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CLL Ask Me Anything: COVID Vaccine & Promising Patient News

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Published on December 8, 2020

CLL Expert Answers Questions About COVID Vaccine & Latest Cancer News

Dr. Philip Thompson of MD Anderson Cancer Center joined Patient Power co-founder Esther Schorr for an informative live Q&A for patients with chronic lymphocytic leukemia (CLL). The discussion included news shared by Dr. Anthony Fauci at the world’s most comprehensive hematology event of the year, the 62nd American Society of Hematology (ASH) Annual Meeting, about whether immunocompromised patients should take a COVID-19 vaccine. The pair also answered questions from patients regarding COVID-19 concerns, advances in CLL treatments, and much more.



Transcript | CLL Ask Me Anything: COVID Vaccine & Promising Patient News

Esther Schorr: Hi there. This is Esther Schorr with Patient Power. And welcome to the ASH 2020 CLL Ask Me Anything program. ASH is the once a year gathering of top researchers and clinicians working in hematology globally, and this year, for the first time, it's completely virtual, so it should be an interesting few days for all of us.

The goal of this live event is to ask an esteemed CLL doctor as many of your questions as we can and get his expert advice. If you're watching this live, you can use the Q&A button at the bottom of your screen and our producer will do his best to share your questions with me, and we'll try to answer as many as we can during the broadcast.

So first, I'd like to introduce our esteemed guest, Dr. Philip Thompson, who is an Assistant Professor in the Department of Leukemia at MD Anderson Cancer Center. Dr. Thompson, are you there? There you are. You got it. There you are. Welcome. So good to have you.

Dr. Thompson: Thank you so much, Esther. It's great to be here.

Esther Schorr: And we've done these things before together, I think, so looking forward to another conversation with you.

Dr. Thompson: Yeah, absolutely.

Esther Schorr: I know that you're presenting your research at ASH also, and we'll touch on that a little bit later in the program, but we've gotten so many viewer questions and we want to answer as many of those as possible, but we're going to prioritize the ones that impact the largest number of patients.

Should CLL Patients Receive a COVID Vaccine?

So as you might imagine, many of the email questions that we got to were about the COVID-19 virus and the vaccines that seem to be on our doorstep, and the most asked question was: “Is it safe for CLL patients to take a COVID vaccine?”

It just so happens that Dr. Fauci, and we've spoken about that, he spoke at ASH this morning and said the following about whether immunocompromised patients should get the vaccine, and I'll just give you a quick quote from him. He said, "I think we should recommend that they get the vaccine. History tells us that people with compromised immune systems, you're not going to have a robust response but some degree of immunity is better than none. This is why we argue for healthy people to get immunized, to create the umbrella of herd immunity to protect those whose immune systems might not be able to respond well."

So, what are your thoughts about that?

Dr. Thompson: Yeah. Well, I 100% agree. I think the first thing that we need to ask ourselves with this vaccine is, is there any safety concern for a patient with CLL? I really don't think there is. So certainly with the first two vaccines that are likely to receive approval, the Moderna vaccine and the Pfizer vaccine, they use a new technology where it's just a small piece of messenger RNA or mRNA. MRNA is essentially the middleman between your DNA, which contains all your genetic material and protein, which is the building block of all of our cells. And essentially, this mRNA encodes the protein of the SARS-CoV-2 spike protein which allows it to attach to human cells and get into those cells and cause damage.

So, by just simply receiving this spike protein, it cannot cause disease. It cannot cause COVID-19. It's not a live virus. It can't replicate. It can't cause any cellular damage. And importantly, in the large phase three studies, which we've seen the headlines for, obviously we haven't seen the data in detail for those published yet, there appears to be really no safety concern in the general population. And I don't see any reason why a patient with CLL or indeed any immunocompromised patient would have a different safety profile for this particular vaccine technology than the general population. So long-winded way of saying I don't think it's going to be unsafe, so that's the most important thing.

Second question then is, well, what's the effectiveness? We can extrapolate from other vaccines that have been given to patients with CLL and certainly, for example, when you look at influenza vaccine and pneumococcal pneumonia vaccine, the Shingrix vaccine, the rates of antibody production in CLL patients are lower than in the general population, but they're not zero. It's not like no patient response. So I think we'll see something similar with this SARS-CoV-2 vaccine that yes, they'll probably be lower than the general population, but I think many patients will respond, and hopefully that will provide much needed protection.

