerate and ineffective treatment. But I think CLL is actually the disease with the highest rates of response. Basically 90 to 95 percent of people with CLL who receive chemotherapy as the front-line treatment will respond to treatment.

And throwing that way—everyone’s very eager to throw all that way in favor of novel agents. And I think the pendulum has swung a little bit too fast in the other direction in all honestly. I think it’s still a highly effective treatment that for many patients can be won in a series of therapies.

Andrew Schorr:         

So, I have to tell you something though, you probably know Steve Rosen, who was at Northwestern, now at City of Hope. And so, he doesn’t believe in chemo, because he worries about second cancers. So, what about that?

Dr. Hill:                     

I think it’s a fair concern, but it’s also important to know that any drug we use can have some potential toxicities. Now ibrutinib is getting a little more attention for some of the cardiac effects it can have, not just in terms of atrial fibrillation, which is an irregular heartbeat, but other cardiac effects. So, I think there’s enough equipoise there to say that. 

Andrew Schorr:         

We once had a doctor explain that equipoise term. Do you want to mention what it is by the way, it’s sort of how you measure things? 

Dr. Hill:                     

Yeah. So, when we do a randomized trial, in particular, like the MURANO trial we just spoke about. Equipoise means that before we actually get the information, we don’t really know which one is better, and that’s why it’s fair to flip a coin and assign that way. So that’s a term that we use to sort of justify why it’s okay to randomize patients and things.

Andrew Schorr:         

Okay. So, Nicole, I have a question for you. So, we’ve been talking about ibrutinib. That is a BTK, Bruton’s tyrosine kinase inhibitor. But now we have others, both improved and pending. So, we had a recent approval as we record this for acalabrutinib, or Calquence. And there’s another nib hanging around that was approved for another condition, mantel cell, zanubrutinib (Brukinsa).

Okay, so are all nibs alike? Or with the side-effect profile, does it vary?

Dr. Lamanna:             

Yeah, so absolutely. So that was the other, I think, highlight of the meeting was looking at some of the newer, second generation if you want to call them, BTK inhibitors. And then we even have non-covalent, we didn’t even start—others that are looking to overcome resistant mutations.

But acalabrutinib and zanubrutinib are starting to get some data and some following, because in the early Phase I, II studies, and now we have a Phase III study, it looks like the side effects potential might be less than ibrutinib. So, there might be less a-fib, less hypertension, less bleeding issues.

There are head to head studies that have been closed. So, there was a study of acalabrutinib versus ibrutinib. There’s going to be a zanubrutinib, ibrutinib, to see head to head, are there really less side effects at equal efficacy. But from a lot of the data that we already have, it does appear that these may have less toxicities. And if so, obviously we’re always trying to have everyone benefit from less side effects of therapy. And so, the data looks very good for all these other second generation BTK inhibitors.

Andrew Schorr:         

Okay. There’s one other class that’s been around, let’s see if I get it right, PI3K. Okay. We had idelalisib. I don’t know that it was used that much. I don’t know. And then there are others, duvelisib and some others. So, we’re talking about combinations and drugs that work differently, and you mentioned venetoclax which works differently than the BTKs. So does this third class come into play as well? Nicole, do you want to just…?

Dr. Lamanna:             

Yeah since we’re all familiar with all these agents. Idelalisib (Zydelig) was really looked at in the relapsed refectory. Patients who have already had treatment for their CLL. There were some front-line studies that were done but halted due to some toxicity issues, and so it never got moved up to front-line therapy. And then some second generation PI3 kinase inhibitors like duvelisib (Copiktra) and others. Duvelisib is approved.

So, they work on a similar pathway to ibrutinib, so the B-cell receptor pathway. And so certainly patients who may have intolerance to ibrutinib can certainly go on to a PI3 kinase inhibitor. Now of course, since there are second generation BTK inhibitors like acalabrutinib and zanubrutinib, can somebody tolerate, there’s been some studies with acala. If you’re intolerant with ibrutinib, many of them can be rechallenged on acalabrutinib. But certainly, you could switch to a PI3 kinase inhibitor.

