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CLL: The Next Generation

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Published on May 5, 2021

Breakthroughs in CLL Treatment and Research

In this video replay, two renowned chronic lymphocytic leukemia (CLL) experts discuss the latest breakthroughs in CLL treatment, including exciting new clinical trials and combination therapies. Dr. Kerry Rogers, MD, is an Assistant Professor in the Division of Hematology at The Ohio State University and Dr. John Allan, MD, is an Assistant Professor of Medicine at Weill Cornell Medicine. They are joined by Patient Power co-founder and care partner Esther Schorr and CLL patient advocate Michele Nadeem-Baker.

Support for this series has been provided by AbbVie Inc. and Genentech, Inc. Patient Power maintains complete editorial control and is solely responsible for program content.


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Transcript | CLL: The Next Generation

Esther Schorr: Good morning. Good afternoon. Good evening. Welcome to our program, “CLL: The Next Generation.” I'm Esther Schorr, co-founder of Patient Power, and I'm delighted to be here today. And I'm even equally delighted to have you meet my co-host today, Michele Nadeem-Baker. Michele?

Michele Nadeem-Baker: Hi, Esther. I am excited to be here too. It's going to be a really great program today. I want to just jump right in and thank our wonderful sponsors for helping this come about, and that's AbbVie, and Genentech. And as always, we appreciate their support, and they have no editorial input into our content.

So, I have with us Dr. John Allan in New York. He is a CLL expert, assistant professor of medicine at Weill Cornell Medicine. And we have Dr. Kerry Rogers in Columbus, Ohio, with us, and she is a CLL expert as well, and she's assistant professor in the Division of Hematology at Ohio State University. Thank you for being with us, Dr. Rogers, and for all of your patients as well.Before we dig into our headline topic, which is “CLL: The Next Generation,” and all of the exciting things that are happening, we're still seeing so many questions about COVID, and the vaccines, and how it relates to CLL and other blood cancers. We've done numerous programs covering most of these topics, all of them as a matter of fact, in many programs, and we encourage all of you watching to check those out, if you still have questions, and many address CLL specific issues. But right now, we're just going to cover a couple of things within that, because that is of such interest, and there is new information being released now for CLL patients. So, first question, Dr. Rogers, is there any reason why patients with CLL should not get the vaccine?

Dr. Rogers: So, the short answer to that is no. Everyone with CLL should get the vaccine. And I've recommended that to all of my CLL patients. Some people might have considerations other than CLL that means they can't get the vaccine, like an allergy to one of the vaccine components, so if someone has a consideration outside of the CLL regarding vaccination, that's still valid. But I do recommend everyone with CLL receive one of the COVID-19 vaccines.

Esther Schorr: Great. And Dr. Allan, we've been seeing, regarding COVID immunity with CLL patients, there's studies, like the Israeli study has been released, and CLL patients speak to each other online and in support groups. And one of the most worrisome trends we're seeing is that as more and more people get vaccinated, CLL patients, and they get these antibody tests, some people are coming up with showing no antibodies. So, first of all, what tests should they receive? I know there are a few out there, and LLS is doing a study and offering, if patients go on their site and register, they can get some free tests. So, first of all, Dr. Allan, which tests should they be getting, and be looking at? And can you explain why some patients are showing antibodies, and others aren't?

Dr. Allan: Yeah, sure. So, it's a complicated scenario here, where there's a few serology tests that have been available, and it's kind of shifted over time as our understanding, time, and technology has rolled out, et cetera. Some of the early serology tests, so serology tests meaning looking for antibodies being produced against the virus, and or vaccine, looked at a nuclear capsid protein, essentially. And this could look for previous infections, and people who had recovered from infection, and who had mounted an antibody response.

It hasn't been until recently, at least, especially at my center in the past few weeks, essentially, that we've had a second serology test become clinically available, looking at antibodies against the spike protein, which is what is being made, and what the vaccines are against. So, the vaccines are producing and presenting the spike protein to us, when we get vaccinated, and then our immune system then makes antibodies against that specific protein, the spike protein.

And so, the serology test typically has to be specific to that to assess any response to the current vaccinations, and the vaccines that are currently available, because they are all producing the spike protein to make an antibody response. And so, it's a complicated scenario, and I think physicians are a little bit confused too, about which antibody tests that they have. In our center, it's very clear, it says the spike, and it has an “S” versus an “N” for the nuclear capsid. And so, it does delineate the two. But this is new, and people are confused by it, and I think some physicians might just start seeing it, and they start to realize they have an ability to test this. So this is coming out, and I think as time goes on over the next several weeks and months, more patients are going to be asking about it, physicians are going to be more aware of their facility, and their center's ability to test for this, and essentially, that's the appropriate test that you would want to look at to assess any type of antibody response.

The issue is, is that typically it's a positive or a negative, and it doesn't really provide a lot of information, and we don't have a lot of evidence to really know what to do with the information. Obviously, if you're positive, I think that's a good thing, and it assesses that your immune system has responded. But it doesn't provide a titer. We know that there are different varying levels of antibody production, and higher titers are going to have more neutralizing capabilities, et cetera.

And so, even if patients have positive tests, we still have to recommend and support them in social distancing, wearing masks, being careful around who they're around, and et cetera, because we don't have an understanding yet that patients are fully immune, so to speak. Likewise, a negative test, I think, puts patients at needing to understand that they might still be at risk for developing COVID. But there are other properties of the immune system. We had talked about this previously off camera, but the T-cell component of the immune system, and how does that interact? And how does that provide immunity? These are things that are not measured by this antibody test.