What Does it Mean When a Vaccine is Live?

Esther Schorr: Okay. I think just in the mix of all of this, the other question that was asked is some vaccines are live, some are not live. Am I interpreting what you were talking about that this is not a live vaccine but it's a manufactured entity so there's not a safety concern about that?

Dr. Thompson: Yeah, absolutely. So there are some vaccines where basically they start by taking the whole virus particle and there's something that's done to it so that it can't create the actual disease. An example of this is the measles vaccine. They so-called attenuate the virus. Smallpox was another one that was like this. And so these live-attenuated vaccines are capable of actual replication in the body. You can even actually sometimes transmit the vaccine virus to other people, but it's not capable of creating a disease, and that's not the case with any of the front runner candidates for SARS-CoV-2 vaccine.

So, in particular, these two that are based on this mRNA technology, the Pfizer and the Moderna that are going to be approved soon most likely, they clearly aren't a live virus, not even the whole virus. It's just literally one very small but very important component of the virus which is this so-called spike protein. And the spike protein is what the virus uses to attach to a cell and then get into the cell and cause trouble. And so these vaccines have produced dramatic antibody responses against this spike protein. In fact, the antibody levels in the early phase studies of this virus, the antibody levels that people that were vaccinated produced were two to four times higher than the antibody levels that people had after recovering from the actual infection.

Should Immunocompromised CLL Patients Receive a COVID Vaccine?

Esther Schorr: But would that be for immunocompromised patients as well?

Dr. Thompson: So we don't know, but there is some data that's been published. There was a study I recall seeing that came from China early in the pandemic where they looked at patients with varying degrees of immune suppression. So they all had hematologic malignancies, so they were patients with chronic malignancies but also a lot of patients with acute leukemia. They looked at antibody levels in those patients and they actually demonstrated quite nice antibody responses in the majority of them, not all but the majority of those patients. And so we haven't been systematically looking I think in terms of our patients that recover from COVID, but I did do it in one of my patients who had acute leukemia and had a transplant and was still on immunosuppressant therapy post-transplant, and she made a nice antibody response to COVID.

Now, will we see the same thing with the vaccine as we see with the actual infection in terms of the antibody responses in immunocompromised patients? Well, it's all hand waving as Dr. Fauci said this morning, but I think I'm reasonably confident that we're going to see antibody responses based on the robustness of the responses in the general population and the fact that patients with leukemia and other blood cancers are capable of clearing the COVID virus and making antibody responses to it.

Esther Schorr: Okay. So just related to this then, there are different kinds of vaccines and the immunity that they provide varies like we get a flu shot once a year, but you get a tetanus shot once every 10 years. And I know Dr. Fauci talked a little bit about maybe we're not quite sure yet, but do you have any sense of how long the immunity to COVID will last or is that still up in the air when you're vaccinated?

Dr. Thompson: Yeah. It's completely up in the air. This is moving so fast. I think he alluded this morning to the unprecedented nature of the vaccine production. What is normally a process that may take five or 10 years has been compressed into such a short time, partly because of all of the amazing new technology that we have. So we don't know is the short answer.

There was concern expressed recently related to loss of immunity in some patients that actually had COVID-19, and there have been small numbers of cases of documented reinfection, definite reinfection in patients, but those are actually very small numbers out of the total number of patients that have actually had the virus. And Dr. Fauci mentioned this morning about the fact that this is part of a family of viruses called coronaviruses, many of which ... There are four that circulate widely in the community and cause essentially the common cold, and our immunity to those does wane relatively rapidly. Now, will we see ... This is a much more severe infection than the common cold. And certainly with the more severe coronavirus infections that emerged that SARS-CoV-1 and MERS, the immunity seems to be much more long-lived than what we see with these common cold coronaviruses. So hopefully it'll be more long-lived.

The other thing that is important to understand is the antibody responses that we see are not the only aspect of immunity. So in some cases, antibody response may wane over time, but we retain what's called T-cell memory. And T-cell memory is probably the most important thing in terms of our immune response to a lot of pathogens. The trouble with it is that it's much harder to measure. You have to design very specialized assays to be able to measure T-cell memory. I did see something published recently that suggested that T-cell memory may be maintained after COVID-19 infection beyond the loss of antibody production, which would be important. What we don't know though is whether the vaccine induces proper T-cell memory or whether it only induces this antibody response.