I think we do have some data, many of it is retrospective data. But I do think we have some data that if you’ve really failed a BTK inhibitor, going to a PI3 kinase inhibitor is probably limited in terms of response duration, because it’s along that same pathway. You might want to switch class to a BCL2 inhibitor like venetoclax in that situation. We do have some data that really just shows it probably is not as good switching from a similar—in that B-cell receptor pathway agent going from a BTK to PI3 if you failed. If you’re intolerant, I think that’s a different issue.

Andrew Schorr:         

All right. So, we’ve talked about three kinds of oral medicines, three classes, right. Go ahead.

Dr. Davids:                

I wanted to pick up on what she was saying with the PI3 kinase inhibitors, because I fully agree. And one of the things that we’ve been interested in is rather than having to choose either the PI3 kinase inhibitor or the venetoclax, what would happen if we put them together?

And we saw some data at this meeting for the first time of those types of combinations. One of them was our study of the approved PI3 kinase inhibitor. It’s called a delta gamma inhibitor, because it targets a couple different types of PI3 kinase. So that drug, given with venetoclax for the first time. This was in a Phase I study, meaning we were trying to figure out what the right dose was and if the drugs were safe to give together.

So, our study was small. So far, we’ve only had 12 patients on. But it does look like a very safe combination and we’re seeing nice responses so far. And we’ve moved that now into a Phase II study to look at a larger number of patients and see how effective that particular combination might be.

Andrew Schorr:         

Okay. So, we’ve talked about oral pills here. But you had, as part of FCR, you had rituximab, and infused monoclonal antibody, a targeted therapy going after the cell. And I had that, and then I had obinutuzumab, a newer one. So, I’ve been hearing about monoclonal antibodies, especially in lymphoma, where it goes after two targets. So, am I right about this? Is that going to come into play, Dr. Hill?

Dr. Hill:                     

Yeah, so bispecific antibodies are sort of antibodies that link in some way to usually CD20, which is part of the…

Andrew Schorr:         

That’s on CLL cells. 

Dr. Hill:                     

…that’s on CLL and other B-cell cancers. And on the other end of the molecule engages T-cells, good normal healthy fighter T cells that can then kill the target. This approach has been—it is successful and there is an FDA approved drug for an acute leukemia, B-cell ALL. And there are data in B-cell non-Hodgkin lymphomas that show that that same drug called blinatumomab (Blincyto) actually has a reasonable activity. We’ve known that actually for several years. But it wasn’t really developed very robustly in B-cell lymphomas.

In terms of CLL, there are some data. I’m not sure it’s the best drug in the next sort of line of things for CLL because we have these other more easily administered pills. The blinatumomab, for instance, has to be given through a continuous infusion in the hospital. So, I don’t rule out that this class of drug may be useful for CLL in the future, but I’m not sure that it’s that high on the next list of things that are going to come up.

Andrew Schorr:         

So, you and I hear, among patients, about CAR T. Chimeric antigen receptor T-cell therapy. And we know some people who’ve had it successfully and some who haven’t. Okay, so should we talk about that?

Michele Nadeem-Baker:       

Yeah, that also is being discussed in the sessions here. And at this point, my jury seems to be out. I’m not at that point where I would need it. We do have patients watching who are at that point. Is it at the point, I think I heard, is it a 20 to 25 percent success rate?

Andrew Schorr:         

And how would you know who? Want to talk about it?

Dr. Davids:                

Let me talk about what it is first. It’s a little confusing. The idea here is you’re using a patient own T cells, there are usually infection fighting cells. But you’re harnessing the patient’s T cells, instead of fighting an infection to fight the CLL itself.

So, the way that it’s done is that you actually take the T cells out of the patient through a process called pheresis. For anyone who gives blood or platelets, these sorts of things, it’s a similar process. So, the cells come out of the patient and they get engineered in the lab to recognize CLL cells more effectively and they actually grow them up outside the body.

