Tag Archive for: mosunetuzumab

What Follicular Lymphoma Treatments Are Available?

What Follicular Lymphoma Treatments Are Available? from Patient Empowerment Network on Vimeo.

Follicular lymphoma patients have different treatment options, but what should patients know about them? Expert Dr. Sameh Gaballa shares an overview of available treatment options and research results of treatment versus watch and wait. 

Dr. Sameh Gaballa is a hematologist/oncologist specializing in treating lymphoid malignancies from Moffitt Cancer Center. Learn more about Dr. Gaballa.

See More from START HERE Follicular Lymphoma

Related Resources:

What Exactly is Follicular Lymphoma? An Expert Explains

What Exactly is Follicular Lymphoma? An Expert Explains

Follicular Lymphoma Patient Expert Q&A: Start Here

Follicular Lymphoma Patient Expert Q&A: Start Here

Newly Diagnosed with Follicular Lymphoma? Start Here

Newly Diagnosed with Follicular Lymphoma? Start Here


Transcript:

Lisa Hatfield:

So, can you speak to the novel pathways and targets that are currently under investigation in follicular lymphoma? And what are the most important highlights to point out to patients and families?

Dr. Sameh Gaballa: 

Yeah, absolutely. So you have to remember, number one, not all patients with follicular lymphoma have to be treated. A fair number of patients can be safely observed initially, because the…so when I was talking about the types of lymphoma, so the aggressive lymphomas, those ones are treatable, but curable, meaning you treat it, goes away, good chance that it goes away and does not come back.

Whereas follicular lymphoma, those are slow-growing lymphomas. They may or may not cause problems. The treatment though, they’re very treatable. There are a lot of treatments available, but the thing is they’re not curable, meaning that they go into remission, they could stay in remission for years, but then eventually they would come back again. So you have to remember that because of that, large trials were done previously where patients who had no symptoms and not a lot of disease, they were randomized, half would get treated.

The other half were on a watch and wait. And the patients who, survival is exactly the same in both groups, there was not really any advantage to early treatment versus treatment as if there’s a reason in the future. And we typically have some indications where we decide, okay, well, it’s time to treat. And those basically have to do if the lymph nodes are big enough or they’re close to an important structure and we don’t want them to grow more and maybe press on an important structure, or if they’re causing some kind of symptom or they’re causing anemia or low platelets. I mean, there has to be one, because there has to be one reason for why you’re trying to treat that patient, because you’re basically trying to fix a problem.

So if there’s no problem initially, it doesn’t make sense to treat it. Now, there are lots of available treatments, it could be only immune therapy, something like rituximab (Rituxan)  or obinutuzumab (Gazyva); these are antibody treatments. There are also combinations with chemotherapies, like bendamustine (Treanda), rituximab for if we have relatively bulky disease. There are options as well that do not involve chemotherapy.

So something like pills like lenalidomide (Revlimid) combined with rituximab, those are also options that can be used in follicular lymphoma. But over the last few years, there have been a lot of changes in follicular lymphoma and a lot of novel targets and a lot of novel treatments available. So, for example, a few years ago now, we’ve had CAR T-cell therapy approved. Right now, we have two products approved, axi-cel and tisagenlecleucel (Kymriah). There’s also data that was presented with liso-cel in follicular lymphoma. So hopefully we might see an approval for that as well. So that’s one class.

There’s also bispecific antibodies, and it’s very exciting times. We had the first bispecific antibody approved in the United States in December of 2022. That’s mosunetuzumab-axgb (Lunsumio). So what is a BiTE antibody? These basically are advanced types of immune therapies where you give the patient an antibody that has two ends to it, one end sticks to the cancer cell, the other end sticks to your immune cells. So it’s basically handholding your own immune cells or your own T cells to go and get attached to the cancer cell and kill it, not chemotherapy. It, of course, can have some immunological side effects like fevers or inflammation initially when it’s done, typically when in the first cycle or second cycle.

But something called cytokine release syndrome rarely can cause neurological toxicity. That’s also very transient usually, and very rare with bispecific antibodies. But those are two up and coming treatments. Right now, they’re approved in patients who’ve had relapsed/refractory disease, meaning they’ve had two or more lines of previous therapies, but they’re…we have them now in trials where we’re looking at those agents in earlier lines of therapy. There are other agents as well.

A few years ago, we had tazemetostat (Tazverik) approved, which is a pill that targets an enzyme in the cells called EZH2 and they basically, this pill tries to ask the cancer cell to differentiate, rather than get stuck and not die. So they differentiate and then they eventually die, so that’s another class of medicine. And we’ve now seen some data with BTK inhibitors. There’s been data presented from the ROSEWOOD Study with zanubrutinib plus obinutuzumab (Brukinsa plus Gazyva); it’s not yet FDA-approved, but the data looks interesting and certainly needs to be looked at further. 


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Follicular Lymphoma Patient Expert Q&A: Start Here

Follicular Lymphoma Patient Expert Q&A: Start Here from Patient Empowerment Network on Vimeo.

The START HERE program bridges lymphoma expert and patient voice, whether you are newly diagnosed, in active treatment or in watch and wait. In this webinar, Dr. Sameh Gaballa provides an overview of the latest in follicular lymphoma, emerging therapies, clinical trials and options for follicular lymphoma progression and recurrence.

Dr. Sameh Gaballa is a hematologist/oncologist specializing in treating lymphoid malignancies from Moffitt Cancer Center. Learn more about Dr. Gaballa.

Download Resource Guide  |  Descargar guía de recursos

See More from START HERE Follicular Lymphoma

Related Resources:

What Exactly is Follicular Lymphoma? An Expert Explains

What Exactly is Follicular Lymphoma? An Expert Explains

What Follicular Lymphoma Treatments Are Available?

Newly Diagnosed with Follicular Lymphoma? Start Here

Newly Diagnosed with Follicular Lymphoma? Start Here


Transcript:

Lisa Hatfield: 

Welcome to the START HERE Patient Empowerment Network Program. This program bridges the expert and patient voice enabling patients and care partners to feel comfortable asking questions of their healthcare team.  Joining me today is Dr. Sameh Gaballa, an oncologist hematologist from Moffitt Cancer Center. Dr. Gaballa’s clinical interests are treating patients with lymphoid malignancies. His research focuses on developing novel targeted agents for treating patients with indolent lymphomas, such as follicular lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphomas. Thank you so much for joining us today, Dr. Gaballa.

Dr. Sameh Gaballa:

Thank you, Lisa. Happy to be here.

Lisa Hatfield:

Thank you. The world is complicated, but understanding your follicular lymphoma diagnosis and treatment options doesn’t have to be. The goal of START HERE is to create actionable pathways for getting the most out of follicular lymphoma treatment and survivorship. 

Before we get started, please remember to download the program resource guide via the QR code. There’s great information there that will be useful during this program and after. So let’s get started. So, Dr. Gaballa, I’d like to talk about what’s on the follicular lymphoma treatment radar. There’s a lot going on in terms of emerging treatment options, clinical trial data, and other learnings for the follicular lymphoma community.  But before we jump into how the armamentarium is expanding, can you provide an explanation of what follicular lymphoma is?

Dr. Sameh Gaballa:

Yeah, absolutely, thank you, Lisa. So, follicular lymphoma is a type of B-cell non-Hodgkin’s lymphoma. What does that mean? It’s basically, so in your body, there are cells that are part of the immune system; these are lymphocytes. These cells normally, their normal function, is to fight infection, they’re part of your immune system. They actually are involved also with fighting cancers, but sometimes they become malignant. But not all lymphomas are the same. Lymphomas are a huge family. So there’s Hodgkin’s lymphoma, there is non-Hodgkin’s lymphoma. Within non-Hodgkin’s lymphoma, there is a type called B-cell non-Hodgkin’s and there’s a T-cell non-Hodgkin’s lymphoma. And then within B-cell non-Hodgkin’s lymphoma, there are two big groups. So one group, they are these aggressive lymphomas that grow quickly, they can make you sick quickly, and these lymphomas we have to treat right away.

And then you have those slow-growing indolent lymphomas that are sometimes very commonly actually diagnosed by chance, or incidentally, that’s usually the most common way these are diagnosed.  And the most common slow-growing indolent lymphoma is going to be follicular lymphoma. Now, where do you find these lymphomas? It’s a blood disease. So, again, we said that those cells are normally borne in the bone marrow, they are in the blood, they’re in the lymph nodes, they’re in the spleen. So usually you would find those malignant cells usually in the lymph nodes, but you could also find them sometimes in the spleen or in the blood or in the bone marrow as well. And the symptoms they cause will be dependent on where they are and how big the, those, the involvement is.

