Recent Advancements in Chronic Lymphocytic Leukemia Care and a Look to the Future

In this interview, Kerry Rogers, MD, from The Ohio State University, provides insight into the newly available treatments for chronic lymphocytic leukemia (CLL) and how care for patients with CLL has changed over time.

Transcript:

Can you discuss some of the recent advancements in chronic lymphocytic leukemia treatment, and how these developments have influenced your approach to patients with CLL?

Kerry Rogers, MD: So, I think the biggest development in CLL has kind of been in the last 10 years focused on targeted agents. So, the decade prior to the last one was really instrumental in developing highly effective chemoimmunotherapy and then kind of the last 10 years we had was developing targeted agents, which are both safer and more effective than chemoimmunotherapy. So, looking at what's going on now, I think, is a lot of work towards how to use our targeted agents better, and also combinations of targeted agents and this has led to treatment being not only more effective but also more tolerable for patients and I think there's been a lot of focus on things that matter to patients like duration of treatment and living with chronic side effects as well as financial toxicity, that some of these combinations of targeted agents can address. So to back up the development of a group of targeted agents called BTK inhibitors has really revolutionized how we treat CLL. Offering like continuous daily oral therapy instead of episodic chemoimmunotherapy and then, of course, kind of around the same time, although slightly farther behind that in clinical development BCL2 inhibitors. Also are an oral therapy that's highly effective for CLL and now we're looking at combinations of those that can be fixed duration or kind of limit treatment exposure. So this would be a drug like venetoclax or BCL2 inhibitor with an anti-CD20 monoclonal antibody given for either one or 2 years, depending on the scenario, or actually combinations of BTK inhibitors with BCL2 inhibitors, and these combination targeted agent regiments are just so effective that you get really deep remissions, allowing people to discontinue treatment, which is huge because continuous treatment, of course, exposes people to chronic physical and financial toxicities as well as some psychologic burden of needing treatment all the time. So I think there's many advantages to that. So, a huge thing the field's kind of done recently is looked at these combinations of targeted agents, and looked at, you know, like BCL2 or BTK inhibitor plus minus an anti CD20 antibody. And I think some effort will continue to be made to try to figure out which of these are most appropriate, for which groups of CLL patients, both based on the CLL disease biology, and also patient factors. So other health conditions that our patients are living with. I do think that you know the field will continue to need novel agents, but the most exciting thing for me right now is to see how people are using kind of the agents we have better, to better accomplish things that really matter for our patients, like limiting treatment exposure in some cases. I do think that you know the development of more BTK inhibitors, including the kind of non-covalent reversible ones that can be effective after the standard, currently used covalent ones stop working has been huge, and of course there are several new BCL2 inhibitors in clinical development. So I'm just excited to see how our continued exploration of targeting these targets in CLL, and in what order and for what timeframe really plays out.

Are there any promising emerging therapies or ongoing clinical trials in the field of CLL that you find particularly intriguing or that you believe may have a significant impact on future treatment approaches?