And then a few weeks later, a patient comes into the hospital, gets a little bit of chemotherapy, not quite as much as with a full FCR treatment. It’s kind of like one cycle of what you had. And then has a reinfusion of their own cells into their body. And then these cells can then, in theory, go around and kill off CLL cells and potentially with great longevity, because these cells can survive sometimes for years, we think.

So, there was some very exciting initial success in this approach in CLL. It’s actually some of the first published studies were in CLL patients. But very quickly, the field moved towards developing this therapy for other B-cell diseases like ALL and diffused large B-cell lymphoma. So, it’s only now in the last couple of years where it’s swung back to explore this technology in CLL patients.

It’s early days. We saw some data at this ASH meeting which did look somewhat promising from one of the compounds called JCAR017, which looks like a little under half of patients will have a complete remission. And these are patients who have already had venetoclax and ibrutinib in many cases, so it certainly looks promising.

But one of the challenges in CLL is that the T cells don’t work so well. That’s why CLL patients often get infections. And so, you’re relying on cells from the patient that may not be as effective.

So, one of the things we’re working on now is trying to combine the CAR-T cells with other drugs that might help the T cells to work better. So, it’s an area that still needs a lot of investigation. It’s not ready for prime time yet in CLL treatment.

Andrew Schorr:         

And that’s important. Now I recently interviewed a fellow I met who was from Ohio. And was being treated at Ohio State. And Jeffery Jones, who you know, they kept blowing through treatments that just weren’t working for him.

And he went to Seattle, with David Maloney out there who we’ve interviewed, and he’s now three years out in that trial. But we know other people who have passed away.

So that comes back to personalization of CLL treatment. How do you know who should get what, when? Nicole, do you want to comment on that?

Dr. Lamanna:             

Oh, sure. That’s the easy question. All the factual stuff. No, I mean, obviously, this is a very difficult question, because there’s a lot of things that come into play when we all see our CLL patients. Not only the person themselves, their age, their co-morbidities, heart disease, kidney function, and then in addition, what their CLL genomics, are they high risk? What the characteristics about their disease are? What prior therapies—if they’re untreated, obviously, we can talk about all that. But when you’re talking about getting to CAR T or maybe even an allogeneic stem cell transplant, you’re talking about how you choose those individuals down the line.

And so, you’re really looking at what their response was to other therapies, what they’ve gotten prior to, what complications or side effects they might have had to those therapies. So, there’s a lot that go into the mix of sort of going from one therapy to another. And so, it’s not a straightforward answer.

And obviously the benefits we see for some of the patients who have had CAR T, we’re trying to figure it out, similar to what we almost used to do with allogeneic stem cell transplant, we had the same difficulties with toxicity. And we would sort of reserve allo for the most refractory, the most relapse refractory patients. Although albeit, was that the right choice too, because then, of course, they did poorer—they might have had more toxicity with an allo.

So eventually, as CAR-T cells become safer and we have more data, I think that that may move. But we have so many of these other therapies in CLL currently, which we did not have let’s say in ALL. That the benefit is now there are many more options for CLL patients. So, I think CAR is still regulated to heavily pretreated right now, heavily pretreated patients. Although again, now the data’s out and now we’re starting to combine CAR T, like Matt was saying, with agents like ibrutinib and so on and so forth, so.

Andrew Schorr:         

So Dr. Hill, what kind of conversations should patients or their loved ones who may be an advocate for them with someone like you or whoever their doctor is, about discussing all of these options and sorting through what fits in with their life, what might work well for them.

Dr. Hill:                     

Yeah, so for starters, I think that it is really important for patients, if they’re being seen by a general oncologist to at least seek a one-time consultation with a CLL specialist. Because the field is moving at warp speed right now, the specialists in the field can’t even agree on things. And there’s so much new data coming out all the time that I think it’s really challenging for general oncologists who are treating an array of different cancers to stay up to date on those.

And they shouldn’t feel like they’re offending their primary oncologist. I think most primary oncologist are comfortable with at least getting a consultation either at the initial diagnosis or at the time that they may need treatment. I think even that second time is probably even more crucial.

