Dr. Mazyar Shadman

When it comes to treating patients with chronic lymphocytic leukemia (CLL), oncologists have a number of treatment options to create a plan that limits the time on any given therapy and reduces the toxicities a patient might face. But for high-risk patients, more work must be done to create effective treatment strategies, according to Dr. Mazyar Shadman of the Seattle Cancer Care Alliance.

, Shadman explained how his approach to treating CLL is more strategic than simply relying on one standard of therapy. “If I only have one tool to treat the disease, I will play with that tool in many different ways. But if I have access to four different tools, then I will give up tool (number) one if I don't feel it's working,” said Shadman.

The way I look at CLL, these days, is we either have what I call standard-risk CLL - these are patients who don't have high-risk features - and then we have high-risk CLL. And those are patients who either have a high-risk molecular marker or they may not have that marker, but their disease progressed on some of our good drugs. So that would be a high-risk disease, right? So, if you have somebody whose disease came back after one or two lines of the best treatment, that's a difficulty.

So, for standard-risk CLL, we're focusing on making treatment time-limited and less toxic. I kind of mentioned this earlier. For high-risk, there's much more to do and we still need treatment strategies that are more effective. As I mentioned earlier, one of the things that we have been doing here and in some (other) major centers really, (is that we) have a program that doesn't focus on a treatment modality but focuses on a strategy. So, if I only have one tool to treat the disease, I will play with that tool in many different ways. But if I have access to four different tools, then I will give up tool (number) one if I don't feel it's working.

I guess my point is, as a center that has access to novel agents, chemotherapy, rarely, but you know, everybody has it - cellular therapy, it could be bispecific therapy, is more important. And if you're very active with CAR T-cell therapy, and that, if needed for selected patients, allogeneic stem cell transplant, I think that it's very critical to know how to sequence these treatments. What is the right time to jump from one treatment to the other.

And again, I repeat, this is not for everybody. The majority of patients these days are fortunate, and they fit in the standard category. And we just have work to do there, but a different type of work. But for high-risk patients, I think it's very important to have a strategy and not just go on treatment and say ‘Oh, it's working. I'm going to forget about CLL until I need to.’ — 

Sometimes the time to move on to another treatment is when you're responding to treatment and everything is fine. So that's why kind of having a plan for your disease and having a more general big picture vision is very important. And that's my main advice for patients with high-risk disease.

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“If I only have one tool to treat the disease, I will play with that tool in many different ways. But if I have access to four different tools, then I will give up tool (number) one if I don't feel it's working,” explained Dr. Mazyar Shadman of the Seattle Cancer Care Alliance, about his approach to treating high-risk chronic lymphocytic leukemia in an interview with CURE®.
 

The Importance of More Thoughtful Treatment Strategies in High-Risk CLL

, Dr. Mazyar Shadman of the Seattle Cancer Care Alliance walked through the three types of treatment modalities being examined in chronic lymphocytic leukemia (CLL) right now: combination therapies that offer the best choice in the first line setting, targeted therapies or immunotherapy approaches that offer a wider range of options, and finally, safer drugs that offer less side effects or toxicities than other treatments.

“There’s a lot of work to do in CLL. We have been very fortunate to be able to provide a lot of options to our patients, but we shouldn't forget that there's a long way to go,” said Shadman.

The goal is to come up with a time-limited treatment that's not chemotherapy, so you can give a non-chemotherapy treatment to patients and then stop and then have a remission for years, and hopefully cure the patient. That's the goal for first line. What are we doing to achieve that? There are a number of clinical trials that are combining all these novel agents together, so combination studies, whether it could be ibrutinib in combination with venetoclax and obinutuzimab. It could be ibrutinib and venetoclax.

Studies have looked at acalabrutinib and venetoclax. And so, in principle, we are trying to use our best drugs up front, going for the disease as strong as we can, with a goal of getting rid of every cell of cancer in the body and then stopping, and then cure the patient or giving them years of remission. So, a lot of the studies that are happening right now are using combination therapies. That's the forefront and probably the biggest thing.

The second category of studies that are happening in the CLL world are to find even better drugs. We have great drugs, but there are still patients whose disease may become refractory or they can relapse after being treated with this great drug. So, there are a couple of new categories that are being tested as a new CLL drug. That could be immunotherapy-based therapies or novel drugs, those are in development. We have a next generation BTK inhibitor category and those are the drugs that inhibit the BTK enzyme but with a different mechanism so you can potentially use them in patients who didn't respond to ibrutinib or acalabrutinib or drugs like that. That category is growing now, and we have studies that are looking at those drugs. We have new targets, I mean, I don't want to name all the drugs, and then bispecific antibodies, which is a form of immunotherapy, and then more, of course, CAR T-cell therapy. So these are just more effective treatments, and this is our second category.

The third category would be drugs that are just safer. They are maybe not better than the current drugs, but this is fewer side effects or with a better toxicity profile. And there's a long list of drugs that are in that category.

So, in general, combination therapies. Number two would be better targeted therapies or immunotherapy approaches, and number three would be safer drugs.

There’s a lot of work to do in CLL. We have been very fortunate to be able to provide a lot of options to our patients, but we shouldn't forget that there's a long way to go. These drugs come with side effects, and they are not 100% effective, so, we need to work on both the efficacy and safety of these products. A lot of these treatments are still given forever, so you have to work on that. And we want to make sure that our patients are both disease-free, but not on a medication. So clinical trials are critical.