Dr Rogers: So I think there's 2 kinds of emerging treatments or treatment strategies in CLL that I think will have a lot of future impact on how we treat CLL. One is combinations of BTK and BCL2 inhibitors, or actually BCL2 inhibitors and antibodies, because those are fixed-duration treatments and so it would allow for people to be off treatment and potentially be retreated with some of the same agents. So it would be kind of episodic fixed-duration treatment with targeted agents and I think it's actually going to take a lot of years to figure out what we like to call sequencing, which is like which agents to take in what order and for how long? And the reason it's going to take a lot of years is because these drugs are so effective, and patients do so well with them. Like, for example, taking any of our targeted agents is a first treatment for CLL. Even CLL with biologic high risk features like deletion 17p. At 5 years over half the patients can expect to still be alive, and with their leukemia controlled. So that means that it takes longer time to figure out you know, like what the best treatment order is because people do so well with each treatment. It takes more years to kinda get there before something else needs to be done. So it's an excellent problem for our patients. But it's something that I think we're going to have to continue to pay attention to as a field. So I really think that learning how to use our targeted agents in combination and in sequence better is going to be huge. The other thing that I think is really exciting is some of the effort made for using the immune system to fight CLL. So the field I particularly saw tumor oncology. But some hematologic oncology. Really had an advancement with the development of immune checkpoint inhibitors. So these are things like PD1 inhibitors. That kind of tell T cells to not be inhibited, and to go after tumor cells. For CLL these drugs were not effective. So it really was being left out of the party for something that was a very important advancement kind of across a lot of different cancers. And that's probably because the CLL cells are so good at evading the immune system and potentially, partially due to immune changes in people living with CLL just in their healthy, immune system function. Which is definitely different and so more recently, there's been the development of bispecific antibodies that actually bring like the CLL cell together with the T cell. To kind of show the T cell, the cancer cell, and so those have been really big in blood cancers and are being investigated in CLL. So I really look forward to seeing if this is a way that CLL patients can benefit from a newer type of immunotherapy. And then also CAR-T cells have been very promising across a variety of hematologic cancers, mostly B cell cancers, because CD19, which is on B cells is kind of the most common target for CAR-T cell therapy. So that's a complex therapy where cells are actually removed from the body through aphoresis and then engineered to express a receptor, on it, that targets a marker, on in this case tumor cells which would be CD19 and in CLL. Even though it's one of the first diseases where CAR-T cells were studied, it actually has not been overly effective in CLL compared to some other diseases, and that could be because the T cell quality is not the same, after getting cell therapy. Or again, due to just the disease state could be evasion by the CLL cells. So we had some promising results from that from a study called TRANSCEND CLL and I look forward to see those things continuing to improve both by specific antibodies and CAR-T cell therapy. Because I think that's going to lead to some really nice advancements and complement our targeted agents really well for people living with CLL. So that's like a more of a developing area compared to the combinations of targeted agents, which is really, we're trying to sort this out over years now for therapies that are known to work extremely well.

Can you speak a bit about your role as a hematologist/oncologist, and how you use clinical pathways in your day-to-day life?

Dr Rogers: So you know, I think clinical pathways can be really important because it can help provide a guideline for how to think about different treatments, or how we want to treat patients in general. So I think, having an approach to how you think about a treatment of people with any condition that you're seeing is really important, and then from there, like how you individualize it for the particular patient. So whenever I think about especially a first treatment for someone with CLL, there's a couple of things that I take into consideration. One is, I always think through what the best standard of care option is, and then I'm fortunate to work at an academic center where we have available clinical trials. So I also think through what their best investigational treatment option is. So for people who are needing a first treatment for CLL, the 2 major approved options are BTK inhibitors as a continuous monotherapy. So the first and class one is ibrutinib, which is more cardiovascular side effect potential. So the 2 that are commonly used now are acalabrutinib and zanubrutinib due to the safer cardiovascular risk profile. And those are drugs that are taken indefinitely and obviously can lead to side effects which are hopefully milder. In most cases, I mean, people should be able to take them and work full time or golf full time, or whatever they want. And then the other side of the coin is a venetoclax therapy, which is a fixed duration for a year, and it's given with 6 months of obinutuzumab and then, you know, there's always a variety of investigational therapies. But when I think through the standard options, I always consider the disease biology of their CLL first. Because patients with deleted 17 PCL tend to have longer progression-free survival with the continuous BTK inhibitor therapy. So, if appropriate for the patient, I will preferentially select that and then, you know, some people have ongoing like atrial fibrillation, severe hypertension, or you know other things that make BTK inhibitors less suitable. So then I would definitely favor the venetoclax-obinutuzumab approach for those individuals, where exposing them to a risk of a BTK inhibitor is not best for them as a person. So I think through like, what's the disease biology, which could be a lateral if they don't have high-risk CLL. We also see super super good responses, for, you know, low risk like mutated non 17 PCLL with event open approach, so usually we will think about favoring that for them. So after the disease biology, you think through again, like you know what other health conditions the person has, like, if you have poor renal function, you know, the venetoclax can be really challenging if you have like trouble with atrial arrhythmias the BTK inhibitors challenging. So it's kinda like options, you know, depending on CLL biology options depending on other health conditions and then to think about these options in the context of what matters most to the patient is helpful, too. I have some patients where the fixed duration of one year for that treatment is extremely attractive. They want to do treatment, finish treatment and get on with you know their life. Get back to their pickle ball schedule, or whatever it is they're doing. And you know, the work, though required for venetoclax and obinutuzumab is harder. So it's several, it's 8 weeks of coming one to 2 days a week to get it started, and then it really gets easier. So I also have some people, you know, some that work full time, and they're like, Oh, I'm, heck no, it's not good for me as a person. It's much more straightforward, it's easier to do and just prefer the continuous daily treatment that's just easy, take a pill and move on.

