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Your Questions, Expert Answers: CLL Treatment, Research and More

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Published on December 12, 2019

During this “Ask the Expert” program, dedicated chronic lymphocytic leukemia (CLL) researcher Dr. William Wierda from MD Anderson Cancer Center joined Patient Power at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando to answer questions on treatment, side effect management, testing and more. What is the side effect profile for novel agents? Is genetic testing recommended for CLL patients in watch and wait? How does minimal residual disease (MRD) status impact care? Watch now to find out from a CLL expert.

This program is sponsored by Pharmacyclics and Janssen. This organization has no editorial control. It is produced by Patient Power, and 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

Transcript | Your Questions, Expert Answers: CLL Treatment, Research and More

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, it’s Andrew Schorr from Patient Power, and of course living with CLL, for what, 23 years. Thank goodness. We’re going to go scuba diving soon, so you can lead a full life, and I hope you can. I’m certainly trying to. We are in Orlando, Florida. And this is our live, Ask the Expert program. We’ll be doing a lot more on CLL, and I’ll tell you about that as we go along.

First of all, whatever we talk about today, remember to discuss with your own doctor, so you get the treatment that’s right for you. If you have a question, and many, many people have, send it to cll@patientpower.info. We’ll do our best to get to it or save it for one of the many other programs that we’re doing, and I’ll tell you about that.

Where are we? Orlando, Florida. It’s beautiful here, although I live in California, so it’s nice there too. But I’m right across the street from the Orlando Orange County Convention Center, 25,000 people who specialize in blood conditions, and especially blood cancers. CLL, of course is one, and CLL gets talked about a lot. So, that’s why we’re doing this now, right here at ground zero. With me is a good friend of mine, Dr. William Wierda. Bill Wierda is the Medical Director in the department of leukemia at MD Anderson Cancer Center, where I initially had treatment way back in 2000, in the FCR trial. Worked for 17 years. Yes, I was treated again at UC San Diego, where you used to be earlier on, and I remain in remission for CLL.

Okay, got questions? Are you ready to go?

Dr. Wierda:         
I’m ready to go, thank you for having me. It’s always a pleasure to sit and chat with you.

Andrew Schorr:          
All right. This is like a game show, we’ll try to do a lightening round as we go here, too.

Okay, Natalie said, “Do patient’s on ibrutinib (Imbruvica), who have terrible mouth sores, get relief from mouth sours if they switch to another drug, acalabrutinib (Calquence)?” Is it all about the ‘nib’ or is it about managing something else? 

Dr. Wierda:         
So, we do see mouth sores in patients who go on ibrutinib, we skin rashes occasionally. They’re not common, there is another problem that can cause mouth sores that we like to make sure isn’t the case in patients who develop mouth sores, and that is herpes, oral herpes outbreaks, which can cause mouth sores. So, in patients who have mouth sores, it’s important to rule that out. You can do a swab for herpes, or you can empirically treat with acyclovir, or valacyclovir. If it doesn’t go away, then it could be from the ibrutinib. We have reduced the dose of ibrutinib in some patients, and that has been successful. 

If that’s not successful, then we do have an alternative, BTK inhibitor that could potentially have the efficacy, could have efficacy, and not have the mouth sores.

Andrew Schorr:          
Okay, so about these drugs though, they all have their own side effect profiles.

Dr. Wierda:         
They all have their own side effect profiles. There are different side effects that each of them have and there are similar side effects. So, one of the side effects that seems to be common across BTK inhibitors is atrial fibrillation, we see that with acalabrutinib, we see it with ibrutinib. One of the questions is, is there difference in the incidence? Is it more common with one or the other? There really isn’t any data yet that clarifies that for us. We do see it with both medications. They both increased risk for bleeding and bruising. Acalabrutinib and ibrutinib, there hasn’t been any comparative data to clarify if there’s a difference between those two agents. So, we do anticipate that risk of atrial fibrillation, risk of bruising or bleeding.