So, it's a complex scenario, we are gaining information, I think it provides information. But there's not a lot of evidence yet to suggest what to do with the information once we have it. And like I said, I'm sending the test frequently on some of my patients to build kind of an anecdotal experience. But I do agree that, and I've seen in my practice, similar results than the study that's been published, as you've stated, where about 40% or so of CLL patients are making antibody responses. It seems a little bit better in the treatment naïve patients. Patients on therapy are making less responses. And so, those patients who are either off of treatment for a period of time, in nice deep remissions, and/or kind of in a watch and wait, low tumor burden, are the ones seemingly that are making these responses. And anecdotally, in my own practice, that is what I've observed as well, in the past two, two-and-a-half weeks that I've now been sending this test on numerous numbers of patients.

Esther Schorr: So, what I'm hearing is, not so great if you were vaccinated, and you've had the antibody test that is currently available, and it said you didn't build those antibodies, but, and it sounds like a big but, that there is a lot of study going on now about the other parts of our immune system that might be initiated to try to protect people who are not protected with these particular antibodies, that they didn't produce. So, still be careful, still distance, wear a mask, but that a little bit of patience, as researchers, medical science, figures out how to get everybody else protected. Is that a fair assessment?

Dr. Allan: Yeah, I think so. I think, even with the positive antibody test, I think I'm still recommending patients not to change their lives too much, and that they still have to protect themselves, trust the ones that they're with, et cetera. I think it does give them a little bit of ease, potentially, to maybe engage a little bit with society, and not necessarily live in these bubbles that we all have, and our patients have, along this past year. But I agree, I think the research is catching up, we're going to know what to do with these results as the outcome data matures, and in another six months or so, we're going to now understand, what do these antibody responses actually mean?

Esther Schorr: Yes.

Dr. Rogers: Is it okay if I add something?

Esther Schorr: Absolutely.

Dr. Rogers: Good. I completely agree with everything that Dr. Allan has said about this topic. I just also wanted to add that this is not unique to the COVID-19 vaccine. So, this is something that's on our mind because of the pandemic, and how much this changed our lives recently. But it's also true of people living with CLL, and antibody responses to seasonal influenza vaccines, pneumonia vaccines, the Shingrix shingles vaccine. So, it's actually something true of people with CLL, that they don't make as good of antibody responses with multiple different vaccines, and not just the COVID-19 ones.

So, I think people should keep that in mind, just thinking about vaccine responses in general, and not just the COVID-19 vaccines. And then the other part is, I would find it hard to believe that even if you don't have antibodies, it didn't do something to show your immune system the spike protein. So, even though I think that not having antibodies or having a low titer would still increase people's risk of getting some sort of symptoms from a COVID-19 infection, I am very hopeful that that still means that people without antibodies have a lower risk of being hospitalized, or dying from COVID. So, that's my hope, and I think it will take several more months to really get the data to find out how people that get COVID-19 after vaccination are doing with it. So, just wanted to add that, in addition to what Dr. Allan had to say.

Esther Schorr: That makes sense. So, Michele, was there anything else we wanted to cover related to COVID?

Michele Nadeem-Baker: Just maybe a couple of other things, in that we're seeing this booster vaccines, would those help? I know, I happen to know one CLL patient who got a third somehow, and finagled third shot, and they still showed no antibodies. So, is it something you're looking at, that CLL patients do get a booster shot, or perhaps a different kind, if maybe they had the Pfizer, or the Moderna, and then they get the J&J, or the other way around? Is anything like that being tested, or looked at?

Dr. Allan: Yeah, I don't know of any. I'm assuming these trials are going out there. I don't know if any of them are going to be specific, necessarily, to CLL patients. But they'll be looking at patients with heme malignancies, and lymphomas, and things like that. I think that we're going to run into the same issue, even with a booster. The CLL immune background is dysfunctional, and as Dr. Rogers was speaking to, this isn't necessarily unique to just the COVID vaccine. This is vaccines in general, and an immune response.

So, I do think that there's a possibility that as patients, especially ones that have been recently treated, let's say, and completed their therapy, and they got their initial vaccine in February, they finished treatment a month or two prior to that. It's possible that a year later, nine months later, 10 months later with a booster, whereas they didn't initially make a response, they might do it at that point in time, as the immune system starts to recover from the therapy, the BTK, the venetoclax (Venclexta), the anti-CD20, whatever it might be, the chemotherapy, et cetera.

And so, I do think there's hope for some patients to potentially convert at that point, as they are in these deep remissions. But I do think there are going to be a significant number of patients that regardless of how many boosters they get, whichever ones they take, that their immune system background is just so dysfunctional from the underlying disease, and or prior treatments, that mounting a response may not be likely for that small patient population.

Esther Schorr: So then maybe this whole idea of herd immunity, of other people, being enough people who have become immune, will tamp this thing down enough, so that we don't have to worry as much about patients who haven't gotten the antibodies. Is that what we're hearing?

Dr. Allan: Yes, exactly. I can let Dr. Rogers speak to that, too.

Esther Schorr: Yeah.

Dr. Rogers: Yeah. Other people getting vaccinated protects everybody. So, immunocompetent adults, and people that do have good antibody responses protect the people around them, as they don't get COVID-19. And also, eventually, all pandemics end eventually. The community spread of this will drop. I mean, we do continue to live with deadly viruses. So, if we get the transmission of COVID-19 back down around the level of other viruses that we live with, that would be a really nice thing.

Esther Schorr: Okay. Yeah. And Michele and I have spoken about all this, and I think we're going to try to do another program, just about how do we, as family units, deal with the uncertainty, and sort of this waiting for research to catch up, or for the virus to say goodbye. So, we'll attack that part of it in another program.