Does Treatment Affect Your Ability to Receive a COVID Vaccine?

Esther Schorr: Okay. So we're getting a number of questions, and I really appreciate our live audience sending these in. Some version of this question is coming up. A number of CLL patients either have just finished treatment or are headed into treatment and where in that timeline should the consideration of getting the vaccine when it's available, where does that fit and what should they be concerned about?

Dr. Thompson: Yeah. This is a really challenging question. I would say the first thing that must be borne in mind by everybody that's making these decisions is that it is crucial that you optimally treat CLL. You can't just forget that you have CLL because there's this COVID pandemic. That said, sometimes there are decisions where it's not a clear-cut decision and there would be several appropriate avenues to take. And so you can, I guess, make decisions to use certain type of therapy or potentially a patient who is in watch and wait and is approaching the time of therapy, sometimes there's a little bit of wiggle room in terms of exactly when you would start the treatment, so there may be decisions that are made on the basis of the timing of when someone might get a vaccine and when you think someone might actually need treatment that could be influenced by the vaccine.

One example I guess I would use is there is some data that CD20 antibodies like rituximab (Rituxan) or obinutuzumab (Gazyva) certainly impact our ability to make immune responses to other vaccines, and it's well-established data in CLL and other diseases where they're used that they impede vaccine response. It's less clear what some of the oral targeted therapies do. So, for example, ibrutinib (Imbruvica) is probably the best study. There is some data that suggests that it inhibits response to influenza or pneumococcal vaccine.

There's another study though from Ohio State where they looked at ibrutinib as an early therapy in a group of patients who otherwise would have been watch and wait, and they split them into patients where they vaccinated them first and then started ibrutinib with a pneumococcal vaccine. And the other half of the patients started the ibrutinib and were then immunized. And actually, the people who were on ibrutinib when they were immunized actually had a better response, so that's rather contrary to some of the other data.

So, it's hard to interpret that. Likewise, there's very little data with venetoclax (Venclexta). But I think it's not unreasonable to anticipate that maybe CD20 antibodies are going to impair responses to the vaccine. Likewise, maybe chemotherapy. So all things being equal, if those therapies are not essential then I'm tending away from those in someone where they might be able to get the vaccine soon.

Now, in terms of someone who's actually on those now or recently had them, should you delay vaccination because of that? I wouldn't because I think we don't have the data to say that that's the case, and it may be harmful to delay immunization, which might be effective. Also, we don't know ... As we alluded to earlier, you talked about the fact that some of this immunity may wane over time to vaccines, and maybe we need a booster once every six months or once every year or once every 10 years, similar to some other vaccines. And it may be that as more data is gathered, a similar thing is determined for this vaccine, and so maybe those patients that had recently received immunosuppressant therapy when they get a booster, it will help. But I wouldn't deliberately delay vaccination because of a recent therapy in this setting.

Esther Schorr: So let me just summarize. I know that at Patient Power, we're going to continue to do programs that specifically deal with COVID-19 and the vaccines. So what I'm hearing is patients with CLL or other immunocompromised conditions shouldn't be afraid to get vaccinated when that becomes available that it's probably a good idea, but there's some measure of individual consultation that needs to happen if you're in treatment or getting ready to go through treatment or have just gone through treatment to make an assessment, the cost benefit analysis of is this the right timing? Is that a good summary?

Dr. Thompson: Yeah. You did that much more quickly than me.

Esther Schorr: No. But you gave us the details. So I think what we're going to do is we'll move on. We're getting some really good questions that don't have to do with the vaccine and with COVID. So let's move on to some of those, and we can always circle back on another program and we'll have to have you back to talk about it.

Information on Hereditary Risks in Chronic Lymphocytic Leukemia

So we got a question here from somebody who's listening in. She says that her husband recently died of multiple myeloma, and she is a high risk CLL patient. And what she wants to know is are her adult sons at higher than normal risk for blood cancers?

Dr. Thompson: Well, firstly, I'm really sorry to hear that. Secondly, as far as CLL goes, there are definitely families in which there's a strong hereditary tendency to develop CLL. There are a small minority of patients who actually develop CLL where there's a hereditary tendency, and the genetic basis for it is not well understood unlike in other diseases like breast cancer, for example.