Ibrutinib has some that seem to be somewhat unique to it, compared to acalabrutinib, and vice versa. So, for ibrutinib, we see some rash, sometimes we see muscle aches and pain, joint aches and pains, oral ulcers, fingernail problems and sores around the nails. With acalabrutinib, we do see headache, particularly in the first month or two when the patients are going on treatment, and we can see with both of them GI intolerance, diarrhea. 

Andrew Schorr:          
I want to make the point though, and we obviously get e-mails from you folks. A lot of people on these medicines will learn more about acalabrutinib, but with Imbruvica or ibrutinib, have been on it for years doing quite well. So, some people have these issues, but not everybody. Or it could change over time too.

Dr. Wierda:     
Yes.

Andrew Schorr:          
Ready for more? Okay, Judy sends this one in, “Still, stage I, watch and wait. Wouldn’t it be best to have the FISH test, and the genetics test done now, before any possible treatment would be needed? My oncologist says, “Not needed yet.”

Dr. Wierda:         
And I would agree with her oncologist. We like to know those things about patients. I like to know them, even when patients are in watch and wait, because my opinion is it gives a much better picture of the patient for me, what to anticipate, how closely I need to watch the patient if they have high risk features. And I’m inclined to see them more frequently to make sure that they’re doing okay. You don’t need those prognostic factors if you’re still in the Watch and Wait. You really do need them though when you’re deciding on treatment and selecting treatment. So, for sure your patients need to have them when they start on treatment.

Andrew Schorr:          
What about when you change treatment? 

Dr. Wierda:         
And when you change treatment. In patients who are in watch and wait, they don’t tend to change, but there is a low chance that they could change. So, if you have them when you’re first diagnosed, then you really do want to recheck them when you start on treatment. Especially, if it’s been a year or two between diagnosis and treatment. So, if you’re being conscientious about resources, etc., you can watch and wait, test before you start treatment, retest if you need to change treatment. 

Andrew Schorr:          
Okay, another test question, and there’s a lot of buzz about this across a number of conditions here. MRD, whether you call it minimal residual disease, measurable residual disease; we got this question from Anne. She says, “What is MRD? What does it measure? And should MRD be a goal, or when do you test for MRD?”

Dr. Wierda:     
So, MRD is minimal residual disease, or measurable residual disease. It’s a test that is a way to look for low levels of leukemia in the blood, or in the bone marrow. It’s important, not in patients who are in watch and wait, or are not treated. But it’s potentially important in patients who are going on treatment, and especially in patients who are going on treatment, where you’re giving treatment for a set period of time.

If you’re giving treatment for a year or two years, and we can talk about the different types of treatment where that’s a goal, and at the end of that time point, if you’re measuring minimal residual disease, the MRD status—so if you’re MRD-negative at the end of that fixed duration treatment, the likelihood of having a long remission is very high, and it’s higher if you're MRD-negative. You’ll have a longer remission than if you’re MRD-positive at the end of treatment. So, it’s a test now that we do on our clinical trials, because it shows how deep the remission is, the quality of the remission is reflected in how low the level of disease if most patients are MRD-negative, that is a very high-quality remission for those patients.

And as I mentioned, we’re testing it—we usually test it serially, through treatment because we like to see how well patents are doing through their treatment, at the end of treatment. And we anticipate that that will correlate with their remission duration, how long they’re in remission. If they’re MRD-negative, it’s going to be a long remission.

Andrew Schorr:          
I don’t know you remember this, but maybe six years ago, I had a test at MD Anderson, and then you called me, and you said, “Andrew, you’re not MRD-negative.” I said, “What does that mean?” And you said, “You’re going to need treatment—probably someday.” Okay, and so I remember that. And guess what. It was a few years later, I needed treatment. Now I’m—your former mentor Tom Kipps says, “I’m really low, I’m not MRD-negative, but I don’t see it as a report card, it just helps me think about it. 

Dr. Wierda:         
Exactly, and that’s just like the prognostic factors and giving us a picture of the patient’s disease, and what to anticipate, and how closely we need to monitor them.

Andrew Schorr:          
Okay. All right, Elliott wrote in, “I developed dermo—I can't even
say it, myositis, due to either my CLL directly, or from—he said he wondered about from ibrutinib, he didn’t know. He wondered whether it was from the drug because it showed up after he started on it, but it’s not gone away, or so he says. Well, is this common? And basically, what do you do about it?