So, I think we're going to move on to what we talked about initially, as the main thrust of the program, which is looking at the future of treatment for CLL patients. So, I want to kind of open up the discussion. We know that there was some exciting news for multiple myeloma patients, that CAR T treatment has recently been approved. Can you, either one of you, maybe we'll start with you, Dr. Rogers, because we've got you front and center. Can you explain what this is? And I know that this has been in the works for CLL as well. Do we have any idea when this is going to happen for CLL patients?

Dr. Rogers: That is an outstanding question. I'll explain what CAR T is. I'm actually not sure when it will be approved for CLL. It is something that people with CLL can get, but it's still investigational, so they can get it as part of a research study.

So, what it is, is they actually take blood, and they do an apheresis, so they put it through a machine, and separate out lymphocytes, but not CLL lymphocytes, a different type called T lymphocytes. Then, this is like very science, science fiction. So, this goes right in with like the Star Trek theme. So, they take the T-cells, they put them in a lab, and they actually stick on the T-cells, on something called a chimeric antigen receptor. So, that's the CAR part of CAR T, and then obviously, T-cells.

And what this is, is then they have to give some sort of treatment, or chemotherapy, to allow the body to accept them back, then these T-cells that were originally the person's, that have been changed in the lab and put back in, now have a receptor on them, that makes them attack the CLL. So, it's basically training, or altering, a specific immune system cell to then go and attack the CLL cells in the body, which is really cool.

So, it kind of tells part of your immune system to go after the leukemia cells. So, it sounds really neat and simple. There are some issues like anything else, you never get anything for free. And it's been kind of a big benefit, but also a lot of side effects, because sometimes when those CAR T-cells get back in the body, they get really activated, because there's so much CLL, they try to attack it, and people can get sometimes very serious immune complications, like something called cytokine release syndrome.

Also, it doesn't work for everybody, and in CLL, there's also a risk that when they take the T-cells out – you know how we were talking about CLL causes the rest of the immune system not to function well? Sometimes that makes it so the T-cells aren't able to be turned into these cool CAR T-cells, to go and attack the leukemia. So, that sometimes doesn't work.And that's actually something that's improved quite a bit, while people have been researching this. It looks like giving drugs like ibrutinib (Imbruvica) prior to collecting the T-cells for this might actually improve the outcome, in terms of making the CAR T in the lab. But I think we have a bit of a ways to go before this gets approved. But it is something that I've personally seen CLL patients benefit from. It's really not for everybody. I think presently, it's best for people where we don't expect some of these oral targeted agents to work really well. So, why do something kind of like really science fiction, and experimental, if you can take pills, either standard or experimental. But it is something that I do think will potentially benefit a large number of CLL patients. I don't actually have a timeline on approval for it, though.

Esther Schorr: So it sounds like, and maybe Dr. Allan, you can speak to this. It sounds like this has been used with some CLL patients, but they have probably been through some other treatments before that didn't work well for them. So, this is not something that you start with, at least at this point in the game.

Dr. Allan: Right. Because we have such great, well tolerated oral therapies, CAR T-cell is still kind of relegated to a treatment that we utilize to kind of rescue patients that are in a tight spot. And typically, in this day and age, I think CAR T-cells are going to be valuable, and I think they're going to be relevant in the CLL space, because there are certain high risk patients that we are still concerned about breaking through drugs like BTK inhibitors, and drugs like Bcl-2 inhibitors, et cetera, and reemerging from relapse, that we will always need new treatments.

I do think there is a possibility that, while CAR T-cell as a mono therapy approach may not ever be the first line therapy that we use, I do think there is a possibility to utilize it for high risk patients, maybe as a consolidated type of procedure, to potentially try to get a very long-term remission, and even potentially even cure. I think we can even invoke that word with some of these treatments that we have, and some of these therapies that we have. As we know, some long-term follow-up from some of the very first CAR T-cell therapy trials showed very long, durable remissions, some greater than five years, et cetera.

So I do think there may be some way to use it in combination, in a frontline therapy. And maybe for those young, fit, high risk patients, that's where it is. Otherwise, I do think the vast majority of patients that don't have very high-risk features, like deletion 17P, and P53 mutation, et cetera, probably can get away with just these oral therapies, and aren't going to need that added toxicity, and those added risks, in that frontline therapy. But I do see it moving up. Right now, it's kind of relegated in this research space. Only right now, and really for these patients who are kind of breaking through these new, novel targeted agents that we have.

Esther Schorr: Okay. So, Michele, you've got a question?

Michele Nadeem-Baker: I do. Well, are you saying because CAR T hasn't been around for a long time, you're unsure on calling it curative for some patients, that you only have enough follow up for, like you were saying, seeing like five years, thus far? Of people –

Dr. Allan: Yeah. I mean, I think we always have to be careful to use that term, because it really... You only know if you're cured when you have 20 years of follow up on that patient, it's never come back. There’re various ways to think about cure, if you're just in remission, and you're doing otherwise, okay, and its small volume of disease, versus really eradicating it completely, and never needing another therapy. But yeah, I think we have to be careful with that. And mostly, it's because that follow up is not that long.

Michele Nadeem-Baker: Well, as you know, we're all hoping for the cure. Right? And that's something we all hope for. And Dr. Rogers, how important... We always hear about MRD, and we hear about... Which is minimal residual disease, and undetectable minimal residual disease. And I see there's debate. Maybe the two of you even have differing opinions on it. Dr. Rogers, how important is that, if it can go up again?

Dr. Rogers: Yeah. So- Michele Nadeem-Baker: Or does it not?