And I think CLL, or in general in oncology, the patient will benefit from, if not being followed by, at least being in close contact with a person or with a center that's focused on their disease, so they know what's happening in the field and whether they're missing trials or new trials that are going on, and (who) they can ask about their options.

“There’s a lot of work to do in CLL,” said Dr. Mazyar Shadman about the treatments currently being investigated in CLL. “We have been very fortunate to be able to provide a lot of options to our patients, but we shouldn't forget that there's a long way to go.”
 

Expert Breaks Down the Three Treatment Modalities Currently Being Investigated in CLL

Patients with chronic lymphocytic leukemia must remain observant and report any side effects, especially if they are serious, to ensure that they get the most out of their upfront treatment, according to Dr. Mazyar Shadman.

®, Shadman, of Seattle Cancer Care Alliance and Fred Hutchinson Cancer Center, discussed ways that patients can play a role in ensuring that they are able to reap the benefits of treatment.

First of all, they need to be well educated about the potential side effects of this treatment. So, some side effects are more serious. And they need to know that if that happens, they need to call the physician or the team as soon as possible. For example, if you're on a Bruton tyrosine kinase inhibitor, and you know (there’s) bleeding, you need to notify your physician. So, just be aware of side effects and know that some of them are more urgent and others are not, but make sure you are in communication with your team.

These days, we have a lot of options we can (use), using BTK inhibitors as an example, we have now next generation BTK inhibitors that are basically better tolerated so we can always switch treatment to one of the novel ones or maybe even change the class to a completely different type of therapy.

Number one would be knowing the side effects. Number two (is) just knowing what to expect, again, a lot of times, it's not uncommon for patients who; we do get a lot of the second opinions and consults. And they just didn't know that this treatment, for example, is not supposed to be stopped. They're like, ‘Oh, I'm taking a nap for a year.’ So, give a realistic expectation to the patient on what to expect from a drug like ibrutinib or acalabrutinib … or duvelisib if you're in the relapsed setting. Also, with venetoclax, just give the realistic expectation (that) yes, we do give the treatment for one year, but I can't promise that at the end of one year, if I stop, you'll be in remission for years, right? It depends on how good (you respond) to the treatment. So, number two would be giving realistic expectations (and) number three … goes back to this principle of a doctor-patient relationship and we have to come up with a plan that both are comfortable with. Some patients just feel safer to be watched a little bit more closely and some don't.

In an interview with CURE®, Dr. Mazyar Shadman discussed ways that patients with chronic lymphocytic leukemia can play a role in ensuring that they are able to reap the benefits of treatment.
 

Expert Advises Patients with CLL on Three Things They Should Be Aware of To Maximize the Benefit of Upfront Treatment

A common mistake that tends to occur when patients are treated for chronic lymphocytic leukemia is the notion that only a patient’s cells are being treated, according to Dr. Mazyar Shadman.

®, Shadman, of Seattle Cancer Care Alliance and Fred Hutchinson Cancer Center, discussed the enormous variety in treatment preference among patients with CLL and said that emphasis should be placed on treating each person according to their wishes.

The main bulk of my discussion is really what they want. You will be surprised at how different patients are in terms of what's important for them. One side of the spectrum, I have patients who really don't want a treatment that's forever, and that makes sense, right? No matter how safe the drug is, no matter how disease-free you are, just for some patients, just the thought of being on medication forever that's for cancer is important. And they just don't want it; they want to be disease-free, but also treatment-free as long as possible. And so that's important for some patients, and in the appropriate setting, if I feel that, yes, you know, we can go with either chemotherapy-based therapy in this patient or now venetoclax-based therapy (which) is a non-chemotherapy and a time-limited option potentially. For those patients based on that decision, of course, that's what I will provide to them.

I also have patients who really don't (care, and will say) “I'm taking four medications for years, four different products, and (if) you give me something, I don't want to deal with the whole rampup and checking MRD, (but) as long as I'm fine,, I'll take it,” so that you see both sides, and you do see patients who still come for chemotherapy. So, yes, patient preference is important. Patients need to understand and need to be educated on what to expect. It's always easy to start treatment. We get patients who come back six months, seven months later, and (say) “You know what, I'm taking this for seven months it works, but can I stop? I mean, what do you mean (this) is going to go forever? The doctor who started didn't talk to me about (that).”

So, I think those conversations are actually very important. And I add one more thing, they're important because we don't have a head-to-head trial that tells me that acalabrutinib or venetoclax — which one is better. If I have that, then I probably won't give that option, or if I do, I make sure they understand that they're going for a treatment that's not superior, but we don't have that. So really, you have to sit and present both treatments and pros and cons and have them decide based on what's the best fit for them. And that's why it's important to have really a comprehensive approach to the patient … I mean, it's really treating a patient, not the molecular kind of finding in the CLL cell, and that's a common mistake: “Oh, I have somebody with a mutated (gene, and) that (means) I give chemo.” No: You have a patient who has CLL whose CLL has this (mutation). So, then you kind of look at the patient and not the other factors.

Articles

In an interview with CURE®, Dr. Mazyar Shadman discussed the enormous variety of treatment preferences among patients with CLL and said that emphasis should be placed on treating each person according to their wishes.
 

Dr. Mazyar Shadman

The Importance of More Thoughtful Treatment Strategies in High-Risk CLL

Expert Breaks Down the Three Treatment Modalities Currently Being Investigated in CLL

Expert Advises Patients with CLL on Three Things They Should Be Aware of To Maximize the Benefit of Upfront Treatment

Conversations Between Patient and Oncologist Are Important in Avoiding 'Common Mistake' When Treating CLL

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