Lisa Hatfield:

Well, thank you for that detailed overview, Dr. Gaballa. We do have follicular lymphoma patients and care partners who are newly diagnosed, in active treatment, watching and waiting, and also living with their disease joining this program. No matter where you are on your journey, START HERE provides easy-to-understand, reliable, and digestible information to help you make informed decisions. Dr. Gaballa, we’re going to dive right into things with a high-level update. So, can you speak to the novel pathways and targets that are currently under investigation in follicular lymphoma? And what are the most important highlights to point out to patients and families?

Dr. Sameh Gaballa:

Yeah, absolutely. So you have to remember, number one, not all patients with follicular lymphoma have to be treated. A fair number of patients can be safely observed initially, because the…so when I was talking about the types of lymphoma, so the aggressive lymphomas, those ones are treatable, but curable, meaning you treat it, goes away, good chance that it goes away and does not come back. Whereas follicular lymphoma, those are slow-growing lymphomas. They may or may not cause problems. The treatment though, they’re very treatable. There are a lot of treatments available, but the thing is they’re not curable, meaning that they go into remission, they could stay in remission for years, but then eventually they would come back again. So you have to remember that because of that, large trials were done previously where patients who had no symptoms and not a lot of disease, they were randomized, half would get treated.

The other half were on a watch and wait. And the patients who, survival is exactly the same in both groups, there was not really any advantage to early treatment versus treatment as if there’s a reason in the future. And we typically have some indications where we decide, okay, well, it’s time to treat. And those basically have to do if the lymph nodes are big enough or they’re close to an important structure and we don’t want them to grow more and maybe press on an important structure, or if they’re causing some kind of symptom or they’re causing anemia or low platelets. I mean, there has to be one, because there has to be one reason for why you’re trying to treat that patient, because you’re basically trying to fix a problem.

So if there’s no problem initially, it doesn’t make sense to treat it. Now, there are lots of available treatments, it could be only immune therapy, something like rituximab (Rituxan)  or obinutuzumab (Gazyva); these are antibody treatments. There are also combinations with chemotherapies, like bendamustine (Treanda), rituximab for if we have relatively bulky disease. There are options as well that do not involve chemotherapy.

So something like pills like lenalidomide (Revlimid) combined with rituximab, those are also options that can be used in follicular lymphoma. But over the last few years, there have been a lot of changes in follicular lymphoma and a lot of novel targets and a lot of novel treatments available. So, for example, a few years ago now, we’ve had CAR T-cell therapy approved. Right now, we have two products approved, axi-cel and tisagenlecleucel (Kymriah). There’s also data that was presented with liso-cel in follicular lymphoma. So hopefully we might see an approval for that as well. So that’s one class.

There’s also bispecific antibodies, and it’s very exciting times. We had the first bispecific antibody approved in the United States in December of 2022. That’s mosunetuzumab (Lunsumio). So what is a BiTE antibody? These basically are advanced types of immune therapies where you give the patient an antibody that has two ends to it, one end sticks to the cancer cell, the other end sticks to your immune cells. So it’s basically , it’s handholding your own immune cells or your own T cells to go and get attached to the cancer cell and kill it, not chemotherapy. It, of course, can have some immunological side effects like fevers or inflammation initially when it’s done, typically when in the first cycle or second cycle.

But something called cytokine release syndrome rarely can cause neurological toxicity. That’s also very transient usually, and very rare with bispecific antibodies. But those are two up and coming treatments. Right now, they’re approved in patients who’ve had relapsed/refractory disease, meaning they’ve had two or more lines of previous therapies, but they’re…we have them now in trials where we’re looking at those agents in earlier lines of therapy. There are other agents as well.

A few years ago we had tazemetostat (Tazverik) approved, which is a pill that targets an enzyme in the cells called EZH2 and they basically, this pill tries to ask the cancer cell to differentiate, rather than get stuck and not die. So they differentiate and then they eventually die, so that’s another class of medicine. And we’ve now seen some data with BTK inhibitors. There’s been data presented from the ROSEWOOD Study with zanubrutinib plus obinutuzumab (Brukinsa plus Gazyva); it’s not yet FDA-approved, but the data looks interesting and certainly needs to be looked at further.

Lisa Hatfield:

Well, thank you for that overview. It seems like as a blood cancer patient myself, it seems like a hopeful time for patients with the treatments that are kind of on the horizon or are in clinical trials right now. So thank you for that.

Dr. Sameh Gaballa:

Absolutely.

Lisa Hatfield:

So it’s that time now where we answer questions, some of which we’ve received from you, the patients watching this. Remember, as patients, we should always feel empowered to ask our healthcare providers any and all questions we might have about our treatment and prognosis. Please remember, however, that this program is not a substitute for medical care. Always consult with your medical team.  So, Dr. Gaballa, let’s start here. How do you explain follicular lymphoma treatment options and prognosis to your newly diagnosed patients? And what does shared decision-making look like in your office?

Dr. Sameh Gaballa:

Oh, absolutely. So follicular lymphoma, you really have to explain to the patient what, how are we coming to the recommendation that we’re currently giving. So if we think this is, this patient is a good candidate for a watch-and-wait approach, for example, we really have to walk them through why that really is the best option and not why should we jump on treatments and vice versa, if we think this patient needs to be treated, how do we really…the patient really has to understand all the other treatment options and why this needs to be treated. Because a lot of patients initially, sometimes when you present them with a watch-and-wait approach, if they don’t know all the background, they might not feel very comfortable because they might think, “Well, I have this cancer in me, and we’re not doing anything about it, and that doesn’t really sound too…something I should be doing.”

But then when you explain to them, “Well, you see, you don’t have a lot of disease, those studies have already been done in the past where patients who were treated or not treated, the survival was the same, so there, you might get side effects from the treatment, but not necessarily have benefits. And in the future, should this need to be treated, we have a lot of things to do.” So, really, so this is kind of the shared decision portion where you just have to walk the patients through why that will be the best situation. There is data with single-agent rituximab, even in patients who are asymptomatic, and we have the UK data, and that’s an option.

And that is also offered to some of the patients, even if they’re not symptomatic and they don’t have a lot of disease, if that’s what really the patient wants, if they’re not really comfortable with a watch and wait. And there’s again some data to help justify that. Again, there’s no advantage in overall survival, but sometimes the patients would kind of feel more in control. They feel like, “Okay, I did something about it.” So that’s the shared approach.

In terms of your other question about prognosis, unfortunately that’s an area of an unmet need. I mean, we have some tools to help us differentiate follicular lymphoma patients from each other, which patient is high-risk, meaning those are the patients who might relapse quickly, or they might not respond well to treatments. Unfortunately, we don’t have great tools. We have something called a FLIPI score, which is, we use a number of parameters including clinical parameters like stage or age and some other parameters as well, and we have a scoring system. But it doesn’t 100 percent predict if this is going to be a high-risk follicular lymphoma or a low-risk.

Unfortunately, the best predictor of prognosis for follicular lymphoma, you would know about retrospectively,  it’s something called POD24, progression of disease in 24 months. Meaning that if you have a patient who’s treated with chemotherapy and immune therapy, and then they go into remission, and then they relapse again in less than 24 months, progression of disease within 24 months, those are the, those represent about 20 percent of follicular   lymphoma patients, and those represent a high-risk group of patients. That’s the best tool that we have. But unfortunately, if you’re diagnosed today, you’re not going to know if you’re in this group or not until you actually need to be treated and not just treated with immune therapy.

It has to be with chemotherapy as well. And then if you relapse within two years, then we know that this is a high-risk entity. There is genetic testing, there is something called a FLIPI-m7 scoring system. But again, these tools are not great to tease out the low risk from the high-risk follicular lymphoma patients. But 80 percent of patients who are not going to be POD24, meaning that they get treated, they’re in remission for two years or more, and actually those patients have very similar survival to the general population. So, yeah, so a lot of times we don’t know right away, but we do have some tools to kind of give us an idea.

Lisa Hatfield:

Great. Thank you for that information. It’s kind of hard for cancer patients to only know what their prognosis is retrospectively, but that’s a great explanation. Thank you. Okay, another patient question, “How does the staging of follicular lymphoma impact treatment choices?”

Dr. Sameh Gaballa:

Yeah, so as you saw, I didn’t really stress too much about staging, because it’s a blood disease. So the vast majority of patients are going to be what we call stage III to IV disease. So, obviously when you see a patient if if they, they might think that, “Oh my God, I have a stage III to IV cancer,” because that’s really what they’re familiar with. But follicular lymphoma is a blood disease, so by default it’s going to be in a lot of lymph nodes, it might be in the bone marrow as well, but stage III to IV disease follicular lymphoma doesn’t, that does not mean that this is a terminal cancer. Patients could live completely in normal life, even with a stage III to IV follicular lymphoma. This is not like a breast cancer or colon cancer where stage is everything.