Dr. Rogers: No, so that's an outstanding question, actually, and I think the better question is, how important is it for an individual? And I think that that really depends on who the individual is, living with CLL, and what they're hoping to accomplish by achieving an MRD negative status. So, as a research tool, it's phenomenal. So being MRD negative doesn't mean there's no CLL in the body, it just means we can't detect it, and that's good. That means that there's a very minimal amount of CLL, and it's a very deep remission.

We know that being MRD negative after chemo immunotherapy treatments means longer times in remission. And sometimes actually having a partial remission with no detectable leukemia, or an MRD negative partial remission, is better than a complete remission. So, this is a very powerful tool, looking at outcomes of groups of patients, to say that people that don't have detectable CLL, or are MRD negative, usually stay in remission longer.

We are seeing that that is also the case with some of these kind of time limited targeted regimens, right? So, like obinutuzumab (Gazyva) and venetoclax, where you take it for a year. So, if you're MRD negative, then it's more likely that you'd stay in remission longer.

But, there are some cases where it doesn't really matter. So, with BTK inhibitors, like ibrutinib, and acalabrutinib (Calquence), people have detectable leukemia years later, but they're still taking the drug, and feeling well, and living their lives. So, in that case, achieving an MRD negative status doesn't necessarily mean that things are going to be better, or continuing to have detectable leukemia means that things are going to be worse for you.

So, it kind of depends on if you're looking at a fixed duration treatment, or one that you're continuing to take like BTK inhibitors. And if the goal is to eliminate leukemia and discontinue treatment with a regimen, or just keep taking it, living with the leukemia, taking a BTK inhibitor, and living your life. So, it's not something for all individuals, that you have to achieve MRD negativity.

The other thing I do want to say is that frequently, the combination regimens that get you deeper MRD negative remissions sometimes have more side effects than just taking one pill. So, you also have to think about who the person is that's going to be taking treatment, what their treatment goals are. Some people, a lot of side effects would be very problematic for them. Then you have someone who's like 42, and a marathon runner, where you can give them a lot of treatment, and they'll be fine.

So I think MRD, just to summarize, is a great research tool for understanding how well new treatments work. And not having MRD after either a chemo immunotherapy like we used to use, or some of these targeted agents that are venetoclax combinations, that are like a time limited treatment, does mean that people stay in remission longer. But, with some treatments like BTK inhibitors, it's not really that important for people, in terms of how well they're going to do with the treatment.

Esther Schorr: So, I wanted to ask one other thing about trials. We were talking about CAR T, and you put that in perspective, that we don't know quite when that's going to be ready. But that, I guess we're fortunate in the overall CLL community, that there's a lot coming down the pipe. So, and this is really to both of you, what are maybe the top two or three trials you think are the most hopeful right now, for, maybe it is getting to the cure, or things that are really helping people that have failed some of the current therapies and combination therapies? Dr. Allan, maybe you'd like to comment on that?

Dr. Allan: Sure, I could talk about some of the things that I've been involved with, that I think are going to be really important for a lot of CLL patients. And one of those is the study, the CAPTIVATE study, which is looking at ibrutinib and venetoclax. It's one of the largest phase two prospective clinical trials that is looking at this combination of drugs.

There's two cohorts. There's one that stops, regardless of an MRD response. And then there is the initial cohort, was a response adapted kind of schema, where patients would continue on either placebo, or a maintenance ibrutinib, depending on their MRD status.

And so for the first time, we're going to start to see, do people who achieve MRD negativity actually benefit from a continuation of treatment? Or will they be able to stop, and have long-term, durable remissions, similarly to someone that continues on therapy?

So I think that's an important study and may change how we treat a lot of patients. I do think it could open up combination therapy to maximize responses for all patients, and potentially allow almost all patients to be able to get off of therapy for a period of time.

The flip side of that, there's a study – the issue with this study is that for the most part, it was studied in patients less than 70 years of age. And so, Dr. Rogers is speaking to this problem, to where you add on therapies, you add on toxicities. And so how do older patients – the disease CLL, is a disease of older patients – how do older patients manage these added drugs, and added toxicities?

And so, there's another study, the GLOW study, which is looking at, basically, the ibrutinib-venetoclax combination against chlorambucil (Leukeran) and obinutuzumab in older patients, and that's a phase three randomized study that has not been reported out yet, but I think is going to also be important in informing the community at large, how do our older patients tolerate this? And can an 80-year-old subject, or patient, tolerate ibrutinib and venetoclax, and not have to come off of the drug, or dose reduce the drug, because then you can potentially start to affect your efficacy long-term, if you're not having that dose intensity that you might need to achieve those outcomes maybe seen in younger patients.

So, those are two studies that I kind of am looking to see the data, and mature. And then there's a lot of other stuff in relapsed/refractory settings, and maybe Dr. Rogers can speak to some of those. I know she's been involved with a lot of them, and some of the newer targets too. So, I don't want to take up all that time, so I'll let Dr. Rogers speak to it.

Esther Schorr: Please, go ahead.

Dr. Rogers: Yeah.

Esther Schorr: Thank you.

Dr. Rogers: Definitely. I was actually thinking of something I was going to add, but before I forget, I do want to build on what Dr. Allan said, the two ongoing US oncology cooperative group trials, one through ECOG, and one through Alliance, are for initial treatment, randomized phase three studies comparing ibrutinib and obinutuzumab, to ibrutinib, obinutuzumab, and venetoclax, which is given short term, as opposed to ibrutinib and obinutuzumab, which is long-term.

The ECOG one is patients less than 70, the Alliance one is 70 and up. So, those will be very interesting, because it's actually comparing indefinite BTK inhibitor treatment to time limited BTK inhibitor venetoclax combination treatment, and we'll get some information about how older and younger people tolerate these drugs. So, I'm very excited to see that. That's going to be really important, and that's kind of along the lines of what Dr. Allan was talking about, too.