Dr. Wierda:         
So, it’s not common, it’s something that’s unusual. If the onset was associated with starting ibrutinib, then there could be an association with the treatment. In terms of any medical intervention, we start a medication, whether it’s an anti-hypertensive, or what have you.

If something happens soon after you start the drug, then you suspect that may be in some way associated with the drug. Whether it’s directly from the drug—and we don’t see dermatomyositis really as something that’s caused by ibrutinib, it may be an immune dysregulation that has been triggered by starting treatment, and becomes clinically revealed in this particular patient, whose gone on a treatment. And in this case, I would probably stop the ibrutinib and treat the dermatomyositis, and it should improve with treatment. And then, he can go back to treating the CLL.

Andrew Schorr:          
Okay. Here are a couple of questions, both from Emile, and also Paul. They’re kind of asking about the same thing, and they’re wondering about some spontaneous changes. So, Emile wants to know, for a patient on Watch and Wait, what could cause a white count to suddenly drop into the normal range after being high for 20 years?

Dr. Wierda:         
So, we do—so, that would be referred to as a spontaneous remission.

Andrew Schorr:          
Which is what Paul asked about.

Dr. Wierda:         
Yeah, we have seen them, and they’ve been reported in the literature. If I were to do a test on Paul, an MRD test, I would anticipate that there would probably be some measurable disease by these special tests that can detect 1 in 10,000, one leukemia cell among 10,000. So, although the white count has gone into the normal range, I would anticipate that I could be able to do a test and show that there’s still CLL there, although at a very low level. The white count does fluctuate over time, usually the trend is it for it to go up. There are patients who remain very stable over years, for 20 years, and rarely we will see the white count go down into the normal range. 

There was a patient that I have taken care of for many years, 15 years. He went on a vaccine trial as an untreated patient, he got a vaccine 15 years ago. His white count stabilized for several years, and over the last five years he’s gone down into the normal range. So, there are fluctuations in where the cells stay, where they like to live, and the levels can increase and decrease over time, even without any treatment. 

Andrew Schorr:                
Okay, so just to—I’m thinking about watch and wait, watch and worry, right? Okay, any new thinking about that? Like, we’re here, you guys are all comparing notes. I went four and a half years, is there anything thinking, with all the different treatments you have now, reason to start earlier, either with one therapy or a combination that can maybe bop CLL on the head and be done with it.

Dr. Wierda:     
Today, I feel much more comfortable and can make a much more compelling argument to watch and wait, than I could five years ago.

Andrew Schorr:          
Really?

Dr. Wierda:         
And the reason for that is there was a recent trial with ibrutinib, where they looked at early treatment with ibrutinib for patients who were in the watch-and-wait phase but were supposedly at higher risk for transitioning over into needing treatment. There didn’t really need to be any clinical benefit with early treatment in that trial. There’ve been many trials done with chemotherapy that have not shown any clinical benefit with early treatment. And our treatments are progressing so fast, and we’re making so much progress in the short-term, my argument is you got to wait because something better is coming along.

We feel that these combinations that we’re working with are probably curative in patients, we need sometimes to demonstrate that. And so, the optimism is so great now that we will have something curative for many patients, and that’s going to happen in a short period of time. And patients need to be okay, and comfortable with waiting because when you need treatment, then you should get it, and I would encourage patients to look for clinical trials with new combinations, etcetera because we think that those are better than what we now have as standard.

Andrew Schorr:          
I’ve got to ask this question folks because we’ve been following all these new ‘nibs, and venetoclax, and different drugs, and Gazyva, obinutuzumab, and all those things. Okay, so you’ve talked about combinations. So, with some of these drugs, we’ve been told, “You have to take them forever. Or some, we can get you to an MRD status, and you can stop.” As you’re combining them in trials, do you think we can have, I guess what you call, fixed duration therapy? By maybe having two powerful, and let’s face it, expensive drugs, or whatever the combination is, but that we can say, “Stop.”