Andrew Schorr:         

And you all take calls—I heard that you’re even doing some video consultations, Nicole.

Dr. Lamanna:             

I am.

Dr. Davids:                

We both are, actually. 

Andrew Schorr:         

Okay, so there are ways for you and your doctor to connect with specialists now. New ways to sort out this broad array of options.

Dr. Hill:                     

Yeah, I think most larger referral centers have various forms of e-consults that can be done. So, if travel is a barrier, that might be worth doing. 

Michele Nadeem-Baker:       

That’s such an important thing to talk about as well. Because there’s so many patients I’ve seen that contact us. They go to a community hospital. They don’t have any centers near them, any cancer centers nor specialists. And they’re going to either their PCP or a general oncologist, and they don’t know all the latest news that’s out.

Andrew Schorr:         

Yes, and what applies to them. So, when I was diagnosed, Michele, in 1996, I was in an HMO. And my dear doctor had to treat every cancer. And so, he was an employee of the HMO. And so, he knew what the standard for many years in CLL had been, which at that time was chlorambucil (Leukeran) and then they were kind of moving to fludarabine (Fludara) and cyclophosphamide (Cytoxan), but certainly not rituximab.

And so, he was recommending treatment. And then other patients said, on the internet in the early days of the Internet, hey, you should see a CLL specialist. And I had never been to Houston, Texas. I went there, I thought everybody wore cowboy boots. They don’t.

I went, and so Dr. Michael Keating there, who’s one of the senior guys in CLL, said no disrespect to your local doctor, but I don’t agree with what he’s recommending, where he’s saying start treatment now and use these drugs. Where I think we’re developing something better.

And in CLL, I like maybe you, and I think you for a while, I was in watch and wait.

Michele Nadeem-Baker:       

The watch and wait or watch and worry, as some people call it. But it’s true. I actually was diagnosed at a cancer center and they did not have a CLL specialist. This is pre-Dana-Farber days. And you would have expected that they would have had a CLL specialist. Hopefully, they do by now, I just don’t want to name it. And that’s why I went to Dana-Farber.

Is that they didn’t explain a thing. They just said you have CLL. I had to get to the point of what does that even mean? I mean, that’s how much we had to drill down. And then he said I’ll see you in a few years.

So that was very scary as a new patient. And also, I wished he had something, suggested, like what your doctor did, to go see someone. But I knew enough to get back to Boston.

Andrew Schorr:         

So, watch and wait, I brought that up.

Dr. Lamanna:             

We need to change that term. Can we change that term?

Dr. Hill:                     

Active surveillance.

Dr. Lamanna:             

Active observation. 

Michele Nadeem-Baker:       

Maybe we should do it right now. Twitter, hashtag. 

Andrew Schorr:         

We know that we can have—hopefully, it’s chronic. Hopefully nonaggressive, although some people, it is more aggressive. But if it is non-aggressive, still, our folks here, and we here, we’ve got all these options. In some many other cancers, you say let’s get on with it. If a woman had breast cancer, let’s get rid of it.

Dr. Hill:                     

So, can I take that one?

Dr. Lamanna:                     

Let me jump on that one next. I think we all felt that way.

Dr. Hill:                     

So, with the introduction of highly effective and well-tolerated treatments, like venetoclax with obinutuzumab, there is approved and opening in 2020 going to be a large national cooperative group trial to compare early intervention with venetoclax obinutuzumab at the time of diagnosis for high-risk patients, and compare that, again in a head to head randomized fashion, with deferred therapy. In other words, you watch and wait or do active surveillance until a traditional treatment indication develops. With the idea that if you can eliminate the high-risk clones or bad cells early in the disease you may be able to prevent what we call genomic instability. Or the acquisition of new mutations that we know occurs, particularly in patients with higher risk disease.

So, this is being led through the SWA group and it’s going to be opening next year and I think a lot of people are excited about that. 

Andrew Schorr:         

So Western Oncology.

Dr. Hill:                     

Sorry, sorry. SWA, yeah.