But why do we have a staging system? Obviously, there’s a need to have staging system for all cancers, but clinically, the only time it makes a difference is there’s a small group of patients who have a truly stage I or II disease, meaning just one group of lymph nodes on one side of the diaphragm that may fit within one radiation field. So if you have someone who’s just coming in with one or a few groups of lymph nodes all in one place, we call that a stage I or II follicular lymphoma, not common, because again, most patients are stage III to IV. The only difference there is you can potentially offer those patients radiation therapy if it’s truly localized, but then you would need to do a bone marrow biopsy and confirm that it’s not in the bone marrow.

And if it is localized within one radiation field, that can be offered and we can sometimes give after radiation therapy, either observe it or consider giving rituximab afterwards. But that’s the only time where we’re going to mention staging, again, uncommon because most, the vast majority of patients are going to be stage III to IV. So why would we do that? Why would we irradiate if it’s only one group of lymph nodes? Because there’s about, I mean, if you irradiated, those lymph nodes will go away, but there’s about maybe a, it’s different. The number is different between studies, but about maybe a third of patients, if you irradiate that group of lymph nodes or one lymph node, it actually might not come again in the future. So you might have very long remissions/possible cure if you…and this is the only situation where we would consider treating someone who does not have symptoms, because you could have very long remissions with radiation.

Lisa Hatfield:

Although follicular lymphoma is a slow-growing cancer, can you speak to the signs that the disease is progressing in the body, what signs that patients might want to look out for?

Dr. Sameh Gaballa:

Yeah, absolutely. So, typically we educate the patients to there are some red flags to look out for, not just for progression,but also for another condition called disease transformation. So, follicular lymphoma does have a, there is a possibility that it can transform from a slow-growing lymphoma to an aggressive lymphoma. Now, this happens at a rate of about maybe 2 to 3 percent per year, but it’s a cumulative risk, so meaning if a patient lives many, many decades, their lifetime risk can be up to as high as 20, 25 percent, 30 percent, depending on the different literature, so there is a chance that these slow-growing lymphomas can transform to an aggressive lymphoma.

And when they do know this, there’s no watch and wait for transformed disease. It has to be treated with chemo immunotherapy because the goal of treatment then is to try to get rid of the aggressive component. What are the signs and symptoms to suggest that you might have transformed disease? This is not something that the patient would typically need to look out for. I tell my patients that, “You don’t need to see, do I have transformed disease or not. This is going to come, and you’re going to know when you have transformed disease. Extreme fatigue, drenching night sweats, the fever sometimes that are not going away.”

The patient might have pain if the lymph node is pressing on some important structure. They may have loss of appetite, loss of weight. So again, something that dramatically happens quickly over a few weeks of time. So if the patient feels sick for one reason or another and they’re not getting better, it can all happen within a few weeks’ time frame. This is the time to get checked early on and go see your oncologist, because then we might need to investigate if there is any potential for transformation. So that’s issue number one.

Issue number two is, which is the much more common scenario, which is the follicular lymphoma is slowly progressing. How would you know? I mean, if you notice a lymph node that in your neck or under the armpits or the groin areas, if they’re growing, then that needs to be evaluated. I mean the patients should expect that those will be growing, they will grow. But they grow over months and years. They don’t grow over weeks.

So anytime you kind of are unsure, if you feel that it’s growing faster than usual, this is, again, something to look out for. And then the B symptoms that I mentioned. So like the sweats, the fevers, the weight, loss of weight, loss of appetite, these are also sometimes things to look out for. Not necessarily, they don’t always mean that it’s transformed disease. It can also be that the follicular lymphoma is also progressing and might need to be treated as well.

Lisa Hatfield:

And then just a quick follow-up to that question. So a patient is watching out for these red flags, but are they going through any kind of regular monitoring in your office? Are you meeting with them on a regular basis? And how frequent might that be for a follicular lymphoma patient who’s watching and waiting?

Dr. Sameh Gaballa:

Yeah. So how does watch and wait look? So, and I tell patients always watch and wait does not mean ignore. Watch and wait means that we’re monitoring the disease, we’re looking at it. How do we do that? So typically we would see the patient maybe every three to six months. And then depending on how do we, when we get a sense or tempo of how their disease is progressing, then we’ll know how often we need to see them. I’ve had, I still have patients where I’m seeing them every three months. And I also have some patients where the disease has been stable for years, I only see them once a year.

In terms of imaging, that’s also sometimes an area of controversy. Typically, initially for the first maybe year or two years, I do like a scan, like a CT scan every six months, just to get a sense of how quick or how slow the disease is progressing. If there’s absolutely no change at all, then sometimes we either don’t do scans and just go by the patient’s symptoms and blood work and physical exam, or we do maybe once a year scan but not more than that. So this is how we would monitor the patients in a watch-and-wait approach.

Lisa Hatfield:

And we have another question about treatment profiles, “What can I do to reduce side effects during active treatment?”

Dr. Sameh Gaballa:

So it depends on what the treatment that you’re getting. If it’s immune therapy, like rituximab alone, those typically don’t really have a lot of side effects. I mean, sometimes with the first one or two treatments, you might get an allergic reaction, an infusion allergic reaction, which is very common, but subsequently it shouldn’t really cause a lot of side effects. If the patient is getting chemotherapy, well, it depends on which chemotherapy they’re getting. But in general, it’s always good to stay hydrated and to stay physically active. So if the patient goes in with a healthy body, well-hydrated, you eat fresh fruits and vegetables, walking 30 to 60 minutes a day, your body is going to handle the side effects much better than if you’re going in, you’re very weak, and your general health is not adequate.

Lisa Hatfield:

Another patient is asking if you can speak to emerging treatment options for patients with relapsed/refractory follicular lymphoma?

Dr. Sameh Gaballa:

Yeah. So the field of follicular lymphoma is changing rapidly. I always tell patients that sometimes the best treatment is actually on a clinical trial because those are going to be the next generation of treatments that are going to get approved in the next few years. But right now we have the most effective therapy really is CAR T-cell therapy. CAR T-cell therapy by far is the most effective treatment we have at this time. It’s approved for patients who have had two or more lines of prior therapies. We also are investigating this.

I actually have a trial here at Moffitt where we’re looking at CAR T-cell therapy as early as in the second line, in patients who have what we call the high-risk ones, the POD24. So a patient with POD24 follicular lymphoma relapsed in less than two years. We have a trial to investigate the role of CAR T-cell therapy in this setting. The other very promising group of treatments, again, is bispecific antibodies, again, currently approved in the third line, mosunetuzumab.

But there are others coming up and have data on epcoritamab-bysp (Epkinly), as well as a lot of other bispecifics, as well as combinations. I mean, epcoritamab-bysp has also data presented with combination with lenalidomide. And right now, the follow-up duration is not very long, but so far, it looks extremely promising with very high response rates. So those also might be coming very soon. And, of course, once something works in the relapsed/refractory setting, we start looking at earlier lines of therapy.

And actually, we’re now looking at trials in the first-line setting with some of these agents as well. Tazemetostat is a pill. It’s also approved in the third-line setting, but we’re also investigating it. We have a trial here where we’re looking at combining it with standard rituximab, lenalidomide, so tazemetostat plus rituximab, lenalidomide as early as in the second line. So that also is interesting. And as I mentioned before, BTK inhibitors currently being looked at in trials might also have a role in follicular lymphoma very soon.

Lisa Hatfield:

And this patient is asking about the significance of bispecific antibody treatment. And you touched on that a little bit. It looks like she’s also asking if there are specific genetic or molecular markers that can predict a patient’s response. And if I try to translate that, maybe she might be asking about targeted therapy.

Dr. Sameh Gaballa:

Yeah, so bispecific antibodies and CAR T-cell therapy, they target something called CD, either CD19 or CD20, and that’s almost universally expressed on B cells. So most of your follicular lymphoma patients are going to be expressing CD19 or CD20. Tazemetostat is the pill that I talked about.  It inhibits an enzyme called EZH2. Some patients have an EZH2 mutation where it seems to work very well. However, tazemetostat also works in patients who don’t have that mutation. So that’s why it’s not very important to check for the mutation.

It seems maybe it works better in patients who do have the mutation, but it does work as well in patients who do not have that mutation. So unlike other malignancies and other cancers, biomarkers are not yet driving a lot of our treatment decisions in follicular lymphoma as of right now.

Lisa Hatfield:

Thank you. Another question. Is it common for follicular lymphoma to transform into a more aggressive type of lymphoma? And how would that change a treatment plan? And maybe how common is it for that to happen?