Also, I would say that unlike in some of those familial cancer syndromes, like a well-known example is the BRCA gene in breast cancer where if you have this BRCA mutation, your lifetime risk of breast cancer is 70% or 80%, so most patients will go on to develop cancer and, therefore, preventative treatment is often done. In the case of CLL, there is nothing that's been identified where you can make such a strong prediction that someone is going to get it. You can just say that, well, maybe there's an increased risk.

In this case, I think the other thing I would say is that in order to determine if there's a familial tendency to CLL here, you would need to know, does this lady have multiple other relatives that had CLL? Particularly, her parents and her siblings because at the moment, it's just her. In terms of her husband, that doesn't really increase the genetic risk because obviously, they're unrelated. So it's hard to ... Really, we start to think of someone having a familial tendency for CLL if there are multiple people, first degree relatives so two siblings or a parent and a child, then you can start to say, okay, maybe there's a familial tendency here. Just one person like her, you can't really tell.

But as far as advice for the children, I tell people. "Look. Maybe there's an increased risk but there's no preventative therapy. There's no case of, well, if we diagnose it early, we can treat it more effectively." So really as far as the children go, it's just about having regular preventative care with your primary care provider, having your regular annual physical. Otherwise, not really doing anything differently. You can't go and sell all of your possessions and move to a remote area.

Esther Schorr: Okay. That's somewhat reassuring for families, but it's still something that people are going to worry about and just keep an eye on.

What Are the Chances that a CLL Patient Develops a Secondary Cancer?

So in that same vein, we have a question from a number of people who are asking about, so you're a CLL patient, how likely are you to get a second cancer? And which cancers are most common to have a general practitioner or your hematologist watch out for?

Dr. Thompson: Yeah. So that's a really important question. It's something I go over with all of my patients. So by far, the biggest problem for CLL patients as far as second cancers go is skin cancer. There's a dramatic increase in the risk of skin cancer, mostly non-melanoma skin cancers, but also melanoma to a lesser extent in patients with CLL. And it's not just related to the treatment that you have for CLL. It's related to the disease itself. So we see people with CLL who have never received therapy and their risk of skin cancer is significantly elevated compared to the general population.

The good thing about skin cancer is that if you're proactive with it, you can diagnose it early and treat it effectively. I also counsel people to be really careful about looking after their skin and avoiding the sun.

The other type of cancer that is increased in CLL patients compared to the general population is what we call head and neck cancers, and by that, I mean cancers of the mouth and the larynx. Those cancers are often driven by the human papillomavirus infection, and it may be that, similarly to the skin cancers, it's the loss of effective immune surveillance that increases the risk of those cancers. Now, those are not hugely common cancers, so unlike skin cancer which is enormously common and then has a markedly increased risk. But I tell people to have their dentist look at them very carefully when they go and have their dental exam.

Then, as far as things like the common cancers that people die from in our community, breast, prostate, colon, lung, they don't seem to be specifically increased in CLL patients, or at least not to the same extent. But certainly, those that have easy screening methods, I tell people to get screened as anyone should because we can dramatically impact the likelihood you'll die from another cancer.

And then the only other thing I would mention is there are some cancers in CLL that we see in people that have had specific types of therapy. So in particular, it seems like chemoimmunotherapy, same with FCR, likely increases the risk of secondary leukemia, which tends to happen in five years or more after treatment. The risk of that related to FCR is somewhere between about 2% and 5% depending on which dataset you look at. And we do think that's related to the specific therapy, and it's something that we hope will reduce in frequency as we move more towards doing targeted therapies rather than chemotherapy.

Esther Schorr: Yeah. And I'm very familiar with that because my husband and partner is a CLL patient, a survivor, and a number of years later, he came down with a myeloproliferative neoplasm (MPN). Fortunately, there are good treatments for both now, but it's something to watch for.

Melanoma as a Secondary Cancer to CLL

I just wanted to follow up on ... because you spoke about melanoma or skin cancer, and Margaret Walsh, who is one of our community members, said, "I recently had a lump removed from my face and I'm awaiting results. Are there particular protocols for treating melanoma in patients with CLL? Is it different than if melanoma is your first cancer?"

