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Current CLL Treatment Options & How to Choose the Right One

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Published on December 4, 2020

How to Choose the Right Chronic Lymphocytic Leukemia Treatment for Your Needs

What treatment options are currently available for chronic lymphocytic leukemia (CLL)? How does chemoimmunotherapy work? What are the differences between monoclonal antibody therapies and targeted therapies? And when you finally have a grasp on all of the options for treatment, how do you determine the treatment path that is best for your needs? 

With so many new CLL treatments becoming available, navigating your treatment journey can be an overwhelming task. In this Ask the Expert segment, Patient Power co-founder and patient advocate Esther Schorr is joined by CLL physician Dr. Nicole Lamanna, MD, Hematologist at Columbia University Herbert Irving Comprehensive Cancer Center to discuss everything you need to know about CLL treatment and finding the one that is best for you. 

This program is sponsored by AbbVie, Inc. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

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Transcript | Current CLL Treatment Options & How to Choose the Right One

Esther Schorr: So, can you please give a quick overview of the difference between treatments? Maybe just a quick overview of the differences between those and where sort of the state of the art in making that decision is for somebody.

What CLL Treatment Options Are Available? How Do They Differ From Each Other?

Dr. Lamanna: Traditional chemoimmunotherapy like fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan) is a cocktail. So, it's three drugs that are given together. And traditionally given once a month approximately, so think of it that way. And it's a finite period of treatment, so it's usually six months or six cycles of treatment. These drugs are all given intravenously, so they're not pills.

But they work on the disease very quickly. And so, because of that, because some of these drugs like fludarabine and cyclophosphamide are a little bit non-specific, they do hit some of your good cells too. And so, folks can see this drastic decline in their good counts as well. And that's I think one of the issues of why it's given over six treatments and there are four weeks in between because your good counts can hit, your bone marrow can take a hit and the good counts decline before your bone marrow recovers again. And sometimes people need support. They might need a shot to help boost their neutrophils or some of the folks may or may not need a transfusion if their hemoglobin were to get too low if they need a boost. And the goal is to eradicate those CLL cells and then your good cells start coming in in the bone marrow.

And so, it's technically a little bit more of what we call an intense program. And so, because of that, the doctor and the team have to watch you a little bit more closely because of that, because it is a little more intense and it's a little bit more suppressive to your immune system as well as your blood counts as well. And so there might be more that needs to be given or things that need to be taken into consideration.

Traditionally, we usually think of folks who are receiving this type of program to be younger and fitter, that they can withstand a little bit more jarring and some of the side effects that come with this treatment. This was generally considered for younger, fitter folks under 70 typically. Although you could be a good 70-year-old who absolutely can do this. So that was one caveat to that treatment. In addition, now that we've learned more about the biology of this treatment, FCR was a gold standard because it worked very well, there were very good responses, but these were all the treatments we sort of... We had several treatments that were intravenous at that time because we didn't have all these new treatments.

As we learn more about the biology, we now actually think about chemoimmunotherapy more for also folks not only who are young and fit but also their prognostic markers. If you are more favorable, we have some very good long-term data for folks who receive FCR, for example, that program, that many of them did well. In other words, some of them are still in remission, 15 years out.

And so is it that this particular treatment also worked well for more favorable folks with CLL and perhaps are some of those individuals who, dare I use the word cured. But maybe, are those folks individuals who do very well because their treatment was very effective because they have the favorable disease? So that's where we still actually talk about if we're going to really partition out patients who might be a real benefit for that treatment option. We're talking about younger, fitter, more favorable characteristics and so that's an option for them.

What Are Monoclonal Antibody Therapies?

When we move to other therapies like monoclonal antibody therapies, there are three that are currently FDA approved. So, rituximab is probably our oldest and gold standard and we have ofatumumab (Arzerra) and obinutuzumab (Gazyva). And these are all intravenous monoclonal antibodies, so they target one of the proteins on your CLL cells called CD20. And so, this is an intravenous treatment as well. Often times, we combine it with other treatments, so as in FCR, rituximab is combined with fludarabine and cyclophosphamide. Obinutuzumab can be combined with some of the oral agents. It can be combined with venetoclax (Venclexta), it can be combined with the BTK inhibitors, acalabrutinib (Calquence), or ibrutinib (Imbruvica), it can be combined with chlorambucil (Leukeran).

So, there's a good percent of patients where their first infusion can get an infusion reaction. We try to get the folks through that and then it goes pretty smoothly. And it also works on autoimmune issues. So, the monoclonal antibodies are very good at autoimmune issues with CLL. So autoimmune blood issues or sometimes even skin or other issues that work very well. So, whether or not somebody gets these drugs in combination with an oral agent or more traditional, intravenous chemotherapy is often how it's most often used. Sometimes it will get used as a single agent for their CLL, but the response durations tend to be a little shorter if you're just doing by itself. Often times, as I've said, it's really combined with another agent where there's a bit of a better bang for the buck. So that's where you'll see the monoclonal antibodies come into play.