So I think the patient preferences there matter more. Patients do think about the cost of their therapy too--these drugs are extremely expensive, and would not be affordable for people without health insurance and even with health insurance, with a good prescription drug benefit, these drugs can be unaffordable. The Medicare part D donut hole can make it unaffordable for folks. So there are assistance programs to help with patient cost, sharing but having that discussion matters, too. Some people very much worry about the ongoing cost of a continuous therapy vs okay, I'll figure it out, for, like, you know, a year, which might actually span to insurance year. So that's 2 donut holes to go through, you know, to do like the ven-obin, and then that will be done. So like those things matter and it can be very individual, specific for what are like the primary concerns for the patients who are gonna go through the treatment. So it's not a pathway so much as like definitely do this treatment. If you know, whatever it's more like a consider an order like the disease biology, patient comorbidities. And then, you know, consider patient preferences, and usually by the time you get there it's clear which of these choices might be best. And then I always work in considering our investigational or clinical trial options at the same time. Some of those have nice benefits, including like, you know, combination drugs for people with higher risk disease that might have a benefit. Some of them have drug provided, which is a benefit to patients who are worried about drug costs for their prescriptions. And some people, actually a lot of people, just really like clinical trial participation. Because they know if they have to experience treatment, they wanna make sure that they're also benefiting other people with their condition by allowing their treatment experience to be captured. So I think that's important, too, to make sure that to discuss the risks and benefits of clinical trial participation at the same time. It's a little trickier for people that have had treatments before, and I think in those cases one of the main things is to look at what treatment they had before and how it ended. So people that took venetoclax for a fixed duration and stopped it because they finished the treatment and they were on remission could take another venetoclax-based therapy. We have people who have gotten BTK inhibitor-venetoclax combination on study with actually obinutuzumab. It was a venetoclax-obinutuzumab study. If they need treatment again, they can probably be retreated with any of those drugs. But if people have taken a drug until their CLL is resistant, then that is kind of a different category of options. So it does become a little more complex.

What has surprised you about your research with BTK inhibitors?

Dr Rogers: So I think there's like, really two things that I found really surprising. One thing that surprised me about my research with BTK inhibitors is that they're actually useful for treating more than just CLL. So we have shown that they actually can reduce the incidence of autoimmune cytopenias, which are ITP or autoimmune, hemolytic anemia. Those are autoimmune conditions where you make antibodies against either red blood cells or platelets, and that happens in between 5 and 25% of people living with CLL and can be a very important complication that in many cases is more difficult to treat than the actual blood cancer, than the actual CLL. So we actually did a retrospective cohort study describing a low incidence of this and it's been gratifying that a few others have done similar series, including a fairly large one from Europe, showing that this is in fact true, that the rates of these complicating autoimmune cytopenias are lower with BTK inhibitor therapy and this was mostly with ibrutinib, because that was around long enough to get this data, but that those are actually lower than with venetoclax. Doesn't mean venetoclax is bad in any way, it just means this is likely a secondary beneficial effect of these and we've actually all seen that they can actually help control some of these autoimmune cytopenias and our CLL patients that are experiencing them. So it's really neat to see that a drug that was, you know really developed in CLL to treat the cancer by blocking B cell receptor signaling through inhibiting BTK, which is in the B cell receptor signaling cascade, can actually affect these autoimmune cytopenias. So in autoimmune hematologic anemia and ITP, the antibodies made against blood cells aren't made by the CLL cells. They're made by healthy, become like bystander B cells and BTK is a non-mutant protein that's also found in healthy B cells. So it's probably an effect on B cell receptor signaling and nonmalignant or healthy B cells, or like normal B cells that result in this effect. So it's really cool to see that. It's cool to see the others have found that too and I think it's something really important to know about BTK inhibitors that I just, I don't know why I found that surprising, but I did. so that's a really interesting thing. I think the other thing that was surprising about BTK inhibitors is actually, that when people have developed resistance to them, like their CLL's become resistant to it. If you actually remove the BTK inhibitor, they can get like a disease flare or if people very early to treatment when they still have a lot of CLL on the body stop taking it. You can actually get lymph nodes coming back. So they kind of like block a homing signal of the CLL cells to the lymph nodes and tissues. So you get this like lymphocytosis, where all the cells go into the blood, but if you stop taking the drug within 24 hours, like they're lymphocytes, come down, lymph nodes, start coming back. So it's just super interesting to see the shift in the compartment that the CLL cells are in in a short period of time, based on whether or not they're actively having B cell receptor signaling blocked through BTK inhibition in the blood, and I don't know, I found that surprising, but it's kind of cool cause you can just see, like, visualize how this affects cell signaling and you look at some other targeted cancer treatments and like, yep, kills the cancer cells, or, if you stop it, you know they can proliferate again. But this really just has some interesting like effects on these cells that aren't dead, but as living cells that affect how they behave and I think that's really interesting and neat.