Dr. Sameh Gaballa:

Yeah. There’s about a 2 to 3 percent chance per year that the slow-growing lymphoma can transform to an aggressive lymphoma. That, if it does transform, I mean we talked about the symptoms and signs, you get sick quickly, rapidly enlarging lymph nodes, loss of weight, loss of appetite, drenching night sweats. No, a transformation, typically we would do a PET scan, see what’s the most active lymph node, try to get a biopsy from that and confirm there is a large cell transformation. Now, that’s a completely different disease, it needs to be treated completely differently, typically with chemoimmunotherapy.

Something like R-CHOP, for example, is one of the most common regimens we use in this scenario. And the goal of treatment here is to try to get rid of the aggressive lymphoma component here so that it does not recur again. I mentioned it’s about a 2 to 3 percent per year, but it depends on how long the patient lives. So if they live many, many, many decades, their lifetime risk is anywhere between 20 to 30 percent max during their lifetime.

Lisa Hatfield:

And As a blood cancer patient myself, this is a great question this patient is asking, “Is there a risk of secondary cancers after receiving treatment for follicular lymphoma?”

Dr. Sameh Gaballa:

So that’s always a concern, and it depends on what treatment they had. So chemotherapy that can potentially damage DNA can lead to second malignancies, including things like acute leukemia. Luckily, that’s not a high risk. That’s a rare side effect from some of those chemotherapies. Some of the pills can do that as well. Something like lenalidomide can sometimes have second malignancies. But we’re talking about rare incidences, and the benefits usually would outweigh the risks. But it’s not with all treatments, meaning some of the other immune therapies that do not involve chemotherapy would not typically be associated with some of those second malignancies. So it just really depends on what exactly the treatment you’re getting.

Lisa Hatfield:

Can you speak to maintenance therapy and monitoring in follicular lymphoma? And what signs of infection should patients and care partners be aware of during treatment?

Dr. Sameh Gaballa:

Yeah, so there have been randomized studies in slow-growing lymphomas that show that if you do, after you get your standard treatment for follicular lymphoma, if you do what we call a maintenance treatment, usually with rituximab, which is an immune therapy, where you do it every two to three months for about two years, we have data showing that that decreases or delays the risk of relapse. However, it doesn’t change the overall survival, meaning that it just has patients in remission longer. When their disease comes back, they just get treated again at that point, and it doesn’t really affect survival.

So it’s one of those shared decision-making with the patients. I usually go over the risks and benefits of maintenance therapy. It’s optional. It’s not a must. During COVID, we pretty much stopped all maintenance treatments, because the risks were outweighing the benefits because maintenance treatment is…will suppress the immune system more, is associated with more infections. And these infections can be anything. I mean, it could be a pneumonia, could be recurrent urinary infections. It could be any type of infection. So there’s always this risk and benefit that we have to discuss with the patient.

Lisa Hatfield:

Well, Dr. Gaballa, thank you so much for being part of this Patient Empowerment Network START HERE program. It’s these conversations that help patients truly empower themselves along their treatment journey. And on behalf of patients like myself and those watching, thank you so much for joining us, Dr. Gaballa.

Dr. Sameh Gaballa:

No, thank you, Lisa. I really appreciate it. Thank you.

Lisa Hatfield:

I’m Lisa Hatfield. Thank you for joining this Patient Empowerment Network program.


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Diagnosed With CLL? Start Here

Diagnosed with CLL? Start Here from Patient Empowerment Network on Vimeo.

What do newly diagnosed chronic lymphocytic leukemia (CLL) patients need to know? Expert Dr. Ryan Jacobs explains how CLL occurs and provides an overview of treatment types. 

Dr. Ryan Jacobs is a hematologist/oncologist specializing in Chronic Lymphocytic Leukemia from Levine Cancer Institute. Learn more about Dr. Jacobs.

Download Resource Guide   |  Descargar Guía en Español

See More from START HERE CLL

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Is It Aging or My CLL?

Is It Aging or My CLL?


Transcript:

Lisa Hatfield:

There’s a lot going on in terms of novel therapies and new options. But before we jump into all of that, the tool box that’s expanding, can you introduce CLL and provide an explanation of what it is and what that means for a newly diagnosed patient?

Dr. Ryan Jacobs:

So chronic lymphocytic leukemia, or CLL, is the most common chronic lymphoma/leukemia. It is really both most of the time. It presents with what we call lymphocytosis, meaning the white blood cell count, and specifically the lymphocyte count is high or elevated. To call it CLL, to make that formal cancer diagnosis, we can generally take a patient’s blood sample and put it through a fancy machine that we call a flow cytometer, that looks for characteristic markers on the outside of the cells, and if there’s a bunch of those cells, we call that a monomorphic population.

So a bunch of those cells that look the same, and they’re B cells, that’s the type of lymphocyte count they are, and they’re over this threshold of 5,000. Then that is the diagnosis right there, we don’t need an invasive procedure. You generally do not need a bone marrow biopsy or a lymph node biopsy. There is in about 15 percent of cases, the disease presents with just in large nymph nodes, and the white count is normal. We call that small lymphocytic lymphoma. It’s considered an overlap with CLL, and I’ve had many patients that have started off with SLL and then eventually manifest elevated lymphocyte count later in their disease course. So it is considered an overlap, the treatment is the same for both of those disease entities.

So that’s the diagnosis of CLL and how it generally shows up initially. In a nutshell, it’s a cancer of the aging population, average age is 70. I have a lot of patients that ask me, “Why did I get CLL?” And the answer is, “We don’t know.” It’s that way with most cancers, unfortunately, we don’t know why one person gets a cancer and the other person doesn’t.

But it obviously has something to do with the aging effect on the DNA of the B lymphocytes because of how much more common it is as patients get older. 

Lisa Hatfield:

We know that therapies are evolving faster, hopefully faster than patients are relapsing, which is a good thing. So when they do relapse, chances are there will be a new option for this patient. But a CLL cure still remains elusive.

So, Dr. Jacobs, if you can speak to…we’ll just jump right into some of the newer, the novel therapies and things that are being investigated with CLL treatment. If you can just speak to some of those newer therapies, the novel pathways and targets that are currently under investigation with CLL, we’d appreciate that.

Dr. Ryan Jacobs:

Sure. We’ve come a long way in how we are managing this common cancer that’s benefiting a lot of patients. And as mentioned, with this cancer being one that is more common in the older population, we do know that the population of the United States specifically is getting older, there’s going to be more 70-year-olds. So these breakthroughs are helping a growing number of CLL patients.

Before 2014, really outside of a clinical trial, the only way we could treat CLL Is with combinations of chemotherapy and an immune therapy, like a monoclonal antibody called rituximab (Rituxan), that was kind of our first, what we would call targeted treatment outside of chemotherapy that we had, and it was, like targeted treatments are, well tolerated. It was an antibody that targets B cells specifically.

So we were combining it with chemo, we would call that chemoimmunotherapy, and it helped a lot of CLL patients. But for many, those were poor prognostic markers in particular, and those with relapse disease, chemotherapy was not very helpful, and it was quite toxic in many circumstances.

So we’ve been fortunate that since 2014, we’ve had a lot of new treatment options, and they’re targeted therapies. It’s not like non-specific cytotoxic chemotherapy, these are treatments that have been developed with specific targets in mind that are unique to the B-cell neoplasm, the B-cell cancer, the CLL. And the first of these that really changed everything was a BTK inhibitor called ibrutinib (Imbruvica), that we got in 2014.

Initially, we can only use it in the relapse setting, but eventually, in 2016, we could start treating patients as a first line of therapy with ibrutinib.  And then in 2019, we had a newer version of BTK inhibitor, we call those second-generation BTK inhibitors. That drug was acalabrutinib. And it eventually was shown in a head-to-head study to be just as effective as ibrutinib in a relapsed patient population, but it had less side effects than ibrutinib. So in, specifically, atrial fibrillation, hypertension. Cardiac toxicities overall were one that they really focused on in that study.

So as a whole, when we were choosing BTK inhibitors, we were shifting away from ibrutinib, shifting to acalabrutinib, and then just as…earlier this year, we had a third BTK inhibitor, zanubrutinib (Brukinsa), that was approved. It’s also considered a second generation BTK inhibitor like ibrutinib and acalabrutinib (Calquence). It treats CLL in the same way, in how it inhibits BTK or Bruton’s tyrosine kinase, that’s over expressed in CLL cells.

But it also has a favorable toxicity profile when compared head to head with ibrutinib, and now we have two second-generation options between acalabrutinib and zanubrutinib. And it’s not really easy for us to know between those two, which is “better.” When we decide to treat with a BTK inhibitor, we’re usually choosing between those two at this point, and we’re trying to personalize the decision for the patient, and there are some different factors they can get involved in that complicated decision.