Dr. Wierda:         
For most of the patients, so for example, Nitin Jain presented data from our ibrutinib venetoclax (Venclexta) data, clinical trial today, here at ASH. This is a trial of ibrutinib for three months, and then combination therapy for up to two years, or 24 cycles. At the end of the 24 cycles, about 75 percent of those patients who reached that time point are MRD-negative. So, they have a very deep remission, and we’re stopping treatment in those patients who are MRD-negative.

So, that’s three fourths of the patients who are MRD-negative, and the expectation in that setting is that they’ll have a set many years of remission before they potentially need treatment, if they’re disease comes back. So, one of the questions is for those three-fourths of the patients, are there are patients who are cured? We don’t know yet. That’s something that we are working on studying. And then, the other question is, for those patients who disease does come back, how long are they in remission, and what’s the expected time to needing the next treatment? And we’ve been discussing a lot internally with, “How are we going to treat those patients?” 

Physicians in their mind, have some thought that you lose all of the potency of the drugs if you use everything together up front, and I don’t think there’s any rationale, or data, that confirms that. So, I think patients, when they need treatment again, will still be responding to the targeted therapies that we have, whether we give a combination targeted therapy, or if we give ibrutinib. And so, we’re looking at patients and how long their remission lasts, and what do we do when the disease comes back and they need to be treated.

Andrew Schorr:          
And no penalty for a cessation.

Dr. Wierda:         
No penalty for cessation, and we haven’t been in this situation on our clinical trial that opened in 2015, where a patient has relapsed and needed to be retreated. So, we’re seeing very good deep remissions that are lasting, and we’re very enthusiastic, very excited. There’s a lot of questions—as we have these clinical trials, there’s a lot more questions that get generated in areas that we need to study and focus on, but it’s all good.

Andrew Schorr:          
Okay, great. John asked the question, he said that he was diagnosed in July 2019, so a few months ago. Stage Zero, CLL, are there any types of CLL that can be dormant for a very long period of time? I should mention my friend Pat in Seattle, he was diagnosed in 1996, high white count, never been treated. So, dormancy, or smoldering that’s stays smoldering? 

Dr. Wierda:         
The smoldering’s usually have a low count. You won't usually see a high count that’s smoldering. 

Andrew Schorr:          
His was 50,000. 

Dr. Wierda:         
So, the answer to the question is yes. And most of the time when I see patients in the clinic, and they’re newly diagnosed, and they have a reasonable white count, 20,000 or higher. If I asked them to go back, if they can go back and look at old lab tests, a lot of times you can see an indication that there probably was CLL there that people just didn’t pick up on years ago. So, the answer to that, yes. Most of the time there’s several years of undiagnosed… 

Andrew Schorr:          
…but there is a percentage of smoldering where it never goes anywhere.

Dr. Wierda:     
Right.

Andrew Schorr:          
What’s that percentage? 

Dr. Wierda:         
I would say it’s less than 20 percent.

Andrew Schorr:          
But Pat’s still there. Yay Pat. Okay, here’s Barry, he says, “Is there higher incidence of Richter’s transformation or syndrome among patients? Just being younger with CLL, do you have to worry about it more?

Dr. Wierda:         
No. The problem with being younger in this situation is that you have a long time that you’re going to have CLL. And if the CLL progresses and needs treatment, then—I mean, a 40-year-old individual wants to live 50 more years, or 40 more years, that’s different than a 70-year-old person who’s willing to take an additional 10 or 20 years.

So, the challenge with younger people isn’t that they have more aggressive CLL, it’s just that they have a longer period of time with the disease. And it’s—things are much better today for younger people because we have all these targeted therapies, and patients are living longer with CLL. My opinion is that for a 70-year-old, in the past, if we only had chemotherapy, or chemoimmunotherapy, my opinion was that their lifespan was shortened by the diagnosis of CLL, if they needed treatment. And now, for a 70-year-old, if they need treatment, that’s not necessarily the case because we have many different treatments that we can give them. They’ll need treatment, but I don’t think they’re lifespan is shortened by…

Andrew Schorr:          
Bill, I got to ask you about CAR T. You guys are really smart, chimeric antigen receptor T-cell therapy, experimental in CLL. Some patients have done really well with it, and some, quite frankly, we know some, and you may know some, who have passed on. We wonder if other things aren’t working, is that an option? So, you at MD Anderson, and your peers been working—first of all, how can you have predictors, whether it’s going to work for somebody? And also, how can you tweak it, so it's maybe more efficient, less expensive, other approaches. So, where are we—there’s buzz here about CAR T. 