I'm really excited about some of the reversible BTK inhibitors. So, there's one that there was some information a while ago, called the ARQ 531, and of course, one where there's a big publication, LOXO-305, and I'm still waiting for the company to tell me how to pronounce their drug name, which I think is “pitrobrutinib” or “pirtobrutinib.”

Esther Schorr: Gesundheit.

Dr. Rogers: Yeah, I've got to like-

Esther Schorr: Bless you.

Dr. Rogers: Yes. I've got to corner someone from LOXO and ask them to teach me to pronounce that correctly. But the nice thing about these drugs is one, I've seen them work in people that are resistant to both, either ibrutinib or acalabrutinib, the currently approved BTK inhibitors and, actually, venetoclax. So, this is a group of people that don't have a lot of standard treatment options. if you are resistant to both ibrutinib, acalabrutinib, and venetoclax, and we've seen responses with these reversible BTK inhibitors. And especially with the LOXO-305 drug, it looks like it has been well tolerated.

And these are drugs that aren't commercially available. So, they're still in research studies, but I'm just so excited to see where that goes, just because of the results in who they've treated with it. And then the other great thing is, they are both BTK inhibitors. So, the same class of drugs as ibrutinib and acalabrutinib, but they bind the BTK protein at a different site, and they bind and unbind it, so it's actually a different mechanism, so people can still continue to benefit from this class of drugs, BTK inhibitors, using a different mechanism. And I think that's really cool too, because it allows for later use of a venetoclax-based treatment. And so, I think that's going to be really neat to see how that plays out, and if those go into combinations, and what that's going to look like.

Esther Schorr: Wow, that's a lot. That's a lot going on. I wanted to slip one question in here from one of our listeners, from Brad, who asked, and it's about this alphabet soup of BTKs, and the “nibs.” Why are CLL specialists still using ibrutinib? Why not use acalabrutinib, or one of the other BTK inhibitors that was developed after ibrutinib?

Dr. Rogers: Oh, can I do this one first?

Esther Schorr: Yeah.

Dr. Rogers: Okay. Dr. Allan says okay. So, there's two BTK inhibitors that are approved in CLL right now. There's ibrutinib and acalabrutinib. Zanubrutinib (Brukinsa) is approved for mantle cell lymphoma, and has been studied in CLL. And then the ones that I was talking about, the ARQ compound, LOXO compound, you can't just prescribe right now, you can only get them in research studies. So, I'm definitely using those, but they're for people who are participating in research studies, not just writing prescriptions.

So, when you write a prescription, and choose between either ibrutinib and acalabrutinib after you've decided which one might be best for your patient, there are... you know, the BTK inhibitors are going to be best. There are some factors that make you pick ibrutinib over acalabrutinib. One thing that doesn't matter to doctors really, but matters a lot to patients, is that ibrutinib is once a day versus twice a day. Most people can take pills twice a day, but there's a select group of people that really just are bothered by taking a pill more than once a day, and for those, ibrutinib is definitely a better choice.

And then of course, there's this interaction with proton pump inhibitors in acalabrutinib, that really makes ibrutinib a better choice in terms of drug interactions, there. So, those are two main reasons that I would pick ibrutinib. Of course, ibrutinib is still in some research studies, if the research study is best for the person that requires ibrutinib.

It's still a little unclear in very young people, with some extremely high-risk disease features, if ibrutinib might have a benefit, because it hits more kinases than acalabrutinib. But that's a personal opinion, and not a very science-backed one, in terms of why one might pick ibrutinib. I'd love to hear what Dr. Allan has to say about this too, if he's willing to share.

Dr. Allan: Yeah, I mean, I agree wholeheartedly with those. I think once-a-day dosing is an attractive part of ibrutinib. I do think we currently lack head-to-head data from some of these studies, although there have been press releases and things, and I think we'll see data regarding ibrutinib versus acalabrutinib in upcoming congresses soon, to really understand that the toxicity differences of this.

I think people really want to see that. If it's drastic toxicity differences, I think that may influence people to switch to a better tolerated BTK inhibitor. But if it's rather subtle, potentially, and what we've heard is more hype, rather than the real data that's been out there, then I think people can go back, and think about some of these personal factors.

You know, I do think zanubrutinib is probably going to have an approval too. It is very well tolerated, but has similar issues with acalabrutinib, in that it's a twice a day medication, but doesn't necessarily seemingly have the PPI issue that we see. So, there is a lot of options out there. I do think there has been a movement probably towards some of the newer generation of BTK inhibitors.

Though, I think people get comfortable with the drug too, and especially outside of CLL experts that have a lot of experience with these drugs, there's sometimes, it's easier to go with a drug that you know how to tolerate the side effects, how to explain the side effects, et cetera. And none of these drugs have proven to be better than the other, in terms of outcome or efficacy. So, you're never shortchanging a patient necessarily, in terms of some longer-term outcome, which is really what would power me to say one drug is truly better than the others. But, obviously, patients need to take these drugs, they're taking them for a long time, we do want to minimize toxicities, and if there's any way to get the same outcome with potentially less side effects, or problems handling or taking the drug, then typically, most physicians start to sway to that way.

Esther Schorr: Okay.

Michele Nadeem-Baker: That was a lot. And that is-

Esther Schorr: That was a lot. That was a great question, and great answers.