Luckily, we are not limited to BTK as a target. I mentioned earlier, we have monoclonal antibody, rituximab like the one I mentioned, but a newer version of rituximab, a more potent version, obinutuzumab. Is one that we have available along with a Bcl-2 inhibitor, venetoclax (Venclexta). That is now, as of 2018, improved in the frontline CLL setting, also approved in the relapsed setting, of course, since 2016.  And we use venetoclax with a monoclonal antibody like obinutuzumab (Gazyva), and together they are a very potent combination that cause pretty rapid cancer cell death, as opposed to the BTK inhibitors that more put the cancer to sleep and require daily dosing indefinitely for as long as the drugs work.

And remarkably, the data on BTK inhibitors tells us that should work for many, many years. They’ve been following some of the patients that got treatment in the first line setting, and eight years out, there’s still more than 50 percent of the patients are free of progression, so they can’t even quote an average response time yet. With eight years of follow-up on the early ibrutinib patients.  The difference with venetoclax combined with a monoclonal antibody like obinutuzumab, is because it causes a more rapid cell death, you can give it on a time-defined schedule. So we tend to give it for one year in the first-line setting and two years in the relapse setting, and the antibody portion is just given for the first six months. 

The BTK inhibitors and venetoclax are oral treatments, so that’s a big win for patients to avoid the infusion center for those treatments, but the IV antibody treatments will still require some trips to the infusion center if you’re doing that combination with venetoclax. For most patients, those two targets are what we’re choosing between, and we try to personalize the decision to the patient. And again, that’s a very complicated discussion on what is “best.” And we use things like the prognostic work-up, medical problems that the patients already have, medicines that patients are on, to help make the best treatment decision for our CLL patients. But those…for in terms of how well that treats the CLL, both of those are considered equivalent options for the large majority of CLL patients.

We’ve got some things on the horizon, but in general, those are two targets that we have at this point. There is for relapsed patients, PI3 kinase inhibitors that are still FDA-approved at this time, that aren’t quite as effective and more toxic, so we sometimes think about using one of those targeted therapies if a patient has already progressed on a BTK inhibitor in venetoclax class. In the future, we are looking towards combining BTK and Bcl-2 inhibitor. Like, for example, there’s been studies already done that I’ve put many patients on, with ibrutinib-venetoclax, and I believe there’s a question about that later.

There’s also an ongoing study that I have opened at my institution that’s looking at acalabrutinib and venetoclax. So taking these two pills together in a time-defined manner, so you don’t have to take the BTK inhibitor indefinitely. And then there are some therapies that have already been improved in other lymphomas, and we wonder if they’re going to have a role in CLL eventually. So we now have bispecific antibodies, so that’s taking a drug like rituximab or obinutuzumab and adding a T-cell engager to it, so it has two targets or it’s bispecific.

And we have that drug, mosunetuzumab (Lunsumio) available in follicular lymphoma and there’s several others in development, and we’ll see how their role comes into play in CLL as well. As well as CAR T-cell therapy, where we take a patient’s T cells and genetically engineer them to attack the cancer. That’s now an approved therapy for many different kinds of lymphomas and multiple myeloma as well.

So we wonder if that’s going to have a role in CLL. But I think for the foreseeable future, it’s going to be looking first at BTK and then Bcl-2 inhibition, or vice versa. And we don’t really know which is better to go first, we think they’re both…they can both be sequenced one after the other. And then maybe it will have some of these other breakthroughs coming in and helping for after patients need something beyond those therapies.

And there’s probably going to be a lot of patients that never need anything beyond those options, those initial couple of targets, because they do so well. I think in the most immediate future, the approval that is going to give us a new great option is going to be for an alternative site BTK inhibitor, or it’s also called a non-covalent BTK inhibitor.

And there’s this drug called pirtobrutinib (Jaypirca), it has been approved in mantle cell lymphoma and likely will get approved in CLL this year. And that drug specifically is a BTK inhibitor that still works even in patients that have, say, progressed on ibrutinib or acalabrutinib or zanubrutinib. That will be a new target available for CLL patients and probably pretty quickly become one of the go-to drugs that we use for relapsed CLL patients that have already been treated with a BTK…with a traditional BTK inhibitor. So growing number of options and it’s really great for our CLL patients. 


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CLL Patient Expert Q&A: Start Here

CLL Patient Expert Q&A: Start Here from Patient Empowerment Network on Vimeo.

The START HERE program bridges the CLL expert and patient voice, whether you are newly diagnosed, in active treatment or in watch and wait. In this webinar, Empowerment lead Lisa Hatfield and expert Dr. Ryan Jacobs  provide an overview of the latest in CLL, managing CLL side effects and options for CLL progression.

Dr. Ryan Jacobs is a hematologist/oncologist specializing in Chronic Lymphocytic Leukemia from Levine Cancer Institute. Learn more about Dr. Jacobs.

Download Resource Guide   |  Descargar Guía en Español

See More from START HERE CLL

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Can CLL Treatment Cause Gastrointestinal Side Effects?


Transcript:

Lisa Hatfield:  

Hello and welcome. My name is Lisa Hatfield, your host for this Patient Empowerment Network program. In this important dialogue, we bridge the expert and patient voice 

to enable you and me to feel comfortable asking questions of our healthcare teams with more precision. The world is complicated, as is a cancer diagnosis, but understanding your CLL doesn’t have to be. The goal is to create actionable pathways for getting the most out of CLL treatment and survivorship. Joining me today is Dr. Ryan Jacobs, a CLL expert from Levine Cancer Institute. Thank you very much for joining us today, Dr. Jacobs, we really appreciate you being here and your time and expertise.

Dr. Ryan Jacobs:

Thanks for having me, Lisa.

Lisa Hatifield:

Before we get started, please remember to download the program resource guide via the QR code. There is great information there that will be useful during this program and after. Okay, let’s get started. So, Dr. Jacobs, I’d like to talk about what’s on the chronic lymphocytic leukemia radar, and rather than saying that entire phrase each time, I’m going to refer to it as CLL, because I’m pretty sure I’ll fumble that up. There’s a lot going on in terms of novel therapies and new options, but before we jump into all of that, the tool box that’s expanding, can you introduce CLL and provide an explanation of what it is and what that means for a newly diagnosed patient?

Dr. Ryan Jacobs: 

So chronic lymphocytic leukemia, or CLL, is the most common chronic lymphoma/leukemia. It is really both most of the time. It presents with what we call lymphocytosis, meaning the white blood cell count, and specifically the lymphocyte count is high or elevated. To call it CLL, to make that formal cancer diagnosis, we can generally take a patient’s blood sample and put it through a fancy machine that we call a flow cytometer, that looks for characteristic markers on the outside of the cells, and if there’s a bunch of those cells, we call that a monomorphic population.

So a bunch of those cells that look the same, and they’re B cells, that’s the type of lymphocyte count they are, and they’re over this threshold of 5,000. Then that is the diagnosis right there, we don’t need an invasive procedure. You generally do not need a bone marrow biopsy or a lymph node biopsy. There is in about 15 percent of cases, the disease presents with just in large nymph nodes and the white count is normal. We call that small lymphocytic lymphoma. It’s considered an overlap with CLL, and I’ve had many patients that have started off with SLL and then eventually manifest elevated lymphocyte count later in their disease course. So it is considered an overlap, the treatment is the same for both of those disease entities.So that’s the diagnosis of CLL and how it generally shows up initially. In a nutshell, it’s a cancer of the aging population, average age is 70. I have a lot of patients that ask me, “Why did I get CLL?” And the answer is, we don’t know. It’s that way with most cancers, unfortunately, we don’t know why one person gets a cancer and the other person doesn’t. But it obviously has something to do with the aging effect on the DNA of the B lymphocytes because of how much more common it is as patients get older.

Lisa Hatifield:

Thank you for that overview, Dr. Jacobs. We do have CLL patients who are watching this who are newly diagnosed, they may be in active treatment, they may be in remission, they may be managing their CLL just fine right now in their lives. So we’re along the whole spectrum of CLL, so thank you for that overview. We know that therapies are evolving faster, hopefully faster than patients are relapsing, which is a good thing. So when they do relapse, chances are there will be a new option for this patient. But a CLL cure still remains elusive. So, Dr. Jacobs, if you can speak to…we’ll just jump right into some of the newer, the novel therapies and things that are being investigated with CLL treatment. If you can just speak to some of those newer therapies, the novel pathways and targets that are currently under investigation with CLL, we’d appreciate that.