Dr. Wierda:     
Right, so there’s a lot of buzz about CAR T. There’s a lot of attention, there’s a lot of enthusiasm. It’s really only available right now for patients with CLL on clinical trial. There’s not a commercially approved product for CLL. Sometimes we can get approval for commercial product for Richter’s transformation, but that’s not common, and it depends on the insurance company that’s approving the CAR-T for Richter’s transformation.

For acute lymphoblastic leukemia and lymphoma, which is a more aggressive B-cell disease, CAR-T is very effective, and complete remission rates about 80 percent. In CLL, in the clinical trials that we’ve been doing, the completely remission rate is lower. It’s about 50 percent. So, we’re trying to figure out why the complete remission rate tends to be lower in CLL compared to other B-cell malignancies. So, we’re trying to figure out ways that we can make the CAR-T cells work better.

One of the approaches has been to give CAR T, along with ibrutinib because we think the ibrutinib may help the CAR-Ts to work better. Patients with CLL, their T-cells don’t work well, they don’t work normally. And that also, I think, applies to these engineered CAR Ts, when you take the T cell out, manipulate it to express the CAR, and then give it back to the patient, it doesn’t work at well as if you do the same thing with a lymphoma patient, or a patient with ALL. So, there is more work to do, it does have toxicities, and we’re interested in CAR NK-cells.

So at our institution has done some work with CAR NK cells, which is a different approach. We’re taking NK-cells from cord blood and engineering them to react against CD-19. We’re giving those to patients as a strategy, so you don’t have the same time factor that you do if you’re producing it from the patients own blood T cells. And then there’s allogenic T cells, which are T cells from donors, that are being engineered with CARs, and those are being testing in patients with CLL. 

Andrew Schorr:          
Okay, so it’s a very active area of research.

Dr. Wierda:     
Very active. Our research—and there’s work to do. And it does have—as you said, there are patients who do well with CAR T-cell therapy. Patients who have disease that’s resistant, or refractory to standard treatments, like BTK inhibitors, and venetoclax. We would like for the response rates to be higher, so that it works for most of the patients.

Andrew Schorr:          
Okay. Dan asked this question, he said, “I’m scheduled to start taking venetoclax for two years, and I know that you can become resistant in time. Is there any insight into what the next course of treatment might be if I become resistant?” And maybe you can explain resistance too. 

Dr. Wierda:         
So, resistance with ibrutinib, or the BTK inhibitors, as well venetoclax, to me, means that the white count is rising, and the lymph nodes are growing while the patient is taking the drug. Resistance is not a common phenomenon with BTK inhibitors, it’s also not a common phenomenon when patients are on venetoclax. So, it sounds—if he’s going to take two years of venetoclax, it sounds like he’s probably getting it as a subsequent treatment, so he’s probably had something before the venetoclax. So, he should get it with rituximab.

So, in this setting, where patients were previously treated, and they’re getting venetoclax, the standard of care is to give with rituximab. And that’s for the first six months, and then we think the rituximab helps the venetoclax to work better, or vice versa. The venetoclax helps the rituximab to work better. And the remissions are deeper, and a better quality with that combination, than if you get venetoclax by itself. And so, he should get two years of the venetoclax, this is the standard treatment. We usually will stop treatment at the end of two years.

Now, there are some patients that we know when you stop in this setting, their remission may be shorter. Patients with the 17P deletion for example, patients who are MRD-positive at the end of the two years. So, you should have a discussion with his physician at the end of the two years about testing for MRD, and discussion if he has 17p deletion about whether he would like to continue the treatment or stop at that point. If you stop at that point, he’s going to get a remission, and depending on how long that remission lasts, if the disease comes back, then he goes back to treatment with venetoclax. 