Michele Nadeem-Baker: I know, and this really is, a lot of this is futuristic information, especially the new BTK inhibitor, the one that begins with a “P” and ends in a “nib,” and we'll find out soon, I guess, how to pronounce that for all of us, and the way that it's done. But another thing that we're very curious about for future things is genomic sequencing, and to learn from you what kind of is... It seems like a very huge breakthrough. Dr. Rogers, why is that?

Dr. Rogers: So actually, sequencing is a really big breakthrough, and it really depends on what you use it for. So, there's multiple ways that sequencing can be used in CLL, just to understand it, and to treat it. One thing is sequencing can be used to look... So, we always think about IGHV mutational status, and this FISH panel testing with deletion 17P, you know, 13Q, those things. So, you can actually add mutations on there as a layer, like NOTCH1 mutations, or, particularly, P53 mutations, which have similar kind of high-risk nature to deletion 17P.

So, you can kind of add some sequencing things done before treatment to the list of things that make an impact on how well you expect people are going to do. I think that's an area where we're going to learn more about how some of these mutations affect treatment outcomes, and how people do in the long-term with CLL. And the goal of, of course, learning that information is to help people select the right treatment for them, and to let them plan for the future. If it's someone that you think will need something like CAR T down the line, or won't, those kinds of things are important.

There's other ways that sequencing is being used. One way that I think is kind of exciting, is we had this discussion earlier about MRD, and the standard way that that's assessed currently in CLL is using flow cytometry to a standard cut off, but you can actually do sequencing in some cases. The, I think company that does this is Adaptive, is called clonoSEQ, and you can actually look at even deeper levels of MRD, using sequencing type technology.

So, that's a really cool, completely different application of sequencing in CLL. That's currently a research tool. But I think that has the potential, as a research tool, to look at depth of response and advance the CLL treatments. And at some point, that might even be something that's applicable to people receiving treatment. So, those are kind of the big areas I was thinking for sequencing right now. There’re also some very research applications of it, which I won't get into, or you won't be able to get me to stop talking for a few minutes.

Michele Nadeem-Baker: So what is the clonoSEQ? Because I've been hearing a lot about that with patients, where they've [inaudible]. So, that does something that patients may hear about, or see that they've had it, flow cytometry, and FISH. So, what does clonoSEQ do versus those?

Dr. Rogers: Yeah, so flow cytometry is the test that's used to diagnose CLL most commonly. It's on the blood, and basically what it is, is they take the blood cells, they paint them with antibodies that have fluorescent markers on them, then they fire it in front of a laser, which sounds also very sci fi, and then they can tell you what markers are on the cells, and that's how you look for CLL.

The technology is really only able to detect CLL to a standard cut off. It's one in 0.0001. And so, that's what the community has been using. ClonoSEQ actually takes CLL cells and sequences them, and kind of learns what the sequence is for them. And then later on, you can take a sample, and look at how much of that sequence is present, and that can actually go to 0.000001. So, you can get an even deeper look as to whether or not any CLL cells are present. So, everyone should expect a flow cytometry. Most people who are having MRD monitored, it's by flow cytometry. But this clonoSEQ technology is a new way of looking at MRD.

Esther Schorr: Dr. Allan, there's obviously an evolution, as Dr. Rogers was talking about. An evolution in the kinds of tests that are available to try to help, whether it's a newly diagnosed CLL patient, or somebody who's headed to re-treatment. So, let's say I'm that patient. What should I be asking for testing now, in either of those scenarios? What do I absolutely need to say, before we make a treatment decision together, doctor, what do I need to ask for, given the state of technology right now, and what information it's going to give?

Dr. Allan: Yeah, so that's great. So typically, we follow the iwCLL guidelines, in terms of a pre- or at-diagnosis workup, or definitely at least a pre-treatment workup. And for the most part, the NCCN and some of the other governing bodies outside of the iwCLL, have also incorporated what should be done before you start treatment.

And typically, that's kind of three big groups. One is the FISH, fluorescence in situ hybridization, 80% of patients with CLL have one of these five different abnormalities that we look for, and FISH is a very specific test. It looks at very specific portions of the chromosomes on certain chromosomes. And frequently CLL patients lose material, and/or kind of add material on, at very specific spots in the DNA and chromosomal structures.

So FISH should be done. And for the most part, patients get that. The next big group is, we look at the IGHV, the antibody gene testing, the immunoglobulin heavy chain. And this has been known since the late 90s, that whether it's mutated or unmutated, is very prognostic and predictive on how somebody might respond to treatment, chemotherapy, when they might need treatment to even start, et cetera.

And so, that's a sequencing test where you sequence the antibody gene. If it's mutated, that's actually a good risk prognostic, it's kind of paradoxical to think about, but mutating the antibody gene is actually a normal maturation process of our B cells, as they try to make a better and better antibody against the antigen that it's specific to.

And so, when we see this mutational pattern, that kind of means the CLL is behaving itself, it's kind of going along the normal maturation patterns, and is a little less rogue and revved up from the get go than the unmutated counterpart, which is the opposite of that. It's about 50/50.

And then the third component that we talked about is this genetic sequencing, looking specifically, at least for P53, many of these sequencing tests we send are large panels of anywhere from 70 to up to four or five hundred different genes, but the recommendations are at least P53 sequencing tests.

One of the caveats here is something that, from ASH this past year, a colleague of ours, Dr. Rogers and mine, is Anthony Mato, with colleagues as well, has presented some data showing how poor we are, as physicians, at obtaining some of this information like FISH, IGHV, and mutational profiling, and actually highlighted the fact that even when we have some of those features, like 17P deletion, patients are probably not getting treated. Some of them are not getting treated as they should. And some are getting chemotherapy, where we know those patients should not be getting chemo.