Dr. Thompson: That's an excellent question. The answer is no. Now, whether there should be or not is probably something we should be looking at in the future. So melanoma, if it is melanoma, melanoma is a disease that is curable in the vast majority of patients by simply excising, cutting out the initial spot, provided you catch it early and it hasn't invaded deep into the tissue or spread elsewhere. It's also a type of cancer where there's been dramatic benefit from new types of immunotherapy. In fact, it's the poster child for immunotherapy amongst cancers. So certainly, for the small number of patients that I've had that have had metastatic skin cancer where the skin cancer has spread somewhere else, generally they're treated the same way as any other patient, usually with immunotherapy in the case of melanoma or with chemotherapy and radiation initially usually in the case of skin, squamous cell carcinomas of the skin.

What Information Can You Share on Combination Therapies for CLL?

Esther Schorr: So you mentioned FCR which has the C in the middle, which is Cytoxan (cyclophosphamide), which I understand is a chemotherapy drug, and I know that you've mentioned that we're moving toward more immunotherapy and less chemotherapy. So this might be a good time to tell us a little bit about what you've presented or you're presenting at ASH as I understand and how it's relevant to our patients. It does have to do with combination therapy and minimal residual disease (MRD). Am I correct?

Dr. Thompson: Yes. I'm presenting an update on a study that we have where we add venetoclax (Venclexta), which is an oral targeted therapy to ibrutinib, which is another oral targeted therapy that affects a different cellular pathway in the CLL cells in order to try and achieve very deep remissions, what we call eradication of minimal residual disease in the hope that we can be able to stop treatment and then have a long period of remission where the patient isn’t needing to take continuous therapy. So yeah.

In CLL, we're not doing a lot of immunotherapy. Most of the new drugs are actually oral targeted medications which block a particular protein or a particular enzyme in the CLL cells. Unfortunately, the only immunotherapy we really have that works in CLL is these antibodies that stick to the surface of the cell and then activate your immune system to kill them. We haven't yet had much success in CLL per se with immune activating antibodies like we've seen in other cancers. The exception being patients with Richter’s transformation who seem to have a unique sensitivity to those drugs.

At this ASH, there is a huge array of studies being presented which look at combinations of targeted therapies. And so essentially, they're all permutations of Bruton's tyrosine kinase inhibitor like ibrutinib or acalabrutinib (Calquence) or zanubrutinib (Brukinsa) combined with venetoclax and then with or without an antibody, mostly obinutuzumab. And essentially, what these all have in common is that they are very potent therapies. They have a very high rate of eradicating all detectable CLL from the body.

You'll probably hear a term called minimal residual disease. Essentially, what this is, is we use a technology where we can detect very small numbers of CLL cells either in the blood or in the bone marrow, usually as few as one CLL cell out of 10,000 normal cells or they're increasingly looking at one CLL cell in a million normal cells. So unsurprisingly if you can't detect any CLL using a very, very, very sensitive test like that, then your patient will have a longer remission because the less disease you have, the longer it will take to grow back if there is still a small amount of disease.

So that's what these new therapies are designed, to try and get people what we call MRD-negative or with undetectable MRD, and then hopefully to stop treatment and observe patients and see, well, okay, does the MRD come back over time? Does the disease itself come back over time?

There are increasing efforts being made to individualize the approach that we take to patients. So by that, instead of just treating everybody for a specific period of time, which often is relatively arbitrary, we might use minimal residual disease, and in particular, we might look at how long it takes patients to eradicate this minimal residual disease. And then based on those things decide, which patients might need a longer duration of therapy compared to which patients who have a very rapid response could stop treatment earlier? And what that might do is spare patients who have a very rapid response from unnecessary side effects of therapy, as well as cost. But also, patients where there is a less effective response, we may be able to continue their therapy for longer and keep them in remission for longer.

So, there's a big focus both on developing these very potent combinations but also in individualizing treatment using these new technologies like MRD analysis. I think it's a very exciting time for the field in general, and the results look fantastic.

Can You Explain Minimal Residual Disease (MRD)?

Esther Schorr: Well, just so that ... I know there may be a percentage of our audience that isn't as familiar with MRD or minimal residual disease and where it fits into relevancy in CLL. Can you just briefly explain how important is it to get somebody to an MRD-negative versus not doing that? What are the trade-offs?