Dr. Lamanna:             

But can I just say, I mean, don’t get me wrong, I think all of us that are sitting here, everybody’s looking to find a cure for CLL. If there was a cure, then as soon as people get diagnosed, they would get that therapy and be done.

We haven’t gotten there yet. Even though what’s great is we do have all these promising agents and we certainly done better and improved survival and lessoned toxicity of therapies over time.

But active observation, we’re not poo-pooing, we don’t want people to think that’s—because people go nobody’s addressing my concerns. If you have a good relationship with your medical team that even when you’re on active observation, they should still be your go-to. And the benefit of doing that is you get to sit on the sidelines and watch the rest of us do all this other data. And thank you for participating in a clinical trial, is really sort of pushing the field forward, getting new drugs. And the field may be completely different two years from now to next year. I mean, it changes all the time.

And so, having that benefit of waiting, you may be on different types of therapies that have less toxicity or be better for the disease as we learn more about the biology and what may work better for certain subgroups. So active observation, I think, we need to change that.

Andrew Schorr:         

You took an oath, do no harm.

Dr. Lamanna:             

Do no harm.

Dr. Davids:                

First, do no harm. And I can’t tell you how many of my patients have been on observation for the last few years and have seen the entire field transform. The treatments that we have now are so much better than what we had just a few years ago.

So, I echo the remarks here. And I think it’s not obvious what pathway is going to win, and I think that’s great story because it has equipoise, as we talked about before. There’s a similar study that’s been ongoing in Germany called the CLL12 study, which took patients and randomized them to ibrutinib as an early intervention strategy when they didn’t otherwise need treatment. And it is comparing it to a placebo intervention. And we actually have seen some of the early data now for that study and it’s been very informative.

I think that really, we are seeing some side-effects from the drug, so there’s no free lunch. There’s been some patients that have had atrial fibrillation and infection and bleeding issues on ibrutinib and maybe those are patients that didn’t need treatment yet.

So, until we really show that we can improve the survival of our patients, we really don’t recommend an early intervention.

Dr. Hill:                     

And that is the primary end point of the US Cooperative group trial. The primary endpoint is overall survival improvement. Not just saying okay, we got your disease under control, because we know we could do that very easily at any point during active surveillance. We can get the disease under control with any of these approaches. But the question is it going to make a difference to do it now or later in a big picture.

Andrew Schorr:         

Okay, let’s talk about control. So how many bone marrow biopsies have you had? 

Michele Nadeem-Baker:       

Countless. So many I can’t remember now.

Dr. Davids:                

All right, that’s my fault. How I wrote the trial.

Andrew Schorr:         

So, none of us enjoy it. My myeloid doctor, because I have another condition, she believes in sedation. So, it’s kind of like a—we described it as colonoscopy without the prep, but anyway, and I just snooze.

But anyway, I recently had a bone marrow biopsy, okay. So, first of all, can we give you enough information without having that? And are there also new forms of testing coming to play to see how we’re doing? 

Michele Nadeem-Baker:       

Maybe we should talk about the purpose of a bone marrow biopsy. Drill it down.

Dr. Davids:                

Not everyone knows, so yeah. So, the idea is that CLL can be in many different places in the body. The three main places we can look are in the blood, in the lymph nodes, which we can see on CAT scans or we can feel on a physical exam. Or in the bone marrow, which we can really only get to by doing a biopsy.

Andrew Schorr:         

It’s a blood factory. 

Dr. Davids:                

Right, exactly. So, by using a small needle with some local anesthetic, sometimes with sedation, we can go in and take a look in the bone marrow and see what’s going on in the factory.

And right now, it remains an important thing to understand how much CLL is there. I think we’re going to get to this MRD, minimal residual disease technique where we can look at sort of a molecular level at how much CLL is in the blood. And we’re hopeful we can move towards a phase where we don’t have to do the bone marrow biopsies, we can really just tell from the blood. But we’re not there yet.