Andrew Schorr:          
Or you many have a new combination.

Dr. Wierda:     
Or you may have a new combination.

Andrew Schorr:          
Because your two years down there, you guys will be much smarter.

Dr. Wierda:         
Exactly.

Andrew Schorr:          
Okay, so here is a question from Phyllis, she said, “I was diagnosed two years ago, feel pretty good except for occasional tiredness. And fatigue, certainly people complain about. Every morning when I wake up, I wonder if today is the day that I will have a negative change in my CLL. How do I calm down?” In other words, it’s just the uncertainty of the future. What do you tell people?

Dr. Wierda:         
Sure. And so, this is a common discussion, especially for patients that I see for their first-time visits. And I think for CLL, most of the time, the majority of time, almost all the time, you don’t see abrupt changes in the disease. So, it’s not like you’re going to go to bed, and the next morning your white counts going to have doubled, or your hemoglobin will have dropped below 10. Things happen gradually. For some patients they’re more gradual than for others, but even though patients who have changes that are more rapid, it’s on the order of months. It’s not on the order of days or weeks where we see changes.

If there are abrupt changes, the nodes are flaring, or they become tender, or the white count goes up rapidly, I usually will recheck the labs to make sure that it’s a true change. And I would look for other things that can explain those changes, like infection. We see changes in white count, we see flare in the nodes in patients who have infection. And sometimes patients with infection don’t manifest the same symptoms as individuals who have a normal immune system. So, you can have a patient whose getting real fatigued and feeling tired, they can a pneumonia, if things are changing and it’s happening quicker, I look for other things.

Andrew Schorr:          
Call the nurse, that’s what I do. You remember Sharon—or Mary with Dr. Kipps, been there many, many years. I just, “Sharon, somethings going on here.” And certainly, infection in CLL, and you talked about heart issues related to some of these drugs. If you’re dealing with heart issues, and somethings acute, ER, right?

Dr. Wierda:         
Yep.

Andrew Schorr:          
Do not pass go. We did a program about that that’s coming out soon. We mentioned about this 17p deletion, we talked about a long time, is that more aggressive CLL? But not you have all these treatments that seem to cover that, and so, Rick says, “Is it possible for those of us with 17p deletion to reach remission?”

Dr. Wierda:         
So, the answer to that is yes. 

Andrew Schorr:                
Yes. 

Dr. Wierda:     
We still worry about patients with 17p deletion because while they do much better today with drugs like ibrutinib, and venetoclax, they still don’t have many years of disease control with those drugs. So, the average period of time ibrutinib, for example, or venetoclax work for patients who have 17p and have some prior treatment, is about two years. So, we can expect about two years’ time where the disease will be controlled. Some patients it might be shorter, in some patients in might be longer, but for CLL, two years is a short period of time, as you know. And so, we still worry about patients with 17p. We’re looking for combinations.

We do see complete deep, complete MRD-negative or undetectable MRD remissions with venetoclax-based therapy. So, yes you can get a remission, yes you can become undetectable with regard to MRD if you have 17p deletion, and get treatment, but we still worry about those patients.

Andrew Schorr:          
Of course, and the patient worries about it, but still sounds like they have a lot to offer you. So, okay, so many of us have other conditions. So, Tom, I think, takes a blood thinner, and he says, “Is there extra risk for CLL patients if they take blood thinners? My doctor always asks about bleeding gums and nosebleeds, so I wouldn’t want to complicate my condition.” So, he worries about that.”

Dr. Wierda:     
So, bleeding problems can happen if you’re on medicines that inhibit the function of your platelets, which is a type of cells that are circulating in your blood. Also, a low platelet count can be a risk for bleeding, and there are drugs that inhibit platelet function that can increase risk for bleeding, aspirin, and then there are blood thinners that patients go on that also increase their risk. So, in patients who are on blood thinners, and particularly those who are on more than one drug that will thin the blood, and in patients who have a low platelet count, we ask about those types of things, because we worry about them. 

Andrew Schorr:          
Okay, but we have co—what do you say? Co-morbidities, is that what you call them?

Dr. Wierda:     
Co-morbidities, yes.