Dr. Ryan Jacobs:

Sure. We’ve come a long way in how we are managing this common cancer that’s benefiting a lot of patients. And as mentioned, with this cancer being one that is more common in the older population, we do know that the population of the United States specifically is getting older, there’s going to be more 70-year-olds. So these breakthroughs are helping a growing number of CLL patients.

Before 2014, really outside of a clinical trial, the only way we could treat CLL Is with combinations of chemotherapy and an immune therapy, like a monoclonal antibody called Rituximab, that was kind of our first, what we would call targeted treatment outside of chemotherapy that we had, and it was, like targeted treatments are, well tolerated.  It was an antibody that targets B cells specifically. So we were combining it with chemo, we would call that chemoimmunotherapy, and it helped a lot of CLL patients. But for many, those were poor prognostic markers in particular, and those with relapse disease, chemotherapy was not very helpful, and it was quite toxic in many circumstances. So we’ve been fortunate that since 2014, we’ve had a lot of new treatment options, and they’re targeted therapies. It’s not like non-specific cytotoxic chemotherapy, these are treatments that have been developed with specific targets in mind that are unique to the B-cell neoplasm, the B cell cancer, the CLL.

And the first of these that really changed everything was a BTK inhibitor called ibrutinib, that we got in 2014. Initially, we can only use it in the relapse setting, but eventually, in 2016, we could start treating patients as a first line of therapy with ibrutinib (Imbruvica). And then in 2019, we had a newer version of BTK inhibitor, we call those second-generation BTK inhibitors. That drug was acalabrutinib (Calquence). And it eventually was shown in a head-to-head study to be just as effective as ibrutinib in a relapsed patient population, but it had less side effects than ibrutinib. So in specifically, atrial fibrillation, hypertension. Cardiac toxicities overall were one that they really focused on in that study. So as a whole, when we were choosing BTK inhibitors, we were shifting away from ibrutinib, shifting to acalabrutinib, and then just as…earlier this year, we had a third BTK inhibitor, zanubrutinib (Brukinsa), that was approved. It’s also considered a second-generation BTK inhibitor like ibrutinib and acalabrutinib.

It treats CLL in the same way, in how it inhibits BTK or Bruton’s tyrosine kinase, that’s overexpressed in CLL cells. But it also has a favorable toxicity profile when compared head to head with ibrutinib, and now we have two second generation options between a acalabrutinib and zanubrutinib. And it’s not really easy for us to know between those two, which is “better.” When we decide to treat with a BTK inhibitor, we’re usually choosing between those two at this point, and we’re trying to personalize the decision for the patient, and there’s some different factors they can get involved in that complicated decision. Luckily, we are not limited to BTK as a target. I mentioned earlier, we have monoclonal antibody, rituximab (Rituxan) like the one I mentioned, but a newer version of Rituximab, a more potent version, obinutuzumab (Gazyva). Is one that we have available along with a Bcl-2 inhibitor, venetoclax. That is now, as of 2018, improved in the frontline CLL setting, also approved in the relapse setting, of course, since 2016.

And we use venetoclax with a monoclonal antibody like obinutuzumab, and together they are a very potent combination that cause pretty rapid cancer cell death, as opposed to the BTK inhibitors that more put the cancer to sleep and require daily dosing indefinitely for as long as the drugs work. And remarkably, the data on BTK inhibitors tells us that should work for many, many years. They’ve been following some of the patients that got treatment in the first line setting, and eight years out, there’s still more than 50 percent of the patients are free of progression, so they can’t even quote an average response time yet. With eight years of follow-up on the early ibrutinib patients. The difference with venetoclax combined with a monoclonal antibody like obinutuzumab, is because it causes a more rapid cell death, you can give it on a time-defined schedule. So we tend to give it for one year in the first-line setting and two years in the relapse setting, and the antibody portion is just given for the first six months.

The BTK inhibitors and venetoclax are oral treatments, so that’s a big win for patients to avoid the infusion center for those treatments, but the IV antibody treatments will still require some trips to the infusion center if you’re doing that combination with venetoclax. For most patients, those two targets are what we’re choosing between, and we try to personalize the decision to the patient. And again, that’s a very complicated discussion on what is “best”. And we use things like the prognostic work-up, medical problems that the patients already have, medicines that patients are on, to help make the best treatment decision for our CLL patients. But those…for in terms of how well that treats the CLL, both of those are considered equivalent options for the large majority of CLL patients. We’ve got some things on the horizon, but in general, those are two targets that we have at this point. There is for relapsed patients, PI3 kinase inhibitors that are still FDA approved at this time, that aren’t quite as effective and more toxic, so we sometimes think about using one of those targeted therapies if a patient has already progressed on a BTK inhibitor in venetoclax class.

In the future, we are looking towards combining BTK and Bcl-2 inhibitor. Like for example, there’s been studies already done that I’ve put many patients on, with ibrutinib-venetoclax, and I believe there’s a question about that later. There’s also an ongoing study that I have opened at my institution that’s looking at acalabrutinib and venetoclax. So taking these two pills together in a time-defined manner, so you don’t have to take the BTK inhibitor indefinitely. And then there’s some therapies that have already been improved in other lymphomas, and we wonder if they’re going to have a role in CLL eventually. So we now have bispecific antibodies, so that’s taking a drug like Rituximab or obinutuzumab and adding a T-cell engager to it so it has two targets or it’s bispecific. And we have that drug, mosunetuzumab (Lunsumio) available in follicular lymphoma, and there are several others in development, and we’ll see how their role comes into play in CLL as well. As well as CAR T-cell therapy, where we take a patient’s T cells and genetically engineer them to attack the cancer. That’s now an approved therapy for many different kinds of lymphomas and multiple myeloma as well. So we wonder if that’s going to have a role in CLL.

But I think for the foreseeable future, it’s going to be looking first at BTK and then Bcl-2 inhibition, or vice versa. And we don’t really know which is better to go first, we think they’re both…they can both be sequenced one after the other. And then maybe it will have some of these other breakthroughs coming in and helping for after patients need something beyond those therapies. And there’s probably going to be a lot of patients that never need anything beyond those options, those initial couple of targets, because they do so well. I think in the most immediate future, the approval that is going to give us a new great option is going to be for an alternative site BTK inhibitor, or it’s also called a non-covalent BTK inhibitor.

And there’s this drug called pirtobrutinib, it has been approved in mantle cell lymphoma and likely will get approved in CLL this year. And that drug specifically is a BTK inhibitor that still works even in patients that have, say, progressed on ibrutinib or acalabrutinib or zanubrutinib. That will be a new target available for CLL patients and probably pretty quickly become one of the go-to drugs that we use for relapsed CLL patients that have already been treated with a BTK…with a traditional BTK inhibitor. So growing number of options and it’s really great for our CLL patients.

Lisa Hatfield:

Thank you for that overview again, Dr. Jacobs. It does sound like there are a lot of new therapies coming out, especially for relapsed patients, super exciting for them. And this is actually a great time to jump right into questions. We have many questions from patients that different patients have submitted. But first, I want to remind everybody that this program is not a substitute for medical care. Please consult with your medical team for advice on your own condition or disease. And, Dr. Jacob, I was taking notes as you were talking, because you had spoken a little bit about a combination of the BTK inhibitor and Bcl-2 inhibitor with venetoclax. And I did a little research last night before I talked with you, and it sounds like that is something that the CAPTIVATE trial is investigating. 

So that’s exciting, and a patient asked about that, what that trial is. And it’s music to my ears as a cancer patient to hear something like “fixed duration,” it’s also investigating a fixed duration so patients and have maybe a bit of a medication vacation. So can you speak to that trial a little bit and explain what it is a little bit on how that might benefit patients with CLL?

Dr. Ryan Jacobs:

Yeah. So one of the best elements of treating with venetoclax is that it produces a deep level of remission in many patients. In fact, when given with the monoclonal antibody obinutuzumab, to CLL patients receiving that treatment as a first line of therapy for their CLL, about three-quarters of CLL patients will get to so deep of a remission that we call them minimal residual disease-negative. And that’s a blood test or a bone marrow test, but more easily done as a blood test, where we can look to a sensitivity of one in 10,000 white cells and determine if there’s any CLL in those 10,000 cells. We can actually go deeper than that, but we say, we call patients negative if they’re less than one in 10,000. And so 75 percent of patients will get to that depth of remission just with obinutuzumab for six months along with venetoclax for a year. So when researchers saw that, they recognized that we could probably stop treatment in those patients getting venetoclax because venetoclax yields these deep responses. And then the next kind of thought was, well, could we give a BTK inhibitor with venetoclax, but also over a defined treatment timeline and maybe get some of the remarkable benefits of treating with a BTK inhibitor but not get stuck being on therapy for years and years.