Dr. Thompson: So the first thing to say is that the importance of getting undetectable minimal residual disease is treatment paradigm dependent. So if, for example, you receive chemotherapy with FCR for six cycles and then stop, which is what was done for most patients a little while back, then if you've got undetectable disease with undetectable MRD in the end of therapy then your remission duration is going to be much longer than if there's still a significant amount of disease there that you can measure.

In contrast, for example, if you're taking ibrutinib and you're taking it continuously, the vast majority of patients, 95% plus, will still have detectable MRD. And in those patients, as long as they continue to take the drug, usually that disease is suppressed and it's not growing and therefore, it's not really important in that setting. It's most important if you're giving essentially a treatment that is time limited. So if you're stopping therapy then the amount of disease you have when you stop therapy will inherently determine how long it is going to take before that disease comes back.

Esther Schorr: Okay. So the less of it that's left, the longer the runway may be before you might need treatment again is what I'm hearing.

Dr. Thompson: And you also need to take into account how fast the disease grows, so the length of the runway and also how fast the plane is going.

Esther Schorr: Got it.

Dr. Thompson: Different people's CLL grows at different rates. Biologically, there are massive differences from patient to patient. So some patients have a disease where the doubling time is five years, and some people have a disease where the doubling time is three months. Now, if you get those two patients to the same level of disease and stop therapy, the person where the doubling time is three months is going to relapse much quicker than the person whose doubling time is five years. So that's where we still have to look at the biology of the disease pre-treatment and factor that into our decision-making as to what type of treatment we choose for a particular patient.

Do Side Effects from CLL Treatment Subside When Treatment Ends?

Esther Schorr: Okay. So let me switch gears just a little bit. We're getting a number of questions about side effects that might come from a treatment. For example, we have somebody who's taking ibrutinib and venetoclax. They've been on it for several months, and they developed AFib. And they're wondering, is there a high probability that this condition will reverse when they stop treatment? So to more generalize it, if somebody is on treatment for CLL and they have these side effects, will those side effects then disappear when they're finished?

Dr. Thompson: Yeah, that's an excellent question. So the data for this is not strong. So certainly there are some side effects where clearly they will go away when you stop therapy. For example, if your white blood cell count, your neutrophils are low because you're taking venetoclax, and you stop it, it will go away. If you're having bruising and bleeding from ibrutinib and you stop it, it will resolve in seven days also.

Atrial fibrillation is a little more complex than that. So definitely when we looked at it, there are a group of patients where when you stop the ibrutinib, their AFib will become much easier to manage. Either it will go away entirely or it will become less frequent and the heart rate won't be as rapid. But there are another group of patients where they will continue to have atrial fibrillation when you stop the ibrutinib. The factors that underlie that are still a little bit poorly understood.

Certainly, I would say that logically, if you look, for example, at what the patient's heart looks like on an ultrasound, an echocardiogram, if you have a patient where, for example, the left atrium, which is where the atrial fibrillation arises, if it's very enlarged, that person is much more likely to have ongoing atrial fibrillation than somewhat his heart is structurally normal, for example. But as far as hard data on that, it's a little sketchy.

But certainly anecdotally, I've seen patients whose atrial fibrillation is easier to manage, in general, it's easier to manage with dose reductions and/or cessation of the ibrutinib. Now, does that mean that you have to stop the ibrutinib because you have atrial fibrillation? Well, not necessarily, so that's an individualized decision, and it depends on how problematic is the atrial fibrillation in terms of your heart function and controlling the rate? And secondly, what is the risk of stroke?

So atrial fibrillation increases your risk of stroke. And generally, in the healthy population, we would give some blood thinning medication to patients to reduce the risk of stroke. Because ibrutinib also thins the blood, that can be a challenging decision to make. And so sometimes, a physician may decide that a patient needs to sop ibrutinib to be able to better manage the atrial fibrillation. But if stopping the ibrutinib is going to be significantly detrimental to the outcome related to the CLL, then that may be counterproductive.

So, you have to weigh those two things. What's the downside of stopping in terms of controlling the disease, but also what are the risks of continuing related to atrial fibrillation? And so that's something that you really need to go into individualized risk assessment.

Esther Schorr: And it sounds like that's true all along that there's a lot more work now and a lot more progress in looking at individualized therapies and combinations of therapies that will work best for each patient. That's what it sounds like.

How Can CLL Patient’s Decide on the Best Combination Therapy?