Andrew Schorr:          
They have lots of heart medicines, all sorts of stuff. 

Dr. Wierda:         
Sure. 

Andrew Schorr:          
Okay, and that may—some of that may affect the choice of any of these new medicines you’re talking about. If you have a heart issue, would you go on a BTK?

Dr. Wierda:         
That’s not a contra-indication to go in on a BTK, really the only contra-indication in that regard to going on a BTK inhibitor is warfarin. Patients who went on the original trials with BTK inhibitors were excluded if they were on warfarin. So, patients have to either go off warfarin, or coumadin, is a blood thinner, and then go on the BTK, and be anticoagulated with an alternative.

Andrew Schorr:          
Okay, so there’s the elephant in the room, I always ask you about this, and maybe it’s changing at this meeting here, the ASH meeting. So, you continued, and at MD Anderson had a place for chemo. Fludarabine (Fludara), cyclophosphamide (Cytoxan) with rituximab (Rituxan), so but yet there are other of your peers who say, “No, chemo dead. We got all these other things, we got all these combinations of pills we can do, or monoclonal antibodies, what do we need chemo for because there’s a slight risk of second cancer, etc.

Dr. Wierda:     
Right.

Andrew Schorr:          
What do you say on that today?

Dr. Wierda:     
So, today we still think there is a role for chemo for a particular group of patients, those are patients who don’t have 17p, or mutated TP53, and do have a mutated immunoglobulin gene, and are younger, and fit, and can tolerate chemotherapy; fludarabine and cyclophosphamide particularly. Those are patients who we’ve treated historically and have many years of follow-up with FCR.

Andrew Schorr:          
God, a 17-year remission.

Dr. Wierda:     
And those are patients who—about half of them remain in remission and don’t have detectable disease longer than 10 years. And that’s the group of patients that we’ve talked about potentially being cured. That’s 50 percent of the patients with a mutated V-gene, who get FCR. In my opinion that’s—I mean, 50 percent is a good cure rate, but it’s still, we do worry about the second malignancies, and the risk with chemotherapy and the challenges we have when we give it.

So, we have a clinical trial that we’ve been working on, where we’re reducing the amount of chemotherapy that we’re using. So, instead of six cycles of chemo, we’re giving three cycles of chemo. We’re adding ibrutinib for—and patients take ibrutinib for a year on that clinical trial. And we’ve changed rituximab (Rituxan) for obinutuzamab, and with that combination, which we call IFCG, and that will be presented tomorrow. We’re seeing everybody who finishes the one year of treatment, they’re all MRD-negative at the end of treatment, and we have correlated this long-term remission with MRD negative status.

So, if you have a mutated V-gene, no 17p, or TP53, you get FCR, and your MRD-negative at the end of the FCR. Those are the ones that we think we are probably curing. So, we have an early indication that we use, which is MRD, and the clinical trial that we’re doing with IFCG, one of the early readouts that we’re looking at is MRD negative status. And we’re very encouraged by what we’ve seen. We have not seen that high of a MRD negative rate with our FCR, our historic FCR. 

Andrew Schorr:          
How long would you be on ibrutinib in the IFCG?

Dr. Wierda:     
One year.

Andrew Schorr:          
Okay. All right, so we’re trying to get to where we had been for many people with FCR, where you have it for a fixed amount of time, and then hopefully the CLLs been knocked way down, or out, and you go on with your life.

Dr. Wierda:         
Exactly. We’re doing that also with the other—for patients who have an unmutated V-gene. For patients who have an unmutated V-gene, we know if we give them FCR, most of them we can get in remission. The problem is, is that their disease will come back, and so for patients with an unmutated V-gene, we prefer to say, “Okay, no chemo. We got a lot of options. We can work on getting you into a deep remission with combination of targeted therapy, and with that deep remission, we should see a long-term remission.

Andrew Schorr:          
Okay. Rob wrote in, “Recent liver workup shows mildly increased liver, LFTs in his liver function test. And the conclusion was CLL is causing an increased LFTs. Would this be a consideration to start treatment?” He hasn’t been on treatment, now something’s going on with his liver, should he start treatment?