So, this is very impactful. And the other side of that is the patients who had no testing – there's clearly 10-15% of those that have some of these high-risk features – are still getting chemotherapy. And so, we really need to look for this stuff, and you need to look for it because it's dynamic. So, it's not just at diagnosis, but anytime you get a treatment, and there's a disease relapse, and you're thinking about a new therapy, this stuff needs to be repeated.

And ultimately, the take home point was kind of, wow, we're not doing a good job. Like 80% of patients sometimes are not getting their IGHV sequencing, and like 75%, or something along those lines, most are not getting P53 sequencing, et cetera. So, I think these things are patients to take to their doctors to ask about this stuff, to remind them to get this information, especially prior to any treatment initiation.

Esther Schorr: Well, hopefully the 150-some people who are on this program today listening, will know to ask those questions if it's ever needed. So, that's very helpful. Thank you. I think, Michele, are we going to move to questions?

Michele Nadeem-Baker: We are. We are. And this is when we're going to ask the audience's questions, those who have sent them in pre-program, and I just want to encourage all of you that if you haven't sent in your questions yet, please do so with the Q&A function at the bottom of your screen, and we will get to as many as we can.

Someone wants to know, and this might be a tough one, how often does a treatment fail? Or maybe it's better to say, so if a treatment does fail, are you always able to switch to others? And I know we spoke about this a little earlier when we ended up going to CAR T. But, so, does this happen often? Now that we have all this genomic profiling? I mean, when do you know? As the specialist, when do you know it's time, "Okay, this one's not working. I'm not going to give it five years, or five months." I don't know. But what do you do?

Dr. Rogers: Yeah. So, how long you expect a treatment to work for, or what you expect the response rate to be, depends a lot on who it is you're giving the treatment to, and also what the treatment is. So if you're talking about people with intermediate, or low risk CLL features, who have never taken a treatment before, that are going to start venetoclax and obinutuzumab, I tell people that I expect them to respond, and I'd be very surprised if things didn't get better very shortly after starting the treatment.

So, you expect that to work, and then you don't know, everyone's different, but if people have low or intermediate disease features, you'd expect them to stay in remission longer than people with high risk disease features.

However, sometimes, because people are different, someone that you expect to have a really long remission won't, or someone that you expect to have a shorter remission will end up having a really long one, and that's okay. So, when you finish a treatment, or if you're taking a treatment like a BTK inhibitor, you have to come for regular visits, to monitor the status of your CLL, even if you finished a treatment and are in remission.

So I don't have a one-size-fits-all answer for how long I expect someone to stay in remission, or have their CLL controlled with a treatment, because it depends on the person. Most people, especially after, when we used to use either chemotherapies that were given for a period of time, and now we have obinutuzumab and venetoclax, which is a fixed period of time. In these studies, I treat people in research studies that have a defined treatment duration, they go into post treatment monitoring. And then you'll see, usually they come back, and I’ll notice that their lymphocyte count has increased, that the CLL might have come back that way. Or, they'll tell me they have some small lymph nodes, or something that's a sign the CLL is back.

And then actually, they go into monitoring again, until you see a reason to treat the CLL. So, that's something to improve by CLL treatment. And that can actually be a long time, even if you see the CLL come back, it could be a long time until you need to do something again. So, you wait for those treatment indications. It is a little bit different for people who are taking BTK inhibitors that are still taking the treatment, or people who have the CLL come back during a treatment, especially with these oral targeted agents.

So, you can see someone doing well on it, and then you see like, oh, their white count is going up, their lymphocyte count's going up. Maybe their other counts are dropping while they're taking it, or they're noticing lymph nodes while they're taking acalabrutinib. And so, in those cases, usually you don't wait for them to have a lot of issues with it, because we've found that you really want to switch treatments once you start to see that their CLL is coming back. Once you're sure it's coming back on that treatment, then you plan a next treatment.

So, it's really nice, most of the time in CLL, you don't come, and you say, "Okay, today's the day we're doing treatment, you have to decide by tomorrow, what you're doing." So, most of the time, there's an opportunity, the vast majority of cases, there's an opportunity to plan what the next treatment is, and then what it is you do next is definitely a discussion between you and your doctor, depending on what treatments you've had previously, because if ibrutinib stopped working, acalabrutinib is not going to work, they have the same mechanism, right?

It's like, "How many treatments have you had before?" And then usually, I tell people what their standard options are, and their investigational options. So, what they could get in a clinical trial. And for people that have had multiple prior treatments, particularly those resistant to BTK inhibitors and venetoclax, their best treatment options are going to be in a clinical trial, or a referral for cellular therapy like CAR T in a research study. So really, what's available to them depends very much as to what they've had before.

Michele Nadeem-Baker: Great. Dr. Allan, we have gotten in a question about a T immune response. Is there any way to measure that?

Dr. Allan: So, no good way. Typical current tools that we have, within looking at T and B cell subsets, et cetera, don't really give any functional data about that. It might talk about levels, and numbers of these specific different types of cells, CD8 cells, CD4 cells, and CD3 T-cells in general. But there's no real functional data. And I think it's more complicated than that.

I do believe there are potential assays looking to follow these clones, and things like that, but I don't know of any good way, outside of research, kind of in vitro tests, that are clinically available to test someone's T-cell immune response specifically to like vaccinations, et cetera. Most of these are kind of in a research setting only, and the current tools that we have, that I'm aware of, are not too helpful in making any assessment of that T-cell immune response in our CLL patients.

Michele Nadeem-Baker: Thank you.

Esther Schorr: Okay. Michele, I think we've got time for two more questions, and I have one here that's kind of interesting. It's not something I've heard of, which doesn't mean it doesn't exist. But somebody, one of our listeners, is asking about NOTCH, and what is NOTCH? What is it used for? Can one of you answer that?