So the CAPTIVATE study was the first really to, in a large Phase II manner, look at that combination in a younger patient population, it was for patients 70 and younger. And it wasn’t in a high risk or anything, it was all comers. But they did have to be 70 and younger and getting treatment as a first-line therapy. So the combination was very effective. As of the last American Society of Hematology meeting in December, four years of data was reported and a large percentage of patients were still free of progression, over 80 percent still free of progression. And that’s three years off therapy at that point.

It was well-tolerated, not many patients had to come off due to toxicity. It was, in fact, less than 10 percent had really significant toxicities requiring discontinuation. So it was a well-tolerated effective treatment.

I do have one of those studies to open at my institution, the acalabrutinib-venetoclax combination, it’s called the MAJIC trial, and it is a large Phase III study that if it’s successful, I think would lead to the approval of giving those two drugs together. But then the extra credit question is, who should get the combination and who should get the drugs separately? And we don’t have an answer for that right now, and that’s a long topic of debate among CLL specialists.

Lisa Hatfield:

Great. Well, thank you. So for that trial you spoke of that you’re conducting right now, is that…is it only relapsed patients who are eligible for that? Or is that for front-line therapy?

Dr. Ryan Jacobs:

No, this is a first-line therapy that the MAJIC study is.

Lisa Hatifield:

Oh good. That’s promising for patients too.

Dr. Ryan Jacobs:

And it has a really good comparator arm, so that won’t be a problem that the standard arm on that study is venetoclax plus obinutuzumab, so it’s comparing against one of our best treatments, and so we really will get the answer of does it look better to use the BTK with the Bcl-2? Or is it not really that much better than just giving an venetoclax with obinutuzumab? And then the one obvious element that I didn’t mention that would be nice for most patients in addition to being efficacious and well-tolerated is if you could get an all-oral combination. Of course, venetoclax with obinutuzumab, you’re still getting quite a few infusions with the obinutuzumab over the first six months. So that’s a lot of time in the infusion center that you could avoid with just the combination of two oral targeted agents. So that would be a breakthrough for patients too, I think.

Lisa Hatfield:

Well, you commented also on something that’s really important for patients to know, and that is that if you go into a clinical trial, you won’t be given nothing for cancer clinical trials, you’re going to be given the standard of care or whatever it’s being compared to. So for patients who are considering that.

Dr. Ryan Jacobs:

That’s a Phase III. Yeah, for Phase III. If you go on an earlier phase trial, you know exactly what you’re getting. There’s usually not any randomization for earlier phase studies, you just get the intended treatment.

Lisa Hatfield:

Okay, great. Well, thank you so much for explaining that. So we have some pretty specific questions, and we have a patient who wrote in and asked, “What is the difference between IGHV-mutated and IGHV-unmutated CLL? And can you talk about treatment considerations for those?”

Dr. Ryan Jacobs:

Yeah. So that’s part of a bigger discussion around the prognostic work-up of CLL and not all CLL is the same, and we’ve done a really good job of figuring out tests to separate out the CLL patients that tend to behave more aggressively and respond to certain kind of therapies, versus those that are more of what we call indolent or slow growing and respond to other kinds of therapies. I do want to say, I haven’t mentioned it yet, we still don’t treat CLL if it’s not causing any problems. And about half of patients get diagnosed as sort of an accident, and they get a blood test for something else, and their white count is elevated, and that leads to a diagnosis, but they feel fine. We still leave those patients alone. Even with these good treatment options we have, we recognize that there are a select percentage of CLL patients that don’t ever need treatment, and so we don’t just want to start treatment in everybody.

But I do still like to check this prognostic work-up, even if I’m not going to start treatment, but I make sure and ask the patient if that’s what…iIn line with what they want. But certainly, if you’re going to start treatment, you’re required by guidelines to check a prognostic work-up, and I would really encourage the CLL patients tuning in to ask their oncologist, “What is my prognostic work-up?” if they’re going to start treatment.  Because of the oncologists, unfortunately, that have to deal with lots of other cancers, maybe don’t always know the right test to send. I’m very spoiled in that I get to just treat lymphoma and specifically focus a lot of my research in CLL and get to stay up with all this. I don’t know how a general oncologist keeps up with everything, honestly.

But the big three tests are going to be the FISH analysis, fluorescence in situ hybridization. And then IGHV mutational analysis, and then also a TP53 mutation analysis. And I don’t really have time to go through all of those, but IGHV is the question I get a lot. “What is that?” It’s one of these rare findings where it’s actually normal to have a mutation at the IGHV. IGHV stands for immune globulin heavy chain variable region, and it is usually mutated in B lymphocytes because it’s part of the process of a mature lymphocyte that is able to make a lot of different kinds of antibodies. And it undergoes somatic hypermutation, is what it’s called, as the B cell matures. Generally in oncology, the more mature a cancer is, the less aggressive it behaves and usually the easier it is to manage, and that is the case with CLL. So think of an unmutated IGHV CLL cancer as a more primitive or a more immature cancer clone, and as such, it is harder to treat.

In about half of patients will be found to be unmuted at the IGHV and historically, all we had was chemo and we knew these patients weren’t going to respond for near as long as the IGHV-mutated patients were to chemo. What’s nice is, with our targeted treatments, particularly the long-term data with the BTK inhibitors, it doesn’t look like it matters whether you’re mutated or you’re unmutated. So that’s one of the really great things with our new treatments for CLL, is it has, the people that have benefited the most are the ones that were doing the worst, so that’s great. It’s not just the patients that were already doing well, that are doing even better.

Lisa Hatfield:

So I just want to take a step back and kind of looking at this through the lens of a newly diagnosed CLL patient. You’d mention that sometimes you don’t treat every CLL patient. So is there something, if you find a patient who does not need treatment, is there something you tell the patients as far as regular monitoring? Will you monitor them to see if it progresses to the point where it requires treatment?

Dr. Ryan Jacobs:

Yeah. And we’re fortunate that this is a blood cancer that most of the time we can follow with a simple blood count and follow the white count, follow how the…follow the health of the bone marrow by looking at things like anemia, low red cell count, or a low platelet count that we call thrombocytopenia. So that’s the easiest thing to follow, but I’m also talking with my patients and examining my patients. I want to know if their length nodes are causing them a lot of pain, because we should treat that, there’s no reason they should live in pain.I want to know if they’re waking up drenched in sweat all the time, if their quality of life has been really affected by that. Or are a dramatic amount of fatigue that we can’t explain by some other cause. And I also, of course, examine the nodes myself and make sure that there’s no alarming findings there. So that’s really what’s involved with checking on a CLL patient that’s on active surveillance, that’s what we call it. And there’s a list of criteria that the oncologist should know in terms of deeming who needs treatment and who doesn’t. And so we’re kind of following the same rules, so to speak, in terms of who gets treated for CLL.

Lisa Hatfield:

Okay, thank you. So we have a patient who asked a series of questions here, and I think you already…you spoke pretty well to the role of the BTK inhibitors in treating CLL. I’m going to kind of clump these together.  So I guess three questions. What treatments do you think are the most beneficial for patients whose CLL has relapsed? What are the poor prognostic indicators for CLL? And along the same lines, what are the high-risk genetic markers for CLL?

Dr. Ryan Jacobs:

It’s a little more complicated discussion in the first line setting because both are options. At this point in time, we haven’t been…at least those that are, I would say, staying up to date on the CLL data, we have not been using chemotherapy for a long time. So most of the relapsed patients will have seen either one of the BTK inhibitors or venetoclax. And so what we do in the second-line setting is just use the other option that they haven’t seen. The data tells us, when you look at what treatments are being prescribed, most patients are going on BTK inhibitors, and they have been around longer than venetoclax in general. So for a lot of patients, that relapsed treatment is going to be venetoclax. Because that has the best data in terms of treating patients that have progressed on a BTK inhibitor like ibrutinib or acalabrutinib or zanubrutinib.

In the near future, we’ll have pirtobrutinib (Jaypirca) and so maybe, maybe some will get that drug before venetoclax, and that’s probably okay. And so we’ll have that additional option. The complicated patients, and I’ve alluded to this, or what do we do after BTK and Bcl-2? What are we left with? I mentioned PI3 kinase, that’s not a great option. There’s still stem cell transplant out there for young patients that are running out of options. Clinical trial is really what I would like to emphasize there.  If you’re a patient that can get to a high volume referral cancer center with a CLL specialist, I would do that. If you have seen BTK inhibitor and venetoclax and are looking for other options.

Lisa Hatfield:  

Great, thank you. So the next question is actually a really good question, I think we can broaden it a little bit. But the question is, “How can I ask my doctor to make sure I am being tested for serum markers?” And more broadly, I think a lot of patients are a little bit nervous about asking questions of their doctor, because they don’t want to feel like they’re questioning their expertise or doubting them. So how in general can we ask our doctor questions if we hear something? Or how we approach our doctor with those types of questions?