Dr. Wierda:     
That’s not usually a reason patients start treatment. I think he needs to see a GI doctor or liver specialist to get a good workup. There are a lot of things that can cause elevation in liver enzymes. Elevation in liver enzymes means that there’s some inflammation in the liver. There’s a lot of medications that can cause elevation in liver enzymes, hepatitis viruses can cause elevation in the liver enzymes. And I think one of the things that people don’t realize is that there are over the counter vitamins and dietary supplements that will commonly cause elevation in liver enzymes.

So, he needs to see a GI specialist, a liver doctor. Get a good evaluation, exclude all of those things that could be causing it if they can't identify anything that could be causing it, like viral hepatitis, and medications, or over the counter supplements. Then have a discussion about perhaps starting treatment for CLL. 

Andrew Schorr:                
All right, but don’t jump to that.

Dr. Wierda:     
Yeah, I wouldn’t jump to that automatically, and it’s not a common—that would be a rare reason that somebody would need to start treatment.

Andrew Schorr:          
Okay, we’re going to wrap up in a second. I just want to make sure we hear what sort of is brewing here. So, there’s a lot of discussion about minimal residual disease, you’re working on a lot of research related to CAR T-cell therapy, but probably even more immediate is you’re looking at combinations of this wealth of medicines. You have both approved and experimental to hopefully get to fix duration therapy for more people.

Dr. Wierda:     
Exactly.

Andrew Schorr:          
Did I get it right?

Dr. Wierda:     
Yes. The other topic that’s being discussed, and we’re starting to see more data on, are the reversible BTK inhibitors. Patients… 

Andrew Schorr:          
…what does that mean?

Dr. Wierda:         
That means—so, the way that ibrutinib works is that is binds chemically to BTK. And when it binds chemically to BTK, it blocks the function of BTK. And when that function is blocked, the CLL cells die, and that’s how ibrutinib works. One of the problems we see in patients who’ve developed resistance to ibrutinib, where their disease is growing on ibrutinib, is that they’ve mutated, so that it can't bind. Ibrutinib cannot bind, it mutates so that it can't bind to BTK. The BTK has become mutated, and so the ibrutinib won't bind, it doesn’t work then. And so, ibrutinib is one of the mechanisms—you just can't bind and knock out the function.

So, some of these other drugs that are being developing, don’t have to bind to that particular same place as ibrutinib binds to. They can bind around it or in a different way, and theoretically, they may have activity in patients who have developed resistance to ibrutinib, or acalabrutinib, any of the irreversible inhibitors, zanubrutinib, acalabrutinib, and ibrutinib. So, there’s several, three or four, reversable inhibitors that are in early clinical development. 

Andrew Schorr:          
Do these just have numbers? Or, where do you? 

Dr. Wierda:     
Yes, so there’s vecabrutinib, there’s loxo 305, and there’s an AQR-503 compound that’s in development. 

Andrew Schorr:          
So, folks, when I originally had FCR, I asked Dr. Keating at MD Anderson, “How do it work?” And he said, “Well, we’re not sure. We think one drug punches CLL in the mouth, and one hits in the stomach, and one chops it off at the knees. So, what your looking—again you got all these different players to get at that CLL cell at that time.

Thank you so much for your questions, and Dr. Bill Wierda, thank you so much for all you do. Cool research, and I’m so glad you have so much more to work with now to help all the 17p, 11q, whatever it is, it sounds like you got stuff to talk to us about.

Dr. Wierda:         
Well, yes. And it’s—I mean, it’s an exciting—it’s been. The last five years have been a really, really exciting time, and the excitement increases and escalates, and like I said, there’s a lot of work for us to do, there’s a lot of things for us to think about. And we have new problems that are much better problems than we use to have with chemoimmunotherapy. And patients are doing exceptionally well, so I spend more time now talking about health maintenance issues with my patients with CLL than with treatment for them.

Andrew Schorr:          
Exercise, eat right, okay, hopefully live longer, higher quality of life. I’m going scuba diving after this. Okay, Bill, thank you so much. 

Dr. Wierda:     
Thank you.

Andrew Schorr:          
Andrew Schorr, remember 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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