Dr. Lamanna:             

And there are certain circumstances where I think bone marrows are very important. There are patients who can develop autoimmune complications. If we’re also looking for patients where maybe they develop cytopenias, their blood counts get low. Maybe they’re on therapy. Is it due to the therapy or is there something else going on? And so, unfortunately, I think there are still some circumstances where bone marrow evaluations are important to do.

Michele Nadeem-Baker:       

I have a question that other patients ask me, have any of you had a bone marrow biopsy?

Dr. Davids:                

No. 

Andrew Schorr:         

Do you know John Gribben, who you know, well, you all know. I don’t know if he said he did one on himself—he couldn’t have done that. But he’s had it. But he’s had it I know. So, some people have had it. But let me ask you about this, other testing. So now you’re doing molecular testing, right. And that looks for one cell in how many?

Dr. Davids:                

Kind of the accepted standard right now is one in 10,000 cells. But we have some new technologies that can look at 1 in 100,000 even 1 in a million cells that we’re exploring.

Andrew Schorr:         

Okay. How does that come into play? Because I know my doctor, Kipps does it, and he talked about a number. What did you say, 0.6? 

Michele Nadeem-Baker:       

Mine.

Andrew Schorr:         

And I don’t know if mine was 0.11 or something like that. And I’m not sure I understand it other than my doctor said that was good. 

Dr. Davids:                

Right. So MRD is really a continuum and its sort of a rough measure of how much CLL is in the body. And I think of it as sort of a threshold effect. So, if we use the table as an analogy, so if you have this amount of disease, I can see that under a microscope. I don’t even need an MRD test. But as I get down to here, just below the table, there I can’t see it with a microscope, but I can use this molecular technique and I can see the cells there. So, as we go down lower and lower, there’s lower levels of detection.

So that’s 1 in 10,000. That would be what we call undetectable for MRD on the more standard tests we’re using now. But there may still be disease even lower at 1 in 100,000 or 1 in a million. So, the lower we can go the more accurately we can assess how much CLL there is in the body.

And the reason that this is so important is that that level of MRD does tend to predict how patients will do in terms of the progression of the disease and their overall survival, at least with chemotherapy-based approaches. And we’re learning now even with some of the venetoclax-based approaches it may also be important. 

Andrew Schorr:         

Nicole, did you want to add?

Dr. Lamanna:             

I was just going say, so that’s what we’re trying to figure out, right, because we have very good data from our chemo immunotherapy days that sort of made a clearer prediction. But with the novel agents, we’re still trying to learn how MRD will come into play for our patients. Can we use MRD in the structure of time-limited duration of therapy? So, you could say if you are MRD-negative or if we can’t detect anything, we could stop therapy. Does it have to be individualized? Do we continue therapy?

These are all the unanswered questions that we don’t have that hopefully some of the future trials will address. People who may still have low level of disease will go on to have continuous therapy, others will be monitored. Because in the end, we don’t know what that means. Because we know, given the ibrutinib data, there are some patients that still have disease that’s obvious, and yet, they’re doing well for many, many years.

So, we have to figure out how to apply MRD in the context of these novel treatments to our patients and then put that into clinical practice. And as Matt was saying, the technology is also getting better, so the level of detection. So standardizing testing for MRD is a whole other discussion.

Andrew Schorr:         

So, Dr. Hill, if you did an MRD test on me and I had, as you say, fixed duration. You took this powerful combination and now we can stop because your MRD is this. If it’s really low, I’m going to Europe. I’m taking a vacation. And that’s what I think—for patients, it’s sort of a report card for us where we can go on with our life.

Dr. Hill:                     

Yes. No, you want to feel like you’re out of the woods so to speak. But I think it’s important that we use the terms—because the terms get confusing. When we say MRD undetectable, I agree with what Matt was saying, is that we can’t detect it. That’s a little bit different from them saying zero. Because negative and zero means there’s nothing there as opposed to saying that we can’t detect it.

So, unless we think we’re curing someone, which we do with other cancers. We can cure certain types of aggressive lymphomas, for instance, with six rounds of chemotherapy and the cancer never comes back. So, by definition, they are cured and have zero cancer cells in their body at the end of treatment.