What Are Targeted Therapies, and Which Ones Are Currently Available?

And then, of course, targeted therapies like the BTK inhibitors of which there are two that are FDA approved. There are ibrutinib and acalabrutinib and then you have zanubrutinib (Brukinsa) which is approved for mantle cell and is in clinical trials for CLL. And then you have venetoclax, which is a Bcl-2 inhibitor. And then you have PI3 kinase inhibitors, we didn't even talk about those, we have idelalisib (Zydelig) and duvelisib (Copiktra), I know there's a lot.

These are all pills. Essentially, they are used differently, a little differently because they're supposed to target some of the different proteins that have to deal with how your B-cells live and die along the cell receptor pathway or in the case of venetoclax, sort of how your cells live or die. How to put breaks on the death of these cells. And so, these are all oral agents. Now traditionally, so ibrutinib was the first to market of the BTK inhibitors and so this was built as a chronic daily oral therapy that one can take indefinitely as long as somebody was tolerating it well and the disease wasn't progressing.

Venetoclax is used a little differently, it's often combined with one of those monoclonal antibody treatments that I just talked about either rituximab or obinutuzumab. But it's given in a shorter duration than the BTK inhibitors traditionally. And some of that data came from some early studies in CLL showing that in patients with previous treated with CLL, that when we started looking at venetoclax and rituximab that patients would get very deep responses in the bone marrow quicker than what we would normally see with the BTK inhibitor.

And because of that, we looked at stopping the venetoclax that have a specified time point. But remember they were also getting in combination with the monoclonal antibody, so with an intravenous drug. So, you get two drugs but it was at a specified time point because many folks their bone marrow would actually, the bone marrow, the CLL cells would be gone from the bone marrow, which is not traditionally what we would see with the BTK inhibitor given by itself. That took a lot more time to clean the bone marrow out. And so, patients would continue the BTKs chronically.

So, there are a few different ways that you can use the oral therapies, some are chronic indefinite therapy, others are maybe a shorter term therapy but with an intravenous component to it. And so that's how they're viewed.

How Do You Choose a Treatment? When Does Treatment Start and Stop?

Esther Schorr: You just gave in five minutes; the library of the incredible number of choices there now are for treating CLL. Again, it's almost an individualized treatment plans. So, given that, with some of these treatments, there was early indication or some studies that said, you might be able to take one of these drugs for a certain amount of time and then stop. Just stop the treatment and wait. Has this thought changed? The ones that you were supposed to take forever, is there now an indication you can stop it and take it again when you relapse?

Dr. Lamanna: This is a really good question and probably what most patients are trying to figure out is, how do you choose one treatment for another, right? Well, that's where your doctor is supposed to come in. Your specialist is supposed to help you, and I'll tell you why. Because it is complicated. All these new novel oral agents are very effective at treating the disease and many of them a lot less side effects than the more traditional chemoimmunotherapy. So then how do we pick? What do we do? Right? We look at your disease profile, so that's all those fancy markers. We're going to talk about that. And then also you yourself.

So, what are your other medical problems that might interfere with or contribute to increased side effects with some of these drugs. Because all these drugs have some side effects. Between traditional chemoimmunotherapy to novel agents, nothing's a free lunch, let's be honest. All of them have some potential for some side effects.

Active observation is very important. Don't undermine it because as we improve therapies and improve what we're doing, the ones who are on active observation are getting to watch what's going on and sitting back and watching as the field is evolving. And what we might be doing today is maybe very what we might not be doing a few years from now. So active observation is very important.

There are certain profiles from the disease perspective. So, we're always looking at what we think is best for the disease first and then we're always looking at the person, too. So, a patient who might have a 17p or p53 deletion, these traditionally have more… Their time to their first treatment as sooner their prognosis is generally considered to be poor. For sure we're going to want a novel agent for these individuals over let's say, chemoimmunotherapy with FCR.

So, there are certain disease types, where we'll be like, "You guys really should be getting a novel agent." That's one. And then we're looking at what patients also want and what their medical problems are. So, if somebody has very poor kidneys, we might say, we're going to veer away from a drug like venetoclax that can cause tumor lysis and kidney issues and we need to monitor your kidneys much more closely. If you have lots of cardiac issues, and may be on blood thinners, we might say, we might avoid BTKs and think of venetoclax.

So, it doesn't mean you can't get... so I'm going to stress that caveat that it doesn't mean I've never treated a person with this problem on this drug, that's not true. But in general, you have options now and so we want to consider your medical problems along with your disease profile that might steer the doctor to recommend certain treatments.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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