Dr. Ryan Jacobs:

So I mentioned asking your doctor, “What’s my prognostic markers?” I think this is probably the easiest way to get that information. And your doctor should be checking those. The question comes up like, what are the “high-risk” markers? We talked about mutated versus unmutated. Thankfully, our novel treatments that doesn’t seem to matter. Same goes with…there’s on FISH there used to be, if you found three copies of chromosome 12, that’s called trisomy 12, that doesn’t seem to matter With our newer treatments. A deletion at chromosome 11, again, used to not do as well with chemo. Novel therapies…doesn’t seem to matter. The one that is still potentially affecting outcomes, even with our novel treatments, are chromosome 17 aberrations, which stately are rare in the initial diagnostic setting. That or a TP53. A deletion at 17p or TP53 mutation probably is only going to be around 10 percent of patients or so. And in the relapse setting though, that number goes up because of the more aggressive cancers emerge, we call that clonal evolution. So maybe in the 20-ish percent range. These patients, we tend to prioritize indefinite therapies first, because it seems like these patients do better if you keep treatment going, as opposed to interrupted therapies like venetoclax. And so we tend to treat those patients with a drug like acalabrutinib or zanubrutinib first and then think about the venetoclax later for those patients.

Lisa Hatfield:

Okay. Okay. And just to clarify, for patients too, I know that a lot of cancers, there are discussions about the 17 deletion, 17p, and then also the TP53 gene. So if I understand correctly, the TP53 gene is housed on chromosome number 17. So if that is missing, then that patient may be missing that gene, that is considered a tumor suppressor gene, which we want. Is that correct?

Dr. Ryan Jacobs:

Right. So it’s either missing, which is what we see on FISH with a deletion, or it can be mutated and that’s the next gen sequencing, and often it will be both in those patients.

We think with indefinite, there’s some really good data that was just released with zanubrutinib. When they looked at 17p-deleted patients, there’s some long-term follow-up with ibrutinib-treated 17p-deleted patients. With chemo these patients would only get about a year or so, but we’re getting maybe even close to normal outcomes with long-term BTK. But we do know if you just give them a year of venetoclax and obinutuzumab for six months and then stop, they do relapse quicker than the other patients. So they relapse after about four years. As opposed to with five years of follow-up with that first line venetoclax approach, there are 62 percent of patients are still free of progression.

Lisa Hatfield:

Oh wow, okay. Thanks for explaining that too. I know that that chromosome 17 and the TP53 gene, that’s talked about in a lot of different cancers and it often come up, “How are those connected?” So thanks for just describing that a bit. So this patient is asking, “For patients who may be eligible for BTK inhibitors, are there specific comorbidities that might contribute to adverse side effects?”

Dr. Ryan Jacobs:

Yeah, so we screen…all BTK inhibitors have some cardiac toxicity. They have been shown with the second-generation BTK inhibitors to have less cardiac toxicity than ibrutinib, specifically atrial fibrillation. So if you have atrial fibrillation, maybe that’s a reason why you might go on venetoclax first as opposed to a BTK inhibitor. But it’s not a contraindication to getting a BTK inhibitor if the atrial fibrillation is under good control.  Other cardiac risk factors would include difficult to control hypertension at baseline, or heart failure. These are all things that might make us think twice about using a BTK inhibitor as our first therapy, because venetoclax has no cardiac toxicities. The other thing to consider is BTK inhibitors all to a degree have, and I describe it to patients, like an aspirin-like effect on the platelets. They do interfere with the platelet binding, which so universally, patients will know to varying levels some easier bruising.

And if patients are on, because of say, they’ve had a heart attack in the past and they’re on aspirin at baseline, or what would even be more concerning if they were on a drug like Plavix because they’ve had a stent placed, that would be something that would really concern me and would definitely push me more towards venetoclax, that again, doesn’t have those anti-platelet interactions. Also, patients who are on blood thinners because of a history of blood clot or atrial fibrillation, there is the potential increased risk for bleeding and bruising there as well. None of these are absolute contraindications, they’re just all what goes into the blender, if you will, of putting lots of information in and coming up with the best treatment decision as personalized for the CLL patient. We’re blessed to have multiple options, but it does make it more of a challenge to find the “best” option.

Lisa Hatfield:

Yeah. Thank you for that. We have several questions from a couple of patients regarding side effects. So the question, “How long will my side effects of my CLL treatment last? And what can be done to reduce those?” And specifically, a patient is asking if there’s a connection with CLL and gastrointestinal issues?

Dr. Ryan Jacobs:

So all of the treatments, including venetoclax, the BTK inhibitors, will have diarrhea listed as a possible side effect. It’s usually low grade. But generally, I have found the gastrointestinal toxicities abate some over time. So if they are present earlier, if you’re able to stick with therapy, they do tend to get better. For the once daily meds, I encourage those patients to try to take the drug in the evening. The GI tract tends to be less active later in the day, and you can sleep off some of the potential gastrointestinal issues. So I’ve had success there. Sometimes we have to lower the dose to just find the best dose to help mitigate some of these. There’s the antidiarrheals that can help if you need them. Imodium. I had a patient I saw earlier this week that Imodium didn’t really work, but good old Pepto Bismol did the trick from time to time. So certainly though, if the gastrointestinal issues are significantly affecting quality of life, we need to come up with a new plan, whether that’s reducing the dose or changing to a different option. Specifically, what’s nice about the BTK inhibitors is they all have data that show if you’re having problems with one, you can switch to the other and likely not have the same problem occur. So that’s nice.

Lisa Hatfield:

Have you ever seen any uncharacteristic side effects several times in your practice? Anything really unique? I’m just curious about that.

Dr. Ryan Jacobs:

Yeah. There’s always the patients, they can have a more severe form of maybe, of a more common side effect, like the…we were talking about diarrhea, I’ve had a patient that actually had a difficult, with venetoclax, had difficulties with the stool incontinence. So that was kind of a severe form of that. It wasn’t so much diarrhea that was the problem. But we were able to ultimately mitigate that with a dose reduction. I would say the way, particularly if it’s an unusual side effect, the best thing to do is to take a break. If it’s a serious side effect that needs to be addressed and it’s affecting quality of life or causing problems, take a break from the treatment. If you take a week off these treatments, particularly venetoclax, taking breaks doesn’t matter. We like not to take long breaks with the BTK inhibitors. But if you take a week off, these drugs don’t have very long half-lives. So if the issue is not getting any better and you’ve been off of treatment for a week, it’s unlikely that that issue is coming from the treatment. So that’s a way I try to sort through some…particularly if they’re unusual side effects sometimes. And certainly, if we deem that the issue is connected to the treatment, I’ll usually try lowering the dose before just giving up.

Lisa Hatfield:

Okay. Thank you. A patient had asked, and I love this question because I often wonder myself when I get up in the morning, my bones are creaking and popping, “How do you know the difference between,” this patient’s talking about fatigue. How does a patient discern, “Well, this is fatigue from my cancer or my treatment,” versus just normal aging? Whether it’s fatigue or bruising or any side effect.

Dr. Ryan Jacobs:  

Yeah. Fatigue is a really…I had an attending physician when I was in my training that said, “Treating fatigue makes me fatigued.” But it’s hard. If it’s really the only problem the CLL patient is having, it can be. All those other problems I had mentioned earlier, the low red cells, the low platelets, the painful nodes, the night sweats, I with close to 100 percent certainty know I can fix those with treatment.Fatigue, I’m not as confident when that’s the only issue that a patient’s having. I try to differentiate between fatigue from other causes and old age, and specifically to CLL. 

They try to put it as a metric and say, if you’re having to spend half the day or more just lying around and you’re not able to do your normal activities of daily living, like that’s a severe level of fatigue and treatment should be considered.I’m looking for somewhat of a precipitous decline, not necessarily just kind of the gradual fatigue that you might more relate to aging. The problem with treating fatigue is you’ll look, if you look at the possible side effects of all of these medicines I talked about, fatigue will be a potential side effect.So you’re sometimes trading one problem and getting another, or maybe the fatigue does get better, but then the patient has some different side effect that’s even worse than the fatigue. So it’s hard to really help when fatigue’s the only issue. But certainly, I have helped some patients with fatigue. We don’t have a test that we can do to know for sure is the fatigue coming from the cancer, or is it coming from something else. 

Lisa Hatfield:

Great. Well, that wraps up our program for today. Thank you so much for joining us, Dr. Jacobs.  I am Lisa Hatfield from Patient Empowerment Network.


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