So actually, we just had a question come in, and I don't know if you can answer this. So what combination therapies are looking best at this point and are they dependent, choice dependent on which chromosomal abnormality you have?

Dr. Thompson: Yeah.

Esther Schorr: A big one.

Dr. Thompson: That's a great question.

Esther Schorr: Yeah.

Dr. Thompson: So I would say that I think that the combination of BTK inhibitor, ibrutinib, acalabrutinib or zanubrutinib with venetoclax certainly seems to produce the highest rate of complete remission, and it seems to produce probably the highest rate of undetectable minimal residual disease, so it certainly seems to be the most potent therapy. It's a convenient therapy because it doesn't have any intravenous infusions. You don't have to have a CD20 antibody which depletes your immune system and creates the inconvenience of having to come to an infusion center.

Now, a really important question, because we've seen the triplet regimens as well where you use those two oral drugs plus an antibody, and we don't know whether that is better than the two oral drugs without the IV. We also don't 100% know whether everybody needs the BTK inhibitor or whether some people, for example, could do really well with venetoclax and obinutuzumab, or are there a group of patients where just the BTK inhibitor by itself is adequate? So definitely, I think that genetics are important in terms of making the decisions.

I think, for example, if you have low risk genetics, I think the likelihood of a prolonged remission after receiving a time limited therapy like venetoclax and obinutuzumab is very high. For those patients, my personal approach is that I like to give them a time limited therapy rather than something that they have to take indefinitely.

Are Treatment Options Dependent on What Chromosomal Abnormality a Patient Has?

In contrast, I think patients who have 17p deletion maybe are the group of patients where it's least suited to having a time limited approach because I think their remissions are going to be shorter. And I think we saw data from Dr. Al-Sawaf for updating the CLL14 data that certainly suggests that the growth rate of disease in patients with 17p deletion and also patients with unmutated IGHV is quicker, and so those patients, when you stop venetoclax, are going to relapse sooner.

So, I certainly think my approach to 17p deletion is to be more circumspect about wanting to give a time limited therapy. But then the big group of patients in between with unmutated IGHV, whether they should get BTK inhibitor-based therapy or venetoclax-based therapy or should they get a combination? That's a more challenging question, but thankfully, there are a number of randomized studies that are ongoing that are going to give us good answers but probably not for quite some time.

What Are the Key Takeaways from ASH 2020 for CLL Patients?

Esther Schorr: It sounds to me like it's a mixed blessing to have a menu so great of tools which you didn't have 10 years ago even or five years ago what to choose for any individual patient. It's a double-edged sword. It sounds like we now have lots and lots of ways of treating CLL, which is the good news. I think the more difficult pill to swallow, pardon the pun, is which one is right for which patient? So I guess what I'd like to do because we're going to need to wrap up, we could go on for another three hours, but what would you say is the headline for CLL patients coming out of ASH this year?

Dr. Thompson: Well, I would say the headline is that the results of these novel targeted agents, even in patients with high risk disease when they're given as the first treatment, are really quite remarkable. We're seeing incredibly high rates of eradication of all detectable disease with combinations of these drugs, extremely low risk of disease progression and generally, very favorable toxicity profiles and tolerability of the drugs. So really, patients can expect to have a good quality of life and extremely good disease control going forward.

And even for the patients with difficult CLL, there are a number of new approaches which are showing enormous promise. So, for example, I'll just mention two things really quickly. One is we're going to see updated data on LOXO-305, which is a new type of BTK inhibitor. It is an oral drug like ibrutinib and acalabrutinib, which targets the BTK, but it works really well in patients who develop a mutation in BTK that results in loss of effectiveness of ibrutinib and acalabrutinib. And so that's a very exciting compound.

We're also going to see some more data from the TRANSCEND study, which is looking at CAR T-cell therapy in patients with CLL. And those data look really exciting also. So even in patients with difficult CLL, there are an increasing number of options that are hopefully going to allow people to continue to live good and long lives.

Are We Close to a Cure for Chronic Lymphocytic Leukemia?

Esther Schorr: So, would it be dangerous to bring up the word cure? Are we getting close to that for CLL?