Andrew Schorr:         

So MRD-negative, you’re not calling what they do in solid tumors, no evidence of disease. You’re not using that term.

Dr. Hill:                     

I would say no evidence of disease but notice no one’s using the word “cure” here. But I think it’s important to know that it is possible to cure blood cancers with systemic or drugs that go everywhere in the body.

Andrew Schorr:         

But since this is a long-term chronic condition, today you can’t say if the people you have, who have you cured already? You don’t know.

Dr. Hill:                     

Exactly. But I think it’s not out of the realm of possibility that we could be curing people with CLL, even though every textbook says its incurable. I think the asterisk there should be with current treatments it’s incurable. But we actually may have already cured some people with venetoclax and ibrutinib and we won’t know for another five years or 10 years.

Dr. Lamanna:             

Or with FCR.

Michele Nadeem-Baker:       

How many years do you know? Because Andrew was in remission for 17 years.

Dr. Lamanna:             

Right. That’s what I’m saying. 

Dr. Hill:                     

And you can talk about a functional cure too. 

Andrew Schorr:         

Seventeen years, no medicine. I just loved my life.

Dr. Lamanna:             

And partially, that might be biology driven and have nothing to do with therapy, that that person didn’t need all that much.

Andrew Schorr:         

Okay. So just to wrap up, for our audience, it sounds like you have an ongoing and growing array of treatments, combinations you’re investigating, new modalities, we’ll see about CAR T or other approaches. So even if you’re living with CLL at detectible but micro levels, it sounds like—it’s always my image of whack-a-mole, that you have something to whack the mole. Is that fair? Not for everybody. I haven’t talked about transplant at all. I don’t hear about that anymore. That you’ve seen from many people, not that people don’t pass away, because they do. But for many people now you have continuing options that materialize based on your research and us participating and you participating that create hope for us.

Dr. Davids:                

Absolutely. It’s a very hopeful time for CLL patients. We have a lot of courageous patients like Michele who have come on these clinical trials and helped us to identify these new standards of care. And so, I’m very hopeful for my CLL patients going forward. 

Dr. Lamanna:             

Yeah, absolutely, it’s a great time for the patients and the researchers. We’re moving the field forward. I think we do need to be—as exciting as all these things are, we need to sometimes pull back and be a little more conservative and wait for some mature data before we translate certain things into prime time or standard of care, I think. Because sometimes I think we get ahead of ourselves. And so, we do need to take a little time to make sure things are being done appropriately. 

Andrew Schorr:         

How about you, doctor? 

Dr. Hill:                     

I completely agree. I tell all my patients that the pace of discovery is likely to outpace their disease. So, by the time they need another treatment, we’ll have another one figured out.

Andrew Schorr:         

Yeah. Good for you. Thank you for all you do.

Michele Nadeem-Baker:       

Thank you so much.

Andrew Schorr:         

These folks do research and they are specialists. They take the calls, they go on video calls, they do all these things to help people around the country, around the world. Are you hopeful?

Michele Nadeem-Baker:       

I am more hopeful than ever now after hearing all things here at ASH. 

Andrew Schorr:         

This woman called me years ago. She was a nervous Nelly.

Michele Nadeem-Baker:       

I was. He is the first CLL patient I ever met out there. 

Andrew Schorr:         

And here we are. Years later.

Michele Nadeem-Baker:       

Exactly. 

Andrew Schorr:         

Okay. Well, thank you for being with us. Remember, take advantage of consulting or having your doctor consult with a specialist on your behalf if you don’t have a specialist right there. So that this array of options is brought to bare for you. And should you have had earlier treatment and come out of remission, what’s available for you then. Always consider clinical trials. And take a look at all we got on Patient Power because we continue to do programs for all of us with CLL.

I’m Andrew Schorr, and you are? 

Michelle Nadeem-Baker:                    

Michele Nadeem-Baker.

Andrew Schorr:         

And what do we like to say?

Andrew Schorr and Michele Nadeem-Baker:           

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.

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