Dr. Rogers: I can. So, NOTCH mutations are a recurrent mutation that's found in CLL. So, you'll see if you do next generation sequencing, I mean, you can do other sequencing techniques, but with the ability to do sequencing panels, we find that people will have a NOTCH mutation in their CLL. So, that's what they're talking about. And I think I saw that in the Q&A, too, and it was asking, is there a different way to treat this? And the short answer to that is not currently. So, I don't know of any way that a NOTCH mutation currently helps you select treatment. If Dr. Allan has a different opinion on that, I'll let him jump in.

Dr. Allan: Yeah, no. I think NOTCH is one of the more common mutations we do see. It associates with other high-risk features. In general, it's more prognostic, in terms of when somebody might need treatment. It seems to associate with time to first treatment in this two-to-three-year range, where you start to see the disease become proliferative.

There are other mutations that we see at very low levels that regulate NOTCH, that also kind of similarly have a similar potential biological impact. But as Dr. Rogers mentioned, there has been no real data in the era of targeted agents that has shown that NOTCH1 mutation predicts for an inferior response rate, or durability of that response once it's achieved.

And unlike in the chemotherapy era, where it did predict someone maybe relapsing sooner, and maybe having a less deep response, in the era of targeted agents it has not really panned out to show that, which is a good thing. It's overcoming this high-risk feature. Ultimately, though, when you do see it, you do have to monitor your patients. I monitor my patients a little differently, their disease can, like I said, be okay, and then two, three years later start to become a little bit more proliferative.

It also associates with Richter's transformation, in many of these studies, that you need to monitor your patients, especially if you see them with a more proliferative fraction of their disease, or their lymph nodes are growing, because you want to kind of catch them before that third or that fourth hit starts.

And so, when I have NOTCH1 mutated patients, as I see the disease activity, despite them maybe not having full blown indications for a therapy that you might need to treat on a clinical trial, off of a clinical trial, I talk about treatment initiation sometimes as I see that disease active, in order to hypothetically prevent potential transformations and/or getting to a point where it's going to be harder to kind of get them out of trouble type situations.

Esther Schorr: Got it. Well, you learn something new every day. I had not heard of NOTCH. So, now I feel very educated. Thank you to the viewer who brought that up. Michele, it sounds like you have the last question for the time we have.

Michele Nadeem-Baker: I do, and I know we're running short on time here. So, if possible, if there's a way to answer, and I don't know if there is a way to answer this briefly. But, Dr. Rogers, can you explain what makes someone a CLL specialist, versus just, say, a hematologist-oncologist?

Esther Schorr: That's a good question.

Michele Nadeem-Baker: Yeah, it is, because we're often suggesting patients see one, right? Or at least have one consult, if they don't live in an area close to one. So, how would you define that?

Dr. Rogers: Oh, that's an excellent question, because I don't think there's a formal certification or degree, or thing you do to get the title. So, I would consider someone to be a CLL expert, so these would be physicians who are hematologist-oncologists who have significant expertise treating CLL. So, people that take care of a large number of CLL patients, and also are involved in kind of the academic CLL community.

So, at least keeping up on the latest research with CLL. It doesn't have to be someone that's doing all the research, but someone that's at least involved in the CLL community. So, definitely someone that has substantial clinical experience taking care of people with CLL, and not just seeing a few people in their practice, but actually seeing a large number of people in their practice that have CLL, and then is keeping up with and engaged in the academic and scientific CLL community. Let's see if Dr. Allan has a different take on that. That's kind of what I think.

Dr. Allan: Yeah, no, I agree wholeheartedly there. I guess we were introduced as experts, but I see myself as a lymphoma doctor, honestly. And so, typically, these CLL experts are people that are caring for heme malignancies, in general, with a focus on CLL. Because obviously CLL is still a relatively rare disease, 20,000 cases diagnosed each year, 200,000 patients living in the US with the disease. So, comparatively to other malignancies, it's relatively rare.

Where Dr. Rogers and I kind of differentiate ourselves is that while we treat heme malignancies, lymphomas, and other leukemias, we participate in those clinical trials. We have experience managing these new drugs, and we do have a large body of patients to derive our experience from to understand the biology, as well as these toxicities of these new drugs, et cetera.

Esther Schorr: Well, I hope it's fair to say that if someone is living in a place where they know they need to see a specialist like either of you and they're not in your proximity, that if there is a local hematologist-oncologist near them, that there can be some connection in consultation with somebody, with the kind of expertise that you have.

Dr. Rogers: Oh yeah, I always like to say it's not like cheating, you can have more than one hematologist. You can't have two that are in charge of doing the same treatment at the same time, but I love working with people that take care of... I see CLL, and then hairy cell leukemia as most of my patients, and hairy cell is much rarer than CLL. So, the majority of patients I take care of are CLL patients. So, I love working with people that have a more broad experience. So, it's not like cheating, you can have two people, and usually it goes better if they know about each other and talk to each other.

Esther Schorr: Of course. So, I know, Michele, we're basically out of time. I know there were questions that we didn't get to for those of you in the audience, and what we're going to do is collect those, and whether we ask Dr. Rogers, or Dr. Allan to answer them afterwards, we'll try to get answers to them, and post them on our website. So, we'll capture those, and thank you for sending them in. So, Michele, want to wrap up here?

Michele Nadeem-Baker: Thank you both for joining us. Dr. Kerry Rogers, thank you so much, and Dr. John Allan, we look forward to seeing you again here at Patient Power.

Esther Schorr: And to all of you that are watching, please remember that knowledge is always the best medicine.

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