Where do you see yourself and your research in the future? What do you want the approach to CLL care to look like?

Dr Rogers: So one thing I really want for the approach to CLL care globally is a direction that the field has really been going in, and that is really focusing on making treatment not only more effective for patients, which is, of course, like extremely necessary, but making treatment kind of more tolerable for patients, too. So I think, as I was kinda saying when I was talking about like my clinical pathway. If you're thinking about treatment, you know, there's some realities of disease biology. But there's also personal considerations which matter a lot. And when you have more options, you can find one that not only fits someone's particular biology of CLL, but one that fits their lifestyle, and I spend a lot of time trying to convince people in clinic, you know, people on observation, people in treatment, you know that they're well, and they should continue living their life despite the fact that they're living with CLL and I'd like to see this kind of research continue where people are saying, Okay, can we give less of these drugs? Can we make a drug that has less side effects for our patients? You know, if we do a combination, can we make it shorter, You know, can we get a BTK inhibitor that doesn't have the same cardiac effects. Can we, and some studies actually with patient reported outcomes, looking at various aspects of what patients are reporting during treatment and I think that it's just really exciting to see that this is becoming, and you know, and it always has been on a physician level, an important aspect of the field. But now we've gotten so good at treating CLL that some of these things can also take a bigger role as how safe is this for people? You know, that you don't have to compromise treatment outcome when you make something safer. You know, it's not like, you know, back in the area of chemotherapy, where it's like, okay, we can make it safer by reducing the dose, and you might not get the same treatment outcome. I think with these targeted agents that's not really the case. So I like the way that it's really, therapy is not only more effective, but also more tolerable for patients and better to take. And so, you know I've done some research on combinations to help with residual resistance disease for people taking BTK inhibitors that have allowed some patients to just continue therapy for a time that might not have otherwise. So I hope that we keep moving in this direction. For our patients living with this condition. So I know a lot of patients want to be cured, and I would like to say we could do that too. But if we can't, I would like to make this as minimally impactful in people's lives as I can. 

Was there anything else you would like to expand on?

Dr Rogers: Yeah, I think there's two things that are really important in CLL medicine today. One is just with a variety of options, we really have to continue to encourage people to participate in clinical trials and offer really high quality clinical trials like we've been doing, because, this is really one, how we are able to deliver tomorrow's treatment today to our patients, and also how we learn as a field what's most important to go after next, or how to improve treatment when we're approaching just kind of one developing clinical pathways, but also for an individual. You know, how can we make treatment more effective? So I think, continuing to advance research and that way is extremely important and also, I think people sometimes forget that CLL is actually the most prevalent adult leukemia in the Western world. Because some things like acute leukemias are, you know, are more medically serious with people. More side effects, need more treatment up front. But CLL affects a lot of people, and as people are living longer than ever with it, the prevalence will only increase. So I think we really need to continue to pay attention to this as a really important problem for our patients and also for our society and health care system.