Dr. Thompson: Well, yeah. So, okay, I think definitely we can cure CLL, definitely, not all CLL. But I think we know that from the chemoimmunotherapy data with FCR that we have patients in remission in 20 years generally who have favorable risk of genetics. And I think that will also be true when we look back on it with venetoclax-based therapy in the front line because honestly, venetoclax-based therapy is achieving deeper remissions than what we get with FCR, so there's no reason to expect that we won't see the same thing in those lower risk patients with venetoclax-base treatment front line.

So, I think, yes, we can cure people with those treatments who have lower risk disease. The challenge then becomes, well, can we cure the people with high risk CLL like 17p deletion? We know we can cure them with a bone marrow transplant. And I would say also I saw Dr. David Porter, who led the initial CAR T-cell study in CLL having done a virtual talk at MD Anderson a couple of months ago where he updated their CAR T-cell, and he was showing pictures of the first patient to be treated with CAR T-cells and his RV trips around the country-

Esther Schorr: Oh my, gosh.

Dr. Thompson: ... and during the pandemic. So this is 10 years since this patient was treated, and this patient had terrible CLL and had failed all available therapies. So I think CAR T-cell therapy can cure people.

So, we know we can cure people with cellular therapy, transplant, and CAR-T. We know we can cure low risk patients with chemotherapy, and I think that probably we will cure those same group of patients with venetoclax-based therapy. So I think it's just a matter of figuring out the big group in the middle and how best we can treat them. We may not have to cure people. We may find that we can ... If the worst thing that happens to someone is that they have to take a pill that's very well tolerated every day for the rest of their life but that maintains their disease under control and they have limited or no side effects, that may be [crosstalk].

Esther Schorr: Could be worse.

Dr. Thompson: Yeah, right.

Esther Schorr: It could be worse. Yeah.

Dr. Thompson: But there's a lot of work to still be done to optimize our approach for all of the various subgroups of patients. I think we're making enormous progress and quite quickly.

Esther Schorr: Dr. Thompson, I've been following ASH and CLL as you know for many, many years, and this is the most encouraging set of information that you shared with our CLL community today, and I really, really appreciate it. I think that people should really take to heart that there are so many options that are being created, and the research that you and others are doing is very, very encouraging. Now, if we can just get rid of this silly virus, I think that we could begin to get back to some sense of normalcy and allow all of you who are treating patients to focus on CLL even more. We can't forget that underlying concern. So I just want to thank you.

Dr. Thompson: Yes. Totally, it's understandable that everyone's focus is on the pandemic because it's one [crosstalk], but I do think it's important to just say that the vaccine ... The data that has been shared publicly or the headlines that have been shared publicly are truly extraordinary. So a 95% effectiveness rate, if this is really sustained and borne out when a larger number of patients are studied, is akin to what we see with the most effective vaccines like the measles vaccine. There's the potential if enough people are actually vaccinated and if we keep an eye on how long it works for that we could even eradicate this thing.

Esther Schorr: Wouldn't that be wonderful? From your lips-

Dr. Thompson: There's an enormous amount of hope there. We've got a dark winter to come first, but there is an enormous amount of hope that there's light at the end of the tunnel as far as the pandemic goes. So now is not the time for people to be letting down their guard and getting pandemic fatigue and going out and being reckless because the cavalry is coming and it's coming more quickly and with greater effectiveness, than I think any of us really could have dreamed. So we're all sick of the pandemic, but there is, as I say, a very bright light at the end of the tunnel.

Esther Schorr: Right. And I would say just to close that I'm guessing from what you just said that this might mean that those patients who are listening and their loved ones need to have that tough talk with their families about the holidays. That as much as we all want to be together that we have to look toward next year, not this year, and just to hunker down and feel like, as you said, the cavalry is coming. We're just going to have to let it get over the hill before we all start celebrating.   

So, Dr. Thompson, thank you so much. As usual, you have provided us not only with information but with a lot of hope for CLL patients. So I want to thank you on behalf of our community and certainly Patient Power.

I want to thank all of you who have logged in and asked questions. And I want to have you please discuss with your doctor what you learned from our program that could improve your care, and don't be shy. A transcript and a replay will come soon to our website so you can review what you've heard today. Please be sure to subscribe to our e-newsletter so you're always in the know, and follow Patient Power on Facebook, on Twitter, on Instagram. And please, don't disconnect just yet. We have a very brief survey that follows as we end, and what you tell us about these programs helps us do better and do more for you. My parting words are to please remember that knowledge can be